register interest

Professor Sarah L Rowland-Jones

Research Area: Immunology
Technology Exchange: Cell sorting, Cellular immunology, Flow cytometry, SNP typing and Transcript profiling
Scientific Themes: Immunology & Infectious Disease and Tropical Medicine & Global Health
Keywords: HIV-1/HIV-2, T-cell, immunity, infant immunology, Africa and China
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The main interest of our group is in understanding immunity to virus infection, with a particular focus on how immune responses modify the outcome of HIV and other viral infections. The main aim is to define correlates of protective immunity against HIV infection that would help in the design of vaccines to prevent infection. An effective HIV vaccine is desperately needed, particularly in the developing world where the greatest burden of HIV disease occurs.

We work closely with clinicians and epidemiologists to study immune responses in clinical cohorts in Kenya, West Africa, Zimbabwe and China, as well as in the UK. In Kenya we focus on infants born to infected mothers, both infected and uninfected, to try and understand why the clinical outcome in HIV-infected children is so much worse than in adults, particularly in sub-Saharan Africa (before the widespread use of early anti-retroviral therapy). In Zimbabwe we are studying a recently-identified group of older children and adolescents with long-term HIV-1 infection who were not diagnosed in early life, partly to understand the mechanisms underlying long-term survival following vertical infection but also to understand the basis of the clinical complications reported in a high proportion of these HIV-infected adolescents. In China we study a village cohort of former plasma donors who became infected with what appear to be very closely related HIV strains whilst taking part in an illegal plasma donation scheme in the mid-1990s: the similar infecting viruses in this cohort magnifies the impact of host genetic and immune factors on viral evolution and clinical outcome.

 Our group has a long-standing interest in the second strain of HIV, HIV-2, which is found predominantly in W. Africa and leads to a high proportion of long-term non-progressors (LTNPs), even though progressors with HIV-2 infection are clinically indistinguishable from people with progressive HIV-1 infection. Our data suggest that the most important differences between progressors and non-progressors with HIV-2 infection lie in their immune response to the virus, with LTNPs having much stronger and more potent T-cell responses that are associated with viral control. We are currently investigating how these protective responses are generated in some people but not in others, as well as looking at the role of host restriction factors from the TRIM family of proteins, TRIM5 alpha and TRIM22, in mediating viral control in HIV-2 infection.

Name Department Institution Country
Prof Tao Dong (RDM) Investigative Medicine Division Oxford University, Weatherall Institute of Molecular Medicine United Kingdom
Professor Mary Carrington National Cancer Institute United States
Dr Rashida Ferrand MRCP London School of Hygiene and Tropical medicine Zimbabwe
Professor Grace John-Stewart University of Washington United States
Professor Eduard Sanders Tropical Medicine Oxford University, Kilifi Kenya
Professor Masafumi Takiguchi Kumamoto University Japan
Professor Katsumi Maenaka U. Hokkaido Japan
Dr Victor Appay Immunity and Infectious Diseases Research Center Pierre et Marie Curie University France
Professor Rob Heyderman FRCP Malawi-Liverpool-Wellcome Trust Clinical Research Programme Malawi
Dr Britta Urban Liverpool School of Tropical Medicine United Kingdom
Dr Assan Jaye MRC Laboratories Gambia
Professor Greg Towers University College London United Kingdom
Keyi Xu Capital Medical University Beijing Di'tan hospital China
Professor Robin Shattock Imperial College, University of London United Kingdom
Dr Tariro Makadzange Department of Medicine University of Zimbabwe, College of Health Sciences Zimbabwe
Rylance J, Mchugh G, Metcalfe J, Mujuru H, Nathoo K, Wilmore S, Rowland-Jones S, Majonga E, Kranzer K, Ferrand RA. 2016. Chronic lung disease in HIV-infected children established on antiretroviral therapy. AIDS, 30 (18), pp. 2795-2803. | Show Abstract | Read more

OBJECTIVE: Respiratory disease is a major cause of morbidity and mortality in HIV-infected children. Despite antiretroviral therapy (ART), children suffer chronic symptoms. We investigated symptom prevalence, lung function and exercise capacity among older children established on ART and an age-matched HIV-uninfected group. DESIGN: A cross-sectional study in Zimbabwe of HIV-infected children aged 6-16 years receiving ART for over 6 months and HIV-uninfected children attending primary health clinics from the same area. METHODS: Standardized questionnaire, spirometry, incremental shuttle walk testing, CD4 cell count, HIV viral load and sputum culture for tuberculosis were performed. RESULTS: A total of 202 HIV-infected and 150 uninfected participants (median age 11.1 years in each group) were recruited. Median age at HIV diagnosis and ART initiation was 5.5 (interquartile range 2.8-7.5) and 6.1 (interquartile range 3.6-8.4) years, respectively. Median CD4 cell count was 726 cells/μl, and 79% had HIV viral load less than 400 copies/ml. Chronic respiratory symptoms were rare in HIV-uninfected children [n = 1 (0.7%)], but common in HIV-infected participants [51 (25%)], especially cough [30 (15%)] and dyspnoea [30 (15%)]. HIV-infected participants were more commonly previously treated for tuberculosis [76 (38%) vs 1 (0.7%), P < 0.001], had lower exercise capacity (mean incremental shuttle walk testing distance 771 vs 889 m, respectively, P < 0.001) and more frequently abnormal spirometry [43 (24.3%) vs 15 (11.5%), P = 0.003] compared with HIV-uninfected participants. HIV diagnosis at an older age was associated with lung function abnormality (P = 0.025). No participant tested positive for Mycobacterium tuberculosis. CONCLUSION: In children, despite ART, HIV is associated with significant respiratory symptoms and functional impairment. Understanding pathogenesis is key, as new treatment strategies are urgently required.

Angin M, Wong G, Papagno L, Versmisse P, David A, Bayard C, Charmeteau-De Muylder B, Besseghir A, Thiébaut R, Boufassa F et al. 2016. Preservation of Lymphopoietic Potential and Virus Suppressive Capacity by CD8+ T Cells in HIV-2-Infected Controllers. J Immunol, 197 (7), pp. 2787-2795. | Show Abstract | Read more

Compared with HIV-1, HIV-2 infection is characterized by a larger proportion of slow or nonprogressors. A better understanding of HIV-2 pathogenesis should open new therapeutic avenues to establish control of HIV-1 replication in infected patients. In this study, we studied the production of CD8(+) T cells and their capacity for viral control in HIV-2 controllers from the French ANRS CO5 HIV-2 cohort. HIV-2 controllers display a robust capacity to support long-term renewal of the CD8(+) T cell compartment by preserving immune resources, including hematopoietic progenitors and thymic activity, which could contribute to the long-term maintenance of the CD8(+) T cell response and the avoidance of premature immune aging. Our data support the presence of HIV-2 Gag-specific CD8(+) T cells that display an early memory differentiation phenotype and robust effector potential in HIV-2 controllers. Accordingly, to our knowledge, we show for the first time that HIV-2 controllers possess CD8(+) T cells that show an unusually strong capacity to suppress HIV-2 infection in autologous CD4(+) T cells ex vivo, an ability that likely depends on the preservation of host immune resources. This effective and durable antiviral response probably participates in a virtuous circle, during which controlled viral replication permits the preservation of potent immune functions, thus preventing HIV-2 disease progression.

Noho-Konteh F, Adetifa JU, Cox M, Hossin S, Reynolds J, Le MT, Sanyang LC, Drammeh A, Plebanski M, Forster T et al. 2016. Sex-Differential Non-Vaccine-Specific Immunological Effects of Diphtheria-Tetanus-Pertussis and Measles Vaccination. Clin Infect Dis, 63 (9), pp. 1213-1226. | Show Abstract | Read more

Vaccines can have nontargeted heterologous effects that manifest as increased protection against nonvaccine infections, as described for measles vaccine (MV), or increased susceptibility to infections and death, as described following diphtheria-tetanus-whole cell pertussis (DTP) vaccination. The mechanisms are unknown, and high-quality immunological studies are lacking. This study was designed to investigate the heterologous effects of MV and DTP in 302 Gambian infants. The results support a sex-differential immunosuppressive effect of DTP on innate proinflammatory responses and T-cell immunity. Males but not females receiving MV had enhanced proinflammatory innate responses. The results point to modified signaling via Toll-like receptor 4 (TLR4) as a possible mechanism for the effects on innate immunity. When both vaccines were administered together, purified protein derivative responses were enhanced in females but downregulated in males. Collectively, these data indicate immunological effects that could account for heterologous effects of MV and DTP, to take forward into prospective trials.

Filteau S, Rowland-Jones S. 2016. Cytomegalovirus Infection May Contribute to the Reduced Immune Function, Growth, Development, and Health of HIV-Exposed, Uninfected African Children. Front Immunol, 7 (JUN), pp. 257. | Show Abstract | Read more

With increasing access to antiretroviral therapy (ART) in Africa, most children born to HIV-infected mothers are not themselves HIV-infected. These HIV-exposed, uninfected (HEU) children are at increased risk of mortality and have immune, growth, development, and health deficits compared to HIV-unexposed children. HEU children are known to be at higher risk than HIV-unexposed children of acquiring cytomegalovirus (CMV) infection in early life. This risk is largely unaffected by ART and is increased by breastfeeding, which itself is critically important for child health and survival. Early CMV infection, namely in utero or during early infancy, may contribute to reduced growth, altered or impaired immune functions, and sensory and cognitive deficits. We review the evidence that CMV may be responsible for the health impairments of HEU children. There are currently no ideal safe and effective interventions to reduce postnatal CMV infection. If a clinical trial showed proof of the principle that decreasing early CMV infection improved health and development of HEU children, this could provide the impetus needed for the development of better interventions to improve the health of this vulnerable population.

Shepherd BL, Bandason T, Ferrand R, Rowland-Jones S, Yindom LM. 2016. HLA-C*16:01:01:02, a recently isolated HLA class I allele from Southern Africa. HLA, 87 (6), pp. 470-471. | Show Abstract | Read more

The full-length nucleotide sequence of HLA-C*16:01:01:02 differs from that of HLA-C*16:01:01:01 with a SNP at 2996C>T.

Shepherd BL, Dauya E, Ferrand R, Rowland-Jones S, Yindom LM. 2016. Isolation of full-length HLA-C*18:02 allele in an individual from Sub-Saharan Africa. HLA, 87 (6), pp. 471-472. | Show Abstract | Read more

The full-length sequence of HLA-C*18:02 differs from that of HLA-C*18:01 by a single nucleotide polymorphism.

Shepherd BL, Ferrand R, Rowland-Jones S, Yindom LM. 2016. HLA-C*06:04:02 a novel HLA-C allele isolated from donors of Southern African descent. HLA, 87 (5), pp. 402-403. | Show Abstract | Read more

HLA-C*06:04:02 allele differs from HLA-C*06:02:01:01 with two nucleotide substitutions in exon 3 and 3' untranslated region (UTR_.

Fish EN, Flanagan KL, Furman D, Klein SL, Kollmann TR, Jeppesen DL, Levy O, Marchant A, Namachivayam S, Netea MG et al. 2016. Changing oral vaccine to inactivated polio vaccine might increase mortality. Lancet, 387 (10023), pp. 1054-1055. | Read more

Rowland-Jones SL. 2016. Chikungunya: out of the tropical forests and heading our way …. Trans R Soc Trop Med Hyg, 110 (2), pp. 85-86. | Read more

Zhang YH, Zhao Y, Rajapaksa US, Lawrence TM, Peng YC, Liu J, Xu K, Hu K, Qin L, Liu N et al. 2016. A Comprehensive Analysis of the Impact of HIV on HCV Immune Responses and Its Association with Liver Disease Progression in a Unique Plasma Donor Cohort. PLoS One, 11 (7), pp. e0158037. | Show Abstract | Read more

OBJECTIVE: Human Immunodeficiency Virus (HIV) and Hepatitis C virus (HCV) co-infection is recognized as a major cause of morbidity and mortality among HIV-1 infected patients. Our understanding of the impact of HIV infection on HCV specific immune responses and liver disease outcome is limited by the heterogeneous study populations with genetically diverse infecting viruses, varying duration of infection and anti-viral treatment. METHODS: Viral-specific immune responses in a cohort of 151 HCV mono- and HIV co-infected former plasma donors infected with a narrow source of virus were studied. HCV and HIV specific T cell responses were correlated with clinical data. RESULTS: HIV-1 accelerated liver disease progression and decreased HCV specific T cell immunity. The magnitude of HCV specific T cell responses inversely correlated with lower HCV RNA load and reduced liver injury as assessed by non-invasive markers of liver fibrosis. HIV co-infection reduced the frequency of HCV specific CD4+ T cells with no detectable effect on CD8+ T cells or neutralizing antibody levels. CONCLUSION: Our study highlights the impact of HIV co-infection on HCV specific CD4+ T cell responses in a unique cohort of patients for both HCV and HIV and suggests a crucial role for these cells in controlling chronic HCV replication and liver disease progression.

Garcia-Knight MA, Slyker J, Payne BL, Pond SL, de Silva TI, Chohan B, Khasimwa B, Mbori-Ngacha D, John-Stewart G, Rowland-Jones SL, Esbjörnsson J. 2016. Viral Evolution and Cytotoxic T Cell Restricted Selection in Acute Infant HIV-1 Infection. Sci Rep, 6 pp. 29536. | Show Abstract | Read more

Antiretroviral therapy-naive HIV-1 infected infants experience poor viral containment and rapid disease progression compared to adults. Viral factors (e.g. transmitted cytotoxic T- lymphocyte (CTL) escape mutations) or infant factors (e.g. reduced CTL functional capacity) may explain this observation. We assessed CTL functionality by analysing selection in CTL-targeted HIV-1 epitopes following perinatal infection. HIV-1 gag, pol and nef sequences were generated from a historical repository of longitudinal specimens from 19 vertically infected infants. Evolutionary rate and selection were estimated for each gene and in CTL-restricted and non-restricted epitopes. Evolutionary rate was higher in nef and gag vs. pol, and lower in infants with non-severe immunosuppression vs. severe immunosuppression across gag and nef. Selection pressure was stronger in infants with non-severe immunosuppression vs. severe immunosuppression across gag. The analysis also showed that infants with non-severe immunosuppression had stronger selection in CTL-restricted vs. non-restricted epitopes in gag and nef. Evidence of stronger CTL selection was absent in infants with severe immunosuppression. These data indicate that infant CTLs can exert selection pressure on gag and nef epitopes in early infection and that stronger selection across CTL epitopes is associated with favourable clinical outcomes. These results have implications for the development of paediatric HIV-1 vaccines.

Garcia-Knight MA, Nduati E, Hassan AS, Gambo F, Odera D, Etyang TJ, Hajj NJ, Berkley JA, Urban BC, Rowland-Jones SL. 2015. Altered Memory T-Cell Responses to Bacillus Calmette-Guerin and Tetanus Toxoid Vaccination and Altered Cytokine Responses to Polyclonal Stimulation in HIV-Exposed Uninfected Kenyan Infants. PLoS One, 10 (11), pp. e0143043. | Show Abstract | Read more

Implementation of successful prevention of mother-to-child transmission of HIV strategies has resulted in an increased population of HIV-exposed uninfected (HEU) infants. HEU infants have higher rates of morbidity and mortality than HIV-unexposed (HU) infants. Numerous factors may contribute to poor health in HEU infants including immunological alterations. The present study assessed T-cell phenotype and function in HEU infants with a focus on memory Th1 responses to vaccination. We compared cross-sectionally selected parameters at 3 and 12 months of age in HIV-exposed (n = 42) and HU (n = 28) Kenyan infants. We measured ex vivo activated and bulk memory CD4 and CD8 T-cells and regulatory T-cells by flow cytometry. In addition, we measured the magnitude, quality and memory phenotype of antigen-specific T-cell responses to Bacillus Calmette-Guerin and Tetanus Toxoid vaccine antigens, and the magnitude and quality of the T cell response following polyclonal stimulation with staphylococcal enterotoxin B. Finally, the influence of maternal disease markers on the immunological parameters measured was assessed in HEU infants. Few perturbations were detected in ex vivo T-cell subsets, though amongst HEU infants maternal HIV viral load positively correlated with CD8 T cell immune activation at 12 months. Conversely, we observed age-dependent differences in the magnitude and polyfunctionality of IL-2 and TNF-α responses to vaccine antigens particularly in Th1 cells. These changes mirrored those seen following polyclonal stimulation, where at 3 months, cytokine responses were higher in HEU infants compared to HU infants, and at 12 months, HEU infant cytokine responses were consistently lower than those seen in HU infants. Finally, reduced effector memory Th1 responses to vaccine antigens were observed in HEU infants at 3 and 12 months and higher central memory Th1 responses to M. tuberculosis antigens were observed at 3 months only. Long-term monitoring of vaccine efficacy and T-cell immunity in this vulnerable population is warranted.

Fryer HR, Van Tienen C, Van Der Loeff MS, Aaby P, Da Silva ZJ, Whittle H, Rowland-Jones SL, de Silva TI. 2015. Predicting the extinction of HIV-2 in rural Guinea-Bissau. AIDS, 29 (18), pp. 2479-2486. | Show Abstract | Read more

OBJECTIVE: This article predicts the future epidemiology of HIV-2 in Caió, a rural region of Guinea Bissau; and investigates whether HIV-2, which has halved in prevalence between 1990 and 2007 and is now almost absent in young adults in Caió, can persist as an infection of the elderly. DESIGN: A mathematical model of the spread of HIV-2 was tailored to the epidemic in Caió, a village in Guinea-Bissau. METHODS: An age-stratified difference equation model of HIV-2 transmission was fitted to age-stratified HIV-2 incidence and prevalence data from surveys conducted in Caió in 1990, 1997 and 2007. A stochastic version of the same model was used to make projections. RESULTS: HIV-2 infection is predicted to continue to rapidly decline in Caió such that new infections will cease and prevalence will reach low levels (e.g. below 0.1%) within a few decades. HIV-2 is not predicted to persist in the elderly. CONCLUSION: HIV-2 is predicted go extinct in Caió during the second half of this century.

Nduati EW, Hassan AS, Knight MG, Muema DM, Jahangir MN, Mwaringa SL, Etyang TJ, Rowland-Jones S, Urban BC, Berkley JA. 2015. Outcomes of prevention of mother to child transmission of the human immunodeficiency virus-1 in rural Kenya--a cohort study. BMC Public Health, 15 (1), pp. 1008. | Show Abstract | Read more

BACKGROUND: Success in prevention of mother-to-child transmission (PMTCT) raises the prospect of eliminating pediatric HIV infection. To achieve global elimination, however, strategies are needed to strengthen PMTCT interventions. This study aimed to determine PMTCT outcomes and identify challenges facing its successful implementation in a rural setting in Kenya. METHODS: A retrospective cohort design was used. Routine demographic and clinical data for infants and mothers enrolling for PMTCT care at a rural hospital in Kenya were analysed. Cox and logistic regression were used to determine factors associated with retention and vertical transmission respectively. RESULTS: Between 2006 and 2012, 1338 infants were enrolled and followed up for PMTCT care with earlier age of enrollment and improved retention observed over time. Mother to child transmission of HIV declined from 19.4 % in 2006 to 8.9 % in 2012 (non-parametric test for trend p = 0.024). From 2009 to 2012, enrolling for care after 6 months of age, adjusted Odds Ratio [aOR]: 23.3 [95 % confidence interval (CI): 8.3-65.4], presence of malnutrition ([aOR]: 2.3 [95 % CI: 1.1-5.2]) and lack of maternal use of highly active antiretroviral therapy (HAART) (aOR: 6.5 [95 % CI: 1.4-29.4]) was associated with increased risk of HIV infection. Infant's older age at enrollment, malnutrition and maternal HAART status, were also associated with drop out from care. Infants who were not actively followed up were more likely to drop out from care (adjusted Hazard Ratio: 6.6 [95 % CI: 2.9-14.6]). DISCUSSION: We report a temporal increase in the proportion of infants enrolling for PMTCT care before 3 months of age, improved retention in PMTCT and a significant reduction in the proportion of infants enrolled who became HIV-infected, emphasizing the benefits of PMTCT. CONCLUSION: A simple set of risk factors at enrollment can identify mother-infant pairs most at risk of infection or drop out for targeted intervention.

Jallow S, Leligdowicz A, Kramer HB, Onyango C, Cotten M, Wright C, Whittle HC, McMichael A, Dong T, Kessler BM, Rowland-Jones SL. 2015. Correction. The presence of prolines in the flanking region of an immunodominant HIV-2 gag epitope influences the quality and quantity of the epitope generated. Eur J Immunol, 45 (9), pp. 2701. | Read more

Yindom L-M, Wang L, Xu K, Dong T, Rowland-Jones SL. 2015. The identification of a killer cell immunoglobulin-like receptor 3DL1*0150209 in an Asian population using molecular techniques TISSUE ANTIGENS, 86 (2), pp. 152-153. | Read more

Yindom L-M, de Silva TI, Rowland-Jones SL. 2015. KIR3DL1*0250103: a novel three-domain KIR allele isolated inWest African samples TISSUE ANTIGENS, 86 (2), pp. 150-151. | Read more

Yindom LM, James K, de Silva TI, Rowland-Jones SL. 2015. KIR3DL1*0040102 – a novel three-domain KIR subtype isolated from donors of African descent. Tissue Antigens, 86 (3), pp. 220-221. | Show Abstract | Read more

KIR3DL1*0040102 allele differs from KIR3DL1*0040101 by a single-nucleotide change at position 12356 (intron 6).

Wang L, Zhang Y, Dong T, Rowland-Jones SL, Yindom LM. 2015. KIR3DS1*0130109: a novel activating three-domain KIR identified using sequence-based typing. Tissue Antigens, 86 (3), pp. 222-223. | Show Abstract | Read more

KIR3DS1*0130109 is similar to KIR3DS1*0130101 except for a A > G change in intron 4.

Wang L, Zhang Y, Dong T, Rowland-Jones SL, Yindom LM. 2015. Detection of a novel KIR3DL1*0150210 allele by sequencing. Tissue Antigens, 86 (4), pp. 311. | Show Abstract | Read more

KIR3DL1*0150210 has seven point mutations compared to the common Asian allele KIR3DL1*0150201.

Yindom LM, de Silva TI, Rowland-Jones SL. 2015. Full-length sequence of KIR3DL1*0310102 detected in DNA samples from West Africa. Tissue Antigens, 86 (4), pp. 312-313. | Show Abstract | Read more

KIR3DL1*0310102 differs from KIR3DL1*0150101 with 11 nucleotide substitutions.

Simpson S, deSilva T, Yindom L-M, Leligdowicz A, Vincent T, Rowland-Jones S. 2015. Polymorphisms in TRIM22 are associated with HIV-2 acquisition and disease progression JOURNAL OF THE INTERNATIONAL AIDS SOCIETY, 18 | Read more

Yindom LM, Wang L, Xu K, Dong T, Rowland-Jones SL. 2015. The identification of a killer cell immunoglobulin-like receptor 3DL1*0150209 in an Asian population using molecular techniques. Tissue Antigens, 86 (2), pp. 152-153. | Show Abstract | Read more

Full-length sequences of KIR3DL1*0150209 differ from those of KIR3DL1*0150201 with seven single-nucleotide polymorphisms.

Jallow S, Leligdowicz A, Kramer HB, Onyango C, Cotten M, Wright C, Whittle HC, McMichael A, Dong T, Kessler BM, Rowland-Jones SL. 2015. The presence of prolines in the flanking region of an immunodominant HIV-2 gag epitope influences the quality and quantity of the epitope generated. Eur J Immunol, 45 (8), pp. 2232-2242. | Show Abstract | Read more

Both the recognition of HIV-infected cells and the immunogenicity of candidate CTL vaccines depend on the presentation of a peptide epitope at the cell surface, which in turn depends on intracellular antigen processing. Differential antigen processing maybe responsible for the differences in both the quality and the quantity of epitopes produced, influencing the immunodominance hierarchy of viral epitopes. Previously, we showed that the magnitude of the HIV-2 gag-specific T-cell response is inversely correlated with plasma viral load, particularly when responses are directed against an epitope, 165 DRFYKSLRA173 , within the highly conserved Major Homology Region of gag-p26. We also showed that the presence of three proline residues, at positions 119, 159 and 178 of gag-p26, was significantly correlated with low viral load. Since this proline motif was also associated with stronger gag-specific CTL responses, we investigated the impact of these prolines on proteasomal processing of the protective 165 DRFYKSLRA173 epitope. Our data demonstrate that the 165 DRFYKSLRA173 epitope is most efficiently processed from precursors that contain two flanking proline residues, found naturally in low viral-load patients. Superior antigen processing and enhanced presentation may account for the link between infection with HIV-2 encoding the "PPP-gag" sequence and both strong gag-specific CTL responses as well as lower viral load.

Yindom LM, de Silva TI, Rowland-Jones SL. 2015. KIR3DL1*0250103: a novel three-domain KIR allele isolated in West African samples. Tissue Antigens, 86 (2), pp. 150-151. | Show Abstract | Read more

The full length sequence of KIR3DL1*0250103 differs from that of KIR3DL1*0150101 with nine single-nucleotide polymorphisms.

Jayasooriya S, de Silva TI, Njie-jobe J, Sanyang C, Leese AM, Bell AI, McAulay KA, Yanchun P, Long HM, Dong T et al. 2015. Early virological and immunological events in asymptomatic Epstein-Barr virus infection in African children. PLoS Pathog, 11 (3), pp. e1004746. | Show Abstract | Read more

Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated EBV-specific CD8+ T-cells. While the events of AIM have been intensely studied, little is known about how these relate to asymptomatic primary infection. Here Gambian children (14-18 months old, an age at which many acquire the virus) were followed for the ensuing six months, monitoring circulating EBV loads, antibody status against virus capsid antigen (VCA) and both total and virus-specific CD8+ T-cell numbers. Many children were IgG anti-VCA-positive and, though no longer IgM-positive, still retained high virus loads comparable to AIM patients and had detectable EBV-specific T-cells, some still expressing activation markers. Virus loads and the frequency/activation status of specific T-cells decreased over time, consistent with resolution of a relatively recent primary infection. Six children with similarly high EBV loads were IgM anti-VCA-positive, indicating very recent infection. In three of these donors with HLA types allowing MHC-tetramer analysis, highly activated EBV-specific T-cells were detectable in the blood with one individual epitope response reaching 15% of all CD8+ T-cells. That response was culled and the cells lost activation markers over time, just as seen in AIM. However, unlike AIM, these events occurred without marked expansion of total CD8+ numbers. Thus asymptomatic EBV infection in children elicits a virus-specific CD8+ T-cell response that can control the infection without over-expansion; conversely, in AIM it appears the CD8 over-expansion, rather than virus load per se, is the cause of disease symptoms.

Wang L, Xu K, Dong T, Rowland-Jones SL, Yindom LM. 2015. KIR3DS1*0130111: a novel KIR allele identified using molecular typing methods. Tissue Antigens, 85 (4), pp. 296-297. | Show Abstract | Read more

KIR3DS1*0130111 differs from KIR3DS1*0130101 with two previously undescribed single nucleotide polymorphisms.

Yindom LM, de Silva TI, Rowland-Jones SL. 2015. KIR3DL1*0250102: a novel three-domain KIR subtype identified in West Africa. Tissue Antigens, 85 (2), pp. 151-152. | Show Abstract | Read more

KIR3DL1*0250102 differs from the common West African KIR3DL1*0150101 by 11 single nucleotide polymorphisms (SNPs).

Yindom LM, de Silva TI, Rowland-Jones SL. 2015. Identification of a novel three-domain KIR allele: KIR3DL1*087 using high-resolution molecular techniques. Tissue Antigens, 85 (2), pp. 153-154. | Show Abstract | Read more

KIR3DL1*087 is significantly different from KIR3DL1*0010101 with multiple non-synonymous changes and insertion/deletion sites.

Shepherd BL, Ferrand R, Munyati S, Folkard S, Boyd K, Bandason T, Jallow S, Rowland-Jones SL, Yindom LM. 2015. HLA Correlates of Long-Term Survival in Vertically Infected HIV-1-Positive Adolescents in Harare, Zimbabwe. AIDS Res Hum Retroviruses, 31 (5), pp. 504-507. | Show Abstract | Read more

African infants with vertically acquired HIV infection progress rapidly, with only 50% surviving beyond 2 years in the absence of treatment. Despite this high initial mortality, recent reports describe a substantial burden of older children living with untreated vertically acquired HIV infection in Southern Africa. The immunological and genetic factors associated with long-term survival following vertical infection are poorly understood. We performed medium-to-high resolution HLA typing on DNA samples obtained from a cohort of presumed vertically HIV-1-infected children and age-matched uninfected controls in Harare, Zimbabwe. Overall, 93 HLA class I alleles were detected in the study population with a significant enrichment of HLA-C*08:02 and -C*08:04 in the HIV-1-infected long-term survivor group. Conversely, HLA-A*02:01, A*34:02, and -B*58:02 were overrepresented in the uninfected control group. Our data indicate that HLA alleles may have differential effects against HIV acquisition and disease progression in vertical HIV-1 infection.

Fryer HR, Van Tienen C, Van Der Loeff MS, Aaby P, Da Silva ZJ, Whittle H, Rowland-Jones SL, de Silva TI. 2015. Predicting the extinction of HIV-2 in rural Guinea-Bissau AIDS, 29 (18), pp. 2479-2486. | Show Abstract | Read more

© 2015 Wolters Kluwer Health, Inc. All rights reserved.Objective: This article predicts the future epidemiology of HIV-2 in Caió, a rural region of Guinea Bissau; and investigates whether HIV-2, which has halved in prevalence between 1990 and 2007 and is now almost absent in young adults in Caió, can persist as an infection of the elderly. Design: A mathematical model of the spread of HIV-2 was tailored to the epidemic in Caió, a village in Guinea-Bissau. Methods: An age-stratified difference equation model of HIV-2 transmission was fitted to age-stratified HIV-2 incidence and prevalence data from surveys conducted in Caió in 1990, 1997 and 2007. A stochastic version of the same model was used to make projections. Results: HIV-2 infection is predicted to continue to rapidly decline in Caió such that new infections will cease and prevalence will reach low levels (e.g. below 0.1%) within a few decades. HIV-2 is not predicted to persist in the elderly.

Wang L, Zhang Y, Dong T, Rowland-Jones SL, Yindom LM. 2015. Detection of a novel KIR3DL1*0150210 allele by sequencing Tissue Antigens, 86 (4), pp. 311. | Read more

Yindom LM, de Silva TI, Rowland-Jones SL. 2015. Full-length sequence of KIR3DL1*0310102 detected in DNA samples from West Africa Tissue Antigens, 86 (4), pp. 312-313. | Read more

Yindom LM, James K, de Silva TI, Rowland-Jones SL. 2015. KIR3DL1*0040102 - a novel three-domain KIR subtype isolated from donors of African descent Tissue Antigens, 86 (3), pp. 220-221. | Show Abstract | Read more

© 2015 John Wiley & Sons A/S.KIR3DL1*0040102 allele differs from KIR3DL1*0040101 by a single-nucleotide change at position 12356 (intron 6).

Wang L, Zhang Y, Dong T, Rowland-Jones SL, Yindom LM. 2015. KIR3DS1*0130109: A novel activating three-domain KIR identified using sequence-based typing Tissue Antigens, 86 (3), pp. 222-223. | Show Abstract | Read more

© 2015 John Wiley & Sons A/S.KIR3DS1*0130109 is similar to KIR3DS1*0130101 except for a A > G change in intron 4.

Yindom LM, James K, de Silva TI, Rowland-Jones SL. 2015. A novel KIR3DL1*0150103 subtype identified in West Africa Tissue Antigens, 86 (1), pp. 70-71. | Show Abstract | Read more

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.A novel KIR3DL1*0150103 found in West Africa with five single nucleotide polymorphisms compared to KIR3DL1*0150101.

Yindom LM, de Silva TI, Rowland-Jones SL. 2015. KIR3DL1*0250103: A novel three-domain KIR allele isolated in West African samples Tissue Antigens, 86 (2), pp. 150-151. | Show Abstract | Read more

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.The full length sequence of KIR3DL1*0250103 differs from that of KIR3DL1*0150101 with nine single-nucleotide polymorphisms

Yindom LM, Wang L, Xu K, Dong T, Rowland-Jones SL. 2015. The identification of a killer cell immunoglobulin-like receptor 3DL1*0150209 in an Asian population using molecular techniques Tissue Antigens, 86 (2), pp. 152-153. | Show Abstract | Read more

© 2015 John Wiley & Sons A/S.Full-length sequences of KIR3DL1*0150209 differ from those of KIR3DL1*0150201 with seven single-nucleotide polymorphisms.

Yindom LM, James K, de Silva TI, Rowland-Jones SL. 2015. A novel KIR3DL1*0150103 subtype identified in West Africa. Tissue Antigens, 86 (1), pp. 70-71. | Show Abstract | Read more

A novel KIR3DL1*0150103 found in West Africa with five single nucleotide polymorphisms compared to KIR3DL1*0150101.

Wang L, Xu K, Dong T, Rowland-Jones SL, Yindom LM. 2015. KIR3DS1*0130111: A novel KIR allele identified using molecular typing methods Tissue Antigens, 85 (4), pp. 296-297. | Show Abstract | Read more

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.KIR3DS1*0130111 differs from KIR3DS1*0130101 with two previously undescribed single nucleotide polymorphisms.

Tansiri Y, Rowland-Jones SL, Ananworanich J, Hansasuta P. 2015. Clinical outcome of HIV viraemic controllers and noncontrollers with normal CD4 counts is exclusively determined by antigen-specific CD8+ T-cell-mediated HIV suppression. PLoS One, 10 (3), pp. e0118871. | Show Abstract | Read more

In this cross-sectional study we evaluated T-cell responses using several assays to determine immune correlates of HIV control that distinguish untreated viraemic controllers (VC) from noncontrollers (NC) with similar CD4 counts. Samples were taken from 65 ART-naïve chronically HIV-infected VC and NC from Thailand with matching CD4 counts in the normal range (>450 cells/μl). We determined HIVp24-specific T-cell responses using standard Interferon-gamma (IFNγ) ELISpot assays, and compared the functional quality of HIVp24-specific CD8+ T-cell responses using polychromatic flow cytometry. Finally, in vitro HIV suppression assays were performed to evaluate directly the activity of CD8+ T cells in HIV control. Autologous CD4+ T cells were infected with primary patient-derived HIV isolates and the HIV suppressive activity of CD8+ T cells was determined after co-culture, measuring production of HIVp24 Ag by ELISA. The HIVp24-specific T-cell responses of VC and NC could not completely be differentiated through measurement of IFNγ-producing cells using ELISpot assays, nor by the absolute cell numbers of polyfunctional HIVp24-specific CD8+ T cells. However, in vitro HIV suppression assays showed clear differences between VC and NC. HIV suppressive activity, mediated by either ex vivo unstimulated CD8+ T cells or HIVp24-specific T-cell lines, was significantly greater using cells from VC than NC cells. Additionally, we were able to demonstrate a significant correlation between the level of HIV suppressive activity mediated by ex vivo unstimulated CD8+ T cells and plasma viral load (pVL) (Spearman r = -0.7345, p = 0.0003). This study provides evidence that in vitro HIV suppression assays are the most informative in the functional evaluation of CD8+ T-cell responses and can distinguish between VC and NC.

Makvandi-Nejad S, Rowland-Jones S. 2015. How does the humoral response to HIV-2 infection differ from HIV-1 and can this explain the distinct natural history of infection with these two human retroviruses? Immunol Lett, 163 (1), pp. 69-75. | Show Abstract | Read more

A substantial proportion of people infected with HIV-2, the second causative agent of acquired immune deficiency syndrome (AIDS), behave as long-term non-progressors (LTNP) and are able to control the infection more effectively than most HIV-1-infected patients. A better understanding of the differences in the natural history of HIV-1 and HIV-2 infection, and how these relate to the relative immunogenicity and evolution of the two virus strains, could provide important insights into the mechanisms of protective immunity in HIV infection. One of the most striking differences is that most people infected with HIV-2 generate high titers of broadly neutralizing antibodies, whereas this is relatively uncommon in HIV-1 infection. In this review we compare the underlying structural differences of the envelope (Env) between HIV-1 and HIV-2, and examine how these might affect the antibody responses as well as their impact on Env evolution and control of viral replication.

Wang L, Yindom LM, Zhang Y, Xu K, Yan H, Dong T, Rowland-Jones SL. 2014. Killer-cell immunoglobulin-like receptor (KIR) genetic diversity in a unique HIV-1 cohort in China IMMUNOLOGY, 143 pp. 157-157.

Yindom LM, Wong G, de Silva TI, Rowland-Jones SL. 2014. A new variant of killer-cell immunoglobulin-like receptor KIR3DL1*03101 isolated using sequence-based techniques Tissue Antigens, 84 (5), pp. 521-522. | Show Abstract | Read more

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.The complete length genomic sequence of KIR3DL1*03101 differs from KIR3DL1*0010101 at multiple intronic and exonic sites.

Yindom LM, James K, de Silva TI, Rowland-Jones SL. 2014. Genomic full length sequence of a novel killer-cell immunoglobulin-like receptor, KIR3DL1*0010103 identified by sequencing Tissue Antigens, 84 (5), pp. 520-521. | Show Abstract | Read more

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd 84 5 November 2014 10.1111/tan.12438 New allele alerts New allele alerts © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.KIR3DL1*0010103 differs from KIR3DL1*0010101 with four single nucleotide polymorphisms.

Yindom LM, Wong G, de Silva TI, Rowland-Jones SL. 2014. Complete genomic sequence of KIR3DL1*0150102. Tissue Antigens, 84 (6), pp. 595-596. | Show Abstract | Read more

Full-length sequence of KIR3DL1*0150102 differs from that of KIR3DL1*0150101 in intron 6.

Yindom LM, de Silva TI, Rowland-Jones SL. 2014. Description of a novel KIR3DL1*0150211 allele isolated using molecular techniques. Tissue Antigens, 84 (6), pp. 596-597. | Show Abstract | Read more

KIR3DL1*0150211 differs from KIR3DL1*0150201 with six single nucleotide polymorphisms in introns 3, 4, 5, and 6.

Yindom LM, James K, de Silva TI, Rowland-Jones SL. 2014. Isolation of full-length genomic sequences of the KIR3DL1*0040103 allele from African donors using sequence-based techniques. Tissue Antigens, 84 (6), pp. 594-595. | Show Abstract | Read more

The full-length genomic sequence of KIR3DL1*0040103 differs from KIR3DL1*0040101 at three nucleotide positions.

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2014. Full length KIR3DS1*0130110 allele isolated by SBT Tissue Antigens, 84 (4), pp. 423-424. | Show Abstract | Read more

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.KIR3DS1*0130110 differs from KIR3DS1*0130101 with two nucleotide substitutions at positions 7322 (G>T) and 12617 (C>A), respectively.

Yindom LM, James K, de Silva TI, Rowland-Jones SL. 2014. Full-length KIR3DL1*022 detected in an African donor Tissue Antigens, 84 (4), pp. 427-429. | Show Abstract | Read more

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.KIR3DL1*022 is significantly different from the most common West African allele - KIR3DL1*01501.

Yindom LM, Wong G, de Silva TI, Rowland-Jones SL. 2014. A new variant of killer-cell immunoglobulin-like receptor KIR3DL1*03101 isolated using sequence-based techniques. Tissue Antigens, 84 (5), pp. 521-522. | Show Abstract | Read more

The complete length genomic sequence of KIR3DL1*03101 differs from KIR3DL1*0010101 at multiple intronic and exonic sites.

Yindom LM, James K, de Silva TI, Rowland-Jones SL. 2014. Genomic full length sequence of a novel killer-cell immunoglobulin-like receptor, KIR3DL1*0010103 identified by sequencing. Tissue Antigens, 84 (5), pp. 520-521. | Show Abstract | Read more

KIR3DL1*0010103 differs from KIR3DL1*0010101 with four single nucleotide polymorphisms.

Yindom LM, James K, de Silva TI, Rowland-Jones SL. 2014. Full-length KIR3DL1*022 detected in an African donor. Tissue Antigens, 84 (4), pp. 427-429. | Show Abstract | Read more

KIR3DL1*022 is significantly different from the most common West African allele - KIR3DL1*01501.

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2014. Full length KIR3DS1*0130110 allele isolated by SBT. Tissue Antigens, 84 (4), pp. 423-424. | Show Abstract | Read more

KIR3DS1*0130110 differs from KIR3DS1*0130101 with two nucleotide substitutions at positions 7322 (G > T) and 12617 (C > A), respectively.

Yindom LM, Wang L, Zhang Y, Rowland-Jones SL, Dong T. 2014. KIR3DS1*0130108 isolated using full length sequence-based typing. Tissue Antigens, 84 (2), pp. 251-252. | Show Abstract | Read more

KIR3DS1*0130108 possesses three SNPs at: 12548C>G, 13804C>G and 13819G>A (introns 6 and 7, respectively) compared to KIR3DS1*0130101. © 2014 John Wiley & Sons A/S.

Yindom LM, Wang L, Rai MA, Dong T, Rowland-Jones SL. 2014. Report of a novel activating killer-cell immunoglobulin-like receptor allele 3DS1*078 identified using sequence-based typing. Tissue Antigens, 84 (2), pp. 252-254. | Show Abstract | Read more

KIR3DS1*078 differs from KIR3DS1*0130101 at position 5586 and at position 14255. © 2014 John Wiley & Sons A/S.

Wang L, Xu K, Dong T, Rowland-Jones SL, Yindom LM. 2014. Identification of KIR3DL1*0150208 using long-range sequence-based techniques Tissue Antigens, 83 (5), pp. 372-373. | Show Abstract | Read more

KIR3DL1*0150208 possesses five point mutations: 3037G>A, 4115A>G, 6053G>C, 8034A>G, and 9446T>C compared to KIR3DL1*0150201. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Wang L, Zhang YH, Dong T, Rowland-Jones SL, Yindom LM. 2014. A novel full-length KIR3DS1*0130106 allele identified by sequencing Tissue Antigens, 83 (5), pp. 371-372. | Show Abstract | Read more

The novel KIR3DS1*0130106 differs from KIR3DS1*0130101 with a single point mutation at position 7211 (G>T). © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Yindom LM, Wang L, Xu K, Dong T, Rowland-Jones SL. 2014. A novel KIR3DS1*0130107 allele isolated by sequencing from an Asian donor. Int J Immunogenet, 41 (3), pp. 267-268. | Show Abstract | Read more

This novel KIR3DS1 allele officially named as KIR3DS1*0130107 was isolated from DNA samples from Asia using high-resolution sequenced-based techniques. KIR3DS1*0130107 differs from the first member of the KIR3DS1*013 subgroup (KIR3DS1*0130101) by a single mutation at position 8922A>G (intron 5), just nine nucleotides away from the start of exon 6.

Kanki PJ, Rowland-Jones S. 2014. The protective effect of HIV-2 infection: implications for understanding HIV-1 immunity. AIDS, 28 (7), pp. 1065-1067. | Read more

Wang L, Yindom LM, Rowland-Jones SL, Dong T. 2014. Identification of the KIR3DL1*0050105 allele by sequence-based techniques Tissue Antigens, 83 (4), pp. 301-302. | Show Abstract | Read more

KIR3DL1*0050105 differs from KIR3DL1*0050101 with two nucleotide substitutions at 6709(C>T) and 13398 (G>A) in introns 5 and 7, respectively. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Wang L, Yan H, Dong T, Rowland-Jones SL, Yindom LM. 2014. Detection of a novel killer-cell immunoglobulin-like receptor allele - KIR3DL1*0150207 - in Asian individuals Tissue Antigens, 83 (4), pp. 304-305. | Show Abstract | Read more

KIR3DL1*0150207 differs from KIR3DL1*0150201 at five nucleotide positions in introns 2, 3, 4 and 5, respectively. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Yindom LM, De Silva TI, Rowland-Jones SL. 2014. A novel KIR3DL1*0200102 allele isolated from a West African donor by sequence-based typing Tissue Antigens, 83 (4), pp. 305-306. | Show Abstract | Read more

KIR3DL1*0200102 allele differs from KIR3DL1*0200101 with four single nucleotide polymorphisms in introns 5 and 6, respectively. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Wang L, Zhang YH, Dong T, Rowland-Jones SL, Yindom LM. 2014. A novel full-length KIR3DS1*0130106 allele identified by sequencing. Tissue Antigens, 83 (5), pp. 371-372. | Read more

Wang L, Xu K, Dong T, Rowland-Jones SL, Yindom LM. 2014. Identification of KIR3DL1*0150208 using long-range sequence-based techniques. Tissue Antigens, 83 (5), pp. 372-373. | Show Abstract | Read more

KIR3DL1*0150208 possesses five point mutations: 3037G>A, 4115A>G, 6053G>C, 8034A>G, and 9446T>C compared to KIR3DL1*0150201. © 2014 John Wiley & Sons A/S.

Yindom LM, Wang L, Rowland-Jones SL, Dong T. 2014. Killer-cell immunoglobulin-like receptor gene 3DL1*077 isolated using long-range sequence-based techniques Tissue Antigens, 83 (3), pp. 206-207. | Show Abstract | Read more

KIR3DL1*077 gene has two non-synonymous mutations (exon 5) and six intronic changes compared to KIR3DL1*0150201. © 2014 John Wiley & Sons A/S.

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2014. A novel KIR3DL1*0070104 allele found in individuals from Asia Tissue Antigens, 83 (3), pp. 204-206. | Show Abstract | Read more

KIR3DL1*0070104 differs from KIR3DL1*0070101 at position 13889 (T>G) in the 3′UTR region of KIR3DL1/S1 locus. © 2014 John Wiley & Sons A/S.

Wang L, Yan H, Dong T, Rowland-Jones SL, Yindom LM. 2014. Detection of a novel killer-cell immunoglobulin-like receptor allele - KIR3DL1*0150207 - in Asian individuals. Tissue Antigens, 83 (4), pp. 304-305. | Show Abstract | Read more

KIR3DL1*0150207 differs from KIR3DL1*0150201 at five nucleotide positions in introns 2, 3, 4 and 5, respectively.

Yindom LM, Wang L, Dong T, Rowland-Jones SL, Zhang Y. 2014. The KIR3DS1*0130105 allele identified using high-resolution sequence-based typing. Tissue Antigens, 83 (4), pp. 302-303. | Show Abstract | Read more

KIR3DS1*0130105 allele differs from KIR3DS1*0130101 with a single mutation at position 6739G>T of intron 5.

Abidi SH, Shahid A, Lakhani LS, Shah R, Okinda N, Ojwang P, Abbas F, Rowland-Jones S, Ali S. 2014. HIV-1 progression links with viral genetic variability and subtype, and patient's HLA type: Analysis of a Nairobi-Kenyan cohort Medical Microbiology and Immunology, 203 (1), pp. 57-63. | Show Abstract | Read more

In a Nairobi-Kenyan cohort of 50 HIV-1 positive patients, we analysed the prevalence of HIV-1 subtypes and human leucocyte antigen (HLA) alleles. From this cohort, 33 patients were selected for the analysis of HIV-1 infection progression markers (i.e. CD4 cell counts and viral loads) and their association with HIV-1 genetic variability and subtype, and patient's HLA type. HIV-1 gag genetic variability, analysed using bioinformatics tools, showed an inverse relationship with CD4 cell count whereas with viral load that relationship was direct. Certain HLA types and viral subtypes were also found to associate with patients' viral load. Associations between disease parameters and the genetic makeup of the host and virus may be crucial in determining the outcome of HIV-1 infection. © 2013 Springer-Verlag Berlin Heidelberg.

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2014. Long-range sequencing revealed a new KIR3DL1*0150204 allele in 20 individuals of Asian descent Tissue Antigens, 83 (2), pp. 123-124. | Show Abstract | Read more

The novel KIR3DL1*0150204 has four point mutations: 3037G>A, 4115A>G, 6053G>C, and 8034A>G compared to KIR3DL1*0150201. © 2014 John Wiley & Sons A/S.

Yindom LM, Wang L, Okala SG, Dong T, Rowland-Jones SL. 2014. Report of a novel KIR3DS1*0130104 allele discovered using advanced molecular techniques Tissue Antigens, 83 (2), pp. 121-122. | Show Abstract | Read more

KIR3DS1*0130104 is identical to KIR3DS1*0130101 except for changes at positions 1768 (C>T) and 12617 (C>A). © 2014 John Wiley & Sons A/S.

Yindom LM, Wang L, Rowland-Jones SL, Dong T. 2014. Two novel KIR3DL1 alleles, 3DL1*0150205 and 3DL1*0150206, identified by full-length DNA sequencing Tissue Antigens, 83 (2), pp. 128-129. | Show Abstract | Read more

KIR3DL1*0150205 and KIR3DL1*0150206 alleles have five and six mutations, respectively, compared with KIR3DL1*0150201. © 2014 John Wiley & Sons A/S.

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2014. Identification of KIR3DL1*0200101 by long-range sequence-based techniques Tissue Antigens, 83 (2), pp. 127-128. | Show Abstract | Read more

The new KIR3DL1*0200101 differs from KIR3DL1*01502 with 12 single nucleotide polymorphisms (SNPs) in two exons and seven introns. © 2014 John Wiley & Sons A/S.

Yindom LM, de Silva TI, Rowland-Jones SL. 2014. Full-length sequence of KIR3DL1*01501 allele found in Sub-Saharan Africa by long-range sequencing Tissue Antigens, 83 (2), pp. 126-127. | Show Abstract | Read more

Full-length KIR3DL1*01501 differing from KIR3DL1*0150201 with 10 SNPs and 2 nucleotide deletion in intron 7. © 2014 John Wiley & Sons A/S.

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2014. Description of a novel KIR3DL1*0050104 allele identified using sequence-based techniques Tissue Antigens, 83 (2), pp. 124-125. | Show Abstract | Read more

KIR3DL1*0050104 allele differs from KIR3DL1*0050101 at nucleotide positions 6709C>T (intron 5) and 11365A>G (intron 6). © 2014 John Wiley & Sons A/S.

Wang L, Yindom LM, Rowland-Jones SL, Dong T. 2014. Identification of the KIR3DL1*0050105 allele by sequence-based techniques. Tissue Antigens, 83 (4), pp. 301-302. | Show Abstract | Read more

KIR3DL1*0050105 differs from KIR3DL1*0050101 with two nucleotide substitutions at 6709(C > T) and 13398 (G > A) in introns 5 and 7, respectively.

Yindom LM, Wang L, Rowland-Jones SL, Dong T. 2014. Killer-cell immunoglobulin-like receptor gene 3DL1*077 isolated using long-range sequence-based techniques. Tissue Antigens, 83 (3), pp. 206-207. | Show Abstract | Read more

KIR3DL1*077 gene has two non-synonymous mutations (exon 5) and six intronic changes compared to KIR3DL1*0150201.

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2014. A novel KIR3DL1*0070104 allele found in individuals from Asia. Tissue Antigens, 83 (3), pp. 204-206. | Show Abstract | Read more

KIR3DL1*0070104 differs from KIR3DL1*0070101 at position 13889 (T > G) in the 3'UTR region of KIR3DL1/S1 locus.

Rafferty H, Sibeko S, Rowland-Jones S. 2014. How can we design better vaccines to prevent HIV infection in women? Front Microbiol, 5 (OCT), pp. 572. | Show Abstract | Read more

The human immunodeficiency virus (HIV) burden in women continues to increase, and heterosexual contact is now the most common route of infection worldwide. Effective protection of women against HIV-1 infection may require a vaccine specifically targeting mucosal immune responses in the female genital tract (FGT). To achieve this goal, a much better understanding of the immunology of the FGT is needed. Here we review the architecture of the immune system of the FGT, recent studies of potential methods to achieve the goal of mucosal protection in women, including systemic-prime, mucosal-boost, FGT-tropic vectors and immune response altering adjuvants. Advances in other fields that enhance our understanding of female genital immune correlates and the interplay between hormonal and immunological systems may also help to achieve protection of women from HIV infection.

Yindom LM, Wang L, Rai MA, Dong T, Rowland-Jones SL. 2014. Report of a novel activating killer-cell immunoglobulin-like receptor allele 3DS1*078 identified using sequence-based typing Tissue Antigens, 84 (2), pp. 252-254. | Show Abstract | Read more

KIR3DS1*078 differs from KIR3DS1*0130101 at position 5586 and at position 14255. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Yindom LM, Wang L, Zhang Y, Rowland-Jones SL, Dong T. 2014. KIR3DS1*0130108 isolated using full length sequence-based typing Tissue Antigens, 84 (2), pp. 251-252. | Show Abstract | Read more

KIR3DS1*0130108 possesses three SNPs at: 12548C>G, 13804C>G and 13819G>A (introns 6 and 7, respectively) compared to KIR3DS1*0130101. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Abidi SH, Kalish ML, Abbas F, Rowland-Jones S, Ali S. 2014. HIV-1 subtype A gag variability and epitope evolution. PLoS One, 9 (6), pp. e93415. | Show Abstract | Read more

OBJECTIVE: The aim of this study was to examine the course of time-dependent evolution of HIV-1 subtype A on a global level, especially with respect to the dynamics of immunogenic HIV gag epitopes. METHODS: We used a total of 1,893 HIV-1 subtype A gag sequences representing a timeline from 1985 through 2010, and 19 different countries in Africa, Europe and Asia. The phylogenetic relationship of subtype A gag and its epidemic dynamics was analysed through a Maximum Likelihood tree and Bayesian Skyline plot, genomic variability was measured in terms of G → A substitutions and Shannon entropy, and the time-dependent evolution of HIV subtype A gag epitopes was examined. Finally, to confirm observations on globally reported HIV subtype A sequences, we analysed the gag epitope data from our Kenyan, Pakistani, and Afghan cohorts, where both cohort-specific gene epitope variability and HLA restriction profiles of gag epitopes were examined. RESULTS: The most recent common ancestor of the HIV subtype A epidemic was estimated to be 1956 ± 1. A period of exponential growth began about 1980 and lasted for approximately 7 years, stabilized for 15 years, declined for 2-3 years, then stabilized again from about 2004. During the course of evolution, a gradual increase in genomic variability was observed that peaked in 2005-2010. We observed that the number of point mutations and novel epitopes in gag also peaked concurrently during 2005-2010. CONCLUSION: It appears that as the HIV subtype A epidemic spread globally, changing population immunogenetic pressures may have played a role in steering immune-evolution of this subtype in new directions. This trend is apparent in the genomic variability and epitope diversity of HIV-1 subtype A gag sequences.

Yindom LM, de Silva TI, Rowland-Jones SL. 2014. A novel KIR3DL1*0200102 allele isolated from a West African donor by sequence-based typing. Tissue Antigens, 83 (4), pp. 305-306. | Show Abstract | Read more

KIR3DL1*0200102 allele differs from KIR3DL1*0200101 with four single nucleotide polymorphisms in introns 5 and 6, respectively.

Afran L, Garcia Knight M, Nduati E, Urban BC, Heyderman RS, Rowland-Jones SL. 2014. HIV-exposed uninfected children: a growing population with a vulnerable immune system? Clin Exp Immunol, 176 (1), pp. 11-22. | Show Abstract | Read more

Through the successful implementation of policies to prevent mother-to-child-transmission (PMTCT) of HIV-1 infection, children born to HIV-1-infected mothers are now much less likely to acquire HIV-1 infection than previously. Nevertheless, HIV-1-exposed uninfected (HEU) children have substantially increased morbidity and mortality compared with children born to uninfected mothers (unexposed uninfected, UU), predominantly from infectious causes. Moreover, a range of phenotypical and functional immunological differences between HEU and UU children has been reported. As the number of HEU children continues to increase worldwide, two questions with clear public health importance need to be addressed: first, does exposure to HIV-1 and/or ART in utero or during infancy have direct immunological consequences, or are these poor outcomes simply attributable to the obvious disadvantages of being born into an HIV-affected household? Secondly, can we expect improved maternal care and ART regimens during and after pregnancy, together with optimized infant immunization schedules, to reduce the excess morbidity and mortality of HEU children?

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2013. Identification of KIR3DL1*0050103 by the sequence-based techniques Tissue Antigens, 82 (6), pp. 444-445. | Show Abstract | Read more

The new KIR3DL1*0050103 allele has a mutation at nucleotide position 6709 (C>T) in intron 5. © 2013 John Wiley & Sons A/S.

Yindom LM, Wang L, Rowland-Jones SL, Dong T. 2013. A novel full length KIR3DL1*0070103 identified by molecular typing Tissue Antigens, 82 (6), pp. 445-446. | Show Abstract | Read more

KIR3DL1*0070103 differs from KIR3DL1*0070101 with two mutations at 11548 * and 13889 (T>G), respectively. © 2013 John Wiley & Sons A/S.

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2014. Full-length genomic sequence of a new KIR3DL1*0150203 allele Tissue Antigens, 83 (2), pp. 122-123. | Show Abstract | Read more

KIR3DL1*0150203 allele differs from KIR3DL1*0150201 at 3037G>A, 4115A>G, 6053G>C, 8034A>G, 10723C>A, and 10747C>G. © 2014 John Wiley & Sons A/S.

Yindom LM, de Silva TI, Rowland-Jones SL. 2014. Full-length sequence of KIR3DL1*01501 allele found in Sub-Saharan Africa by long-range sequencing. Tissue Antigens, 83 (2), pp. 126-127. | Show Abstract | Read more

Full-length KIR3DL1*01501 differing from KIR3DL1*0150201 with 10 SNPs and 2 nucleotide deletion in intron 7.

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2014. Full-length genomic sequence of a new KIR3DL1*0150203 allele. Tissue Antigens, 83 (2), pp. 122-123. | Show Abstract | Read more

KIR3DL1*0150203 allele differs from KIR3DL1*0150201 at 3037G>A, 4115A>G, 6053G>C, 8034A>G, 10723C>A, and 10747C>G.

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2014. Long-range sequencing revealed a new KIR3DL1*0150204 allele in 20 individuals of Asian descent. Tissue Antigens, 83 (2), pp. 123-124. | Show Abstract | Read more

The novel KIR3DL1*0150204 has four point mutations: 3037G>A, 4115A>G, 6053G>C, and 8034A>G compared to KIR3DL1*0150201.

Yindom LM, Wang L, Rowland-Jones SL, Dong T. 2014. Two novel KIR3DL1 alleles, 3DL1*0150205 and 3DL1*0150206, identified by full-length DNA sequencing. Tissue Antigens, 83 (2), pp. 128-129. | Show Abstract | Read more

KIR3DL1*0150205 and KIR3DL1*0150206 alleles have five and six mutations, respectively, compared with KIR3DL1*0150201.

Rai MA, Zhang Y, Yindom LM, Holmes J, Yu LM, Hao C, Rostron T, Yan H, Zhang YL, Cai C et al. 2013. HLA correlates in a cohort of slow progressors from China: Effects on HIV-1 disease progression AIDS, 27 (17), pp. 2822-2824. | Show Abstract | Read more

We looked at our HIVRslow progressors cohort to determine if there were any human leukocyte antigen (HLA) correlates for protection. No statistically significant allelic differences were found between the HIVRand control cohorts using regression analysis, though trendswere noted. Data for Elite Controllers showed an increased frequency of BM57. Likewise, no correlation was inferred with the clinical data of the HIVRcohort. We hypothesize that the protective effect of HLA alleles may have been lost over time. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Abidi SH, Shahid A, Lakhani LS, Shah R, Okinda N, Ojwang P, Abbas F, Rowland-Jones S, Ali S. 2014. HIV-1 progression links with viral genetic variability and subtype, and patient's HLA type: analysis of a Nairobi-Kenyan cohort. Med Microbiol Immunol, 203 (1), pp. 57-63. | Show Abstract | Read more

In a Nairobi-Kenyan cohort of 50 HIV-1 positive patients, we analysed the prevalence of HIV-1 subtypes and human leucocyte antigen (HLA) alleles. From this cohort, 33 patients were selected for the analysis of HIV-1 infection progression markers (i.e. CD4 cell counts and viral loads) and their association with HIV-1 genetic variability and subtype, and patient's HLA type. HIV-1 gag genetic variability, analysed using bioinformatics tools, showed an inverse relationship with CD4 cell count whereas with viral load that relationship was direct. Certain HLA types and viral subtypes were also found to associate with patients' viral load. Associations between disease parameters and the genetic makeup of the host and virus may be crucial in determining the outcome of HIV-1 infection.

Yindom LM, Wang L, Rowland-Jones SL, Dong T. 2013. A novel full length KIR3DL1*0070103 identified by molecular typing. Tissue Antigens, 82 (6), pp. 445-446. | Show Abstract | Read more

KIR3DL1*0070103 differs from KIR3DL1*0070101 with two mutations at 11548 (G>A) and 13889 (T>G), respectively. © 2013 John Wiley & Sons A/S.

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2013. Identification of KIR3DL1*0050103 by the sequence-based techniques. Tissue Antigens, 82 (6), pp. 444-445. | Show Abstract | Read more

The new KIR3DL1*0050103 allele has a mutation at nucleotide position 6709 (C>T) in intron 5. © 2013 John Wiley & Sons A/S.

de Silva T, Peng Y, Leligdowicz A, Zaidi I, Li L, Griffin H, Blais M-E, Vincent T, Saraiva M, Yindom L-M et al. 2013. THE ROLE OF CD8+T-CELL RESPONSES IN THE PATHOGENESIS OF HIV-2, A NATURALLY CONTAINED HUMAN RETROVIRAL INFECTION JOURNAL OF INFECTION, 67 (4), pp. 344-344. | Read more

Rai MA, Zhang Y, Yindom LM, Holmes J, Yu LM, Hao C, Rostron T, Yan H, Zhang YL, Cai C et al. 2013. HLA correlates in a cohort of slow progressors from China: effects on HIV-1 disease progression. AIDS, 27 (17), pp. 2822-2824. | Show Abstract | Read more

We looked at our HIV + slow progressors cohort to determine if there were any human leukocyte antigen (HLA) correlates for protection. No statistically significant allelic differences were found between the HIV + and control cohorts using regression analysis, though trends were noted. Data for Elite Controllers showed an increased frequency of B*57. Likewise, no correlation was inferred with the clinical data of the HIV + cohort. We hypothesize that the protective effect of HLA alleles may have been lost over time.

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Scopus

Nyamweya S, Hegedus A, Jaye A, Rowland-Jones S, Flanagan KL, Macallan DC. 2013. Comparing HIV-1 and HIV-2 infection: Lessons for viral immunopathogenesis Reviews in Medical Virology, 23 (4), pp. 221-240. | Show Abstract | Read more

HIV-1 and HIV-2 share many similarities including their basic gene arrangement, modes of transmission, intracellular replication pathways and clinical consequences: both result in AIDS. However, HIV-2 is characterised by lower transmissibility and reduced likelihood of progression to AIDS. The underlying mechanistic differences between these two infections illuminate broader issues of retroviral pathogenesis, which remain incompletely understood. Comparisons between these two infections from epidemiological, clinical, virologic and immunologic viewpoints provide a basis for hypothesis generation and testing in this 'natural experiment' in viral pathogenesis. In terms of epidemiology, HIV-2 remains largely confined to West Africa, whereas HIV-1 extends worldwide. Clinically, HIV-2 infected individuals seem to dichotomise, most remaining long-term non-progressors, whereas most HIV-1 infected individuals progress. When clinical progression occurs, both diseases demonstrate very similar pathological processes, although progression in HIV-2 occurs at higher CD4 counts. Plasma viral loads are consistently lower in HIV-2, as are average levels of immune activation. Significant differences exist between the two infections in all components of the immune system. For example, cellular responses to HIV-2 tend to be more polyfunctional and produce more IL-2; humoral responses appear broader with lower magnitude intratype neutralisation responses; innate responses appear more robust, possibly through differential effects of tripartite motif protein isoform 5 alpha. Overall, the immune response to HIV-2 appears more protective against disease progression suggesting that pivotal immune factors limit viral pathology. If such immune responses could be replicated or induced in HIV-1 infected patients, they might extend survival and reduce requirements for antiretroviral therapy. © 2013 John Wiley & Sons, Ltd.

de Silva TI, Peng Y, Leligdowicz A, Zaidi I, Li L, Griffin H, Blais ME, Vincent T, Saraiva M, Yindom LM et al. 2013. Correlates of T-cell-mediated viral control and phenotype of CD8(+) T cells in HIV-2, a naturally contained human retroviral infection. Blood, 121 (21), pp. 4330-4339. | Show Abstract | Read more

While a significant proportion of HIV-2-infected individuals are asymptomatic and maintain undetectable viral loads (controllers), 15% to 20% progress to AIDS and are predicted by detectable viremia. Identifying immune correlates that distinguish these 2 groups should provide insights into how a potentially pathogenic retrovirus can be naturally controlled. We performed a detailed study of HIV-2-specific cellular responses in a unique community cohort in Guinea-Bissau followed for over 2 decades. T-cell responses were compared between controllers (n = 33) and viremic subjects (n = 27) using overlapping peptides, major histocompatibility complex class I tetramers, and multiparameter flow cytometry. HIV-2 viral control was significantly associated with a high-magnitude, polyfunctional Gag-specific CD8(+) T-cell response but not with greater perforin upregulation. This potentially protective HIV-2-specific response is surprisingly narrow. HIV-2 Gag-specific CD8(+) T cells are at an earlier stage of differentiation than cytomegalovirus-specific CD8(+) T-cells, do not contain high levels of cytolytic markers, and exhibit low levels of activation and proliferation, representing distinct properties from CD8(+) T cells associated with HIV-1 control. These data reveal the potential T-cell correlates of HIV-2 control and the detailed phenotype of virus-specific CD8(+) T cells in a naturally contained retroviral infection.

Nyamweya S, Hegedus A, Jaye A, Rowland-Jones S, Flanagan KL, Macallan DC. 2013. Comparing HIV-1 and HIV-2 infection: Lessons for viral immunopathogenesis. Rev Med Virol, 23 (4), pp. 221-240. | Show Abstract | Read more

HIV-1 and HIV-2 share many similarities including their basic gene arrangement, modes of transmission, intracellular replication pathways and clinical consequences: both result in AIDS. However, HIV-2 is characterised by lower transmissibility and reduced likelihood of progression to AIDS. The underlying mechanistic differences between these two infections illuminate broader issues of retroviral pathogenesis, which remain incompletely understood. Comparisons between these two infections from epidemiological, clinical, virologic and immunologic viewpoints provide a basis for hypothesis generation and testing in this 'natural experiment' in viral pathogenesis. In terms of epidemiology, HIV-2 remains largely confined to West Africa, whereas HIV-1 extends worldwide. Clinically, HIV-2 infected individuals seem to dichotomise, most remaining long-term non-progressors, whereas most HIV-1 infected individuals progress. When clinical progression occurs, both diseases demonstrate very similar pathological processes, although progression in HIV-2 occurs at higher CD4 counts. Plasma viral loads are consistently lower in HIV-2, as are average levels of immune activation. Significant differences exist between the two infections in all components of the immune system. For example, cellular responses to HIV-2 tend to be more polyfunctional and produce more IL-2; humoral responses appear broader with lower magnitude intratype neutralisation responses; innate responses appear more robust, possibly through differential effects of tripartite motif protein isoform 5 alpha. Overall, the immune response to HIV-2 appears more protective against disease progression suggesting that pivotal immune factors limit viral pathology. If such immune responses could be replicated or induced in HIV-1 infected patients, they might extend survival and reduce requirements for antiretroviral therapy.

Abidi SH, Shahid A, Lakhani LS, Khanani MR, Ojwang P, Okinda N, Shah R, Abbas F, Rowland-Jones S, Ali S. 2013. Population-specific evolution of HIV Gag epitopes in genetically diverged patients. Infect Genet Evol, 16 pp. 78-86. | Show Abstract | Read more

BACKGROUND: Under the host selection pressure HIV evolves rapidly to override crucial steps in the antigen presentation pathway. This allows the virus to escape binding and recognition by cytotoxic T lymphocytes. Selection pressures on HIV can be unique depending on the immunogenetics of host populations. It is therefore logical to hypothesize that the virus evolving in a given population will carry signature mutations that will allow it to survive in that particular host milieu. OBJECTIVES: The aim of this study was to perform a comparative analysis of HIV-1 Gag subtype A sequences from two genetically diverged populations, namely, Kenyan and Pakistani. We analyzed unique mutations that could intercept the antigen processing pathway and potentially change the repertoire of Gag epitopes in each study group. METHODS: Twenty-nine Kenyan and 56 Pakistani samples from HIV-1 subtype A-infected patients were used in this study. The HIV-1 gag region p24 and p2p7p1p6 was sequenced and mutations affecting proteasomal degradation, TAP binding, HLA binding and CTL epitope generation, were analyzed using the in silico softwares NetChop and MAPPP, TAPPred, nHLAPred and CTLPred, respectively. RESULTS: Certain mutations unique to either Pakistani or Kenyan patients were observed to affect sites for proteasomal degradation, TAP binding, and HLA binding. As a consequence of these mutations, epitope pattern in these populations was altered. CONCLUSION: Unique selection pressures can steer the direction of viral epitope evolution in the host populations. Population-specific HIV epitopes have to be taken into account while designing treatment as well as vaccine for HIV.

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2014. Description of a novel KIR3DL1*0050104 allele identified using sequence-based techniques. Tissue Antigens, 83 (2), pp. 124-125. | Show Abstract | Read more

KIR3DL1*0050104 allele differs from KIR3DL1*0050101 at nucleotide positions 6709C>T (intron 5) and 11365A>G (intron 6).

Yindom LM, Wang L, Dong T, Rowland-Jones SL. 2014. Identification of KIR3DL1*0200101 by long-range sequence-based techniques. Tissue Antigens, 83 (2), pp. 127-128. | Show Abstract | Read more

The new KIR3DL1*0200101 differs from KIR3DL1*01502 with 12 single nucleotide polymorphisms (SNPs) in two exons and seven introns.

Yindom LM, Wang L, Okala SG, Dong T, Rowland-Jones SL. 2014. Report of a novel KIR3DS1*0130104 allele discovered using advanced molecular techniques. Tissue Antigens, 83 (2), pp. 121-122. | Show Abstract | Read more

KIR3DS1*0130104 is identical to KIR3DS1*0130101 except for changes at positions 1768 (C>T) and 12617 (C>A).

Afolabi MO, Ndure J, Drammeh A, Darboe F, Mehedi SR, Rowland-Jones SL, Borthwick N, Black A, Ambler G, John-Stewart GC et al. 2013. A phase I randomized clinical trial of candidate human immunodeficiency virus type 1 vaccine MVA.HIVA administered to Gambian infants. PLoS One, 8 (10), pp. e78289. | Show Abstract | Read more

BACKGROUND: A vaccine to decrease transmission of human immunodeficiency virus type 1 (HIV-1) during breast-feeding would complement efforts to eliminate infant HIV-1 infection by antiretroviral therapy. Relative to adults, infants have distinct immune development, potentially high-risk of transmission when exposed to HIV-1 and rapid progression to AIDS when infected. To date, there have been only three published HIV-1 vaccine trials in infants. TRIAL DESIGN: We conducted a randomized phase I clinical trial PedVacc 001 assessing the feasibility, safety and immunogenicity of a single dose of candidate vaccine MVA.HIVA administered intramuscularly to 20-week-old infants born to HIV-1-negative mothers in The Gambia. METHODS: Infants were followed to 9 months of age with assessment of safety, immunogenicity and interference with Expanded Program on Immunization (EPI) vaccines. The trial is the first stage of developing more complex prime-boost vaccination strategies against breast milk transmission of HIV-1. RESULTS: From March to October 2010, 48 infants (24 vaccine and 24 no-treatment) were enrolled with 100% retention. The MVA.HIVA vaccine was safe with no difference in adverse events between vaccinees and untreated infants. Two vaccine recipients (9%) and no controls had positive ex vivo interferon-γ ELISPOT assay responses. Antibody levels elicited to the EPI vaccines, which included diphtheria, tetanus, whole-cell pertussis, hepatitis B virus, Haemophilus influenzae type b and oral poliovirus, reached protective levels for the vast majority and were similar between the two arms. CONCLUSIONS: A single low-dose of MVA.HIVA administered to 20-week-old infants in The Gambia was found to be safe and without interference with the induction of protective antibody levels by EPI vaccines, but did not alone induce sufficient HIV-1-specific responses. These data support the use of MVA carrying other transgenes as a boosting vector within more complex prime-boost vaccine strategies against transmission of HIV-1 and/or other infections in this age group. TRIAL REGISTRATION: ClinicalTrials.gov NCT00982579. The Pan African Clinical Trials Registry PACTR2008120000904116.

Powell TJ, Peng Y, Berthoud TK, Blais ME, Lillie PJ, Hill AV, Rowland-Jones SL, McMichael AJ, Gilbert SC, Dong T. 2013. Examination of influenza specific T cell responses after influenza virus challenge in individuals vaccinated with MVA-NP+M1 vaccine. PLoS One, 8 (5), pp. e62778. | Show Abstract | Read more

Current influenza vaccines stimulate neutralising antibody to the haemagglutinin antigen but as there is antigenic drift in HA it is difficult to prepare a vaccine in advance against an emergent strain. A potential strategy is to induce CD8(+) and CD4(+) T cells that recognize epitopes within internal proteins that are less subject to antigenic drift. Augmenting humoral responses to HA with T cell responses to more conserved antigens may result in a more broadly protective vaccine. In this study, we evaluate the quality of influenza specific T cell responses in a clinical trial using MVA-NP+M1 vaccination followed by influenza virus challenge. In vaccinated volunteers, the expression of Granzyme A, Perforin and CD57 on influenza HLA A*02 M158-66 antigen specific cells was higher than non-vaccinated volunteers before and after challenge despite a similar frequency of antigen specific cells. BCL2 expression was lower in vaccinated volunteers. These data indicate that antigen specific T cells are a useful additional measure for use in human vaccination or immunization studies.

De Silva TI, Van Tienen C, Onyango C, Jabang A, Vincent T, Van Der Loeff MFSVD, Coutinho RA, Jaye A, Rowland-Jones S, Whittle H et al. 2013. Population dynamics of HIV-2 in rural West Africa: Comparison with HIV-1 and ongoing transmission at the heart of the epidemic AIDS, 27 (1), pp. 125-134. | Show Abstract | Read more

Objectives: To compare the population dynamics of HIV-2 and HIV-1, and to characterize ongoing HIV-2 transmission in rural Guinea-Bissau. Design: Phylogenetic and phylodynamic analyses using HIV-2 gag and env, and HIV-1 env sequences, combined with epidemiological data from a community cohort. Design: Samples were obtained from surveys in 1989-1991, 1996-1997, 2003 and 2006-2007. Phylogenies were reconstructed using sequences from 103 HIV-2-infected and 56 HIV-1-infected patients using Bayesian Evolutionary Analysis by Sampling Trees (BEAST), a relaxed molecular clock and a Bayesian skyline coalescent model. Results: Bayesian skyline plots showed a strong increase in the 1990s of the HIV-1 effective population size (Ne) in the same period that the Ne of HIV-2 came into a plateau phase. The population dynamics of both viruses were remarkably similar following initial introduction. Incident infections were found more often in HIV-2 transmission clusters, with 55-58% of all individuals contributing to ongoing transmission. Some phylogenetically linked sexual partners had discordant viral loads (undetectable vs. detectable), suggesting host factors dictate the risk of disease progression in HIV-2. Multiple HIV-2 introductions into the cohort are evident, but ongoing transmission has occurred predominantly within the community. Conclusion: Comparison of HIV-1 and HIV-2 phylodynamics in the same community suggests both viruses followed similar growth patterns following introduction, and is consistent with the hypothesis that HIV-1 may have played a role in the decline of HIV-2 via competitive exclusion. The source of ongoing HIV-2 transmission in the cohort appears to be new HIV-2 cases, rather than the pool of older infections established during the early growth of HIV-2. © 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Stewart-Jones GB, Simpson P, van der Merwe PA, Easterbrook P, McMichael AJ, Rowland-Jones SL, Jones EY, Gillespie GM. 2012. Structural features underlying T-cell receptor sensitivity to concealed MHC class I micropolymorphisms. Proc Natl Acad Sci U S A, 109 (50), pp. E3483-E3492. | Show Abstract | Read more

Polymorphic differences distinguishing MHC class I subtypes often permit the presentation of shared epitopes in conformationally identical formats but can affect T-cell repertoire selection, differentially impacting autoimmune susceptibilities and viral clearance in vivo. The molecular mechanisms underlying this effect are not well understood. We performed structural, thermodynamic, and functional analyses of a conserved T-cell receptor (TCR) which is frequently expanded in response to a HIV-1 epitope when presented by HLA-B*5701 but is not selected by HLA-B*5703, which differs from HLA-B*5701 by two concealed polymorphisms. Our findings illustrate that although both HLA-B*57 subtypes display the epitope in structurally conserved formats, the impact of their polymorphic differences occurs directly as a consequence of TCR ligation, primarily because of peptide adjustments required for TCR binding, which involves the interplay of polymorphic residues and water molecules. These minor differences culminate in subtype-specific differential TCR-binding kinetics and cellular function. Our data demonstrate a potential mechanism whereby the most subtle MHC class I micropolymorphisms can influence TCR use and highlight their implications for disease outcomes.

de Silva T, Leligdowicz A, Rowland-Jones S. 2012. Effect of HIV-2 infection on HIV-1 disease progression. N Engl J Med, 367 (20), pp. 1961-1962. | Read more

Kong R, Li H, Georgiev I, Changela A, Bibollet-Ruche F, Decker JM, Rowland-Jones SL, Jaye A, Guan Y, Lewis GK et al. 2012. Epitope mapping of broadly neutralizing HIV-2 human monoclonal antibodies. J Virol, 86 (22), pp. 12115-12128. | Show Abstract | Read more

Recent studies have shown that natural infection by HIV-2 leads to the elicitation of high titers of broadly neutralizing antibodies (NAbs) against primary HIV-2 strains (T. I. de Silva, et al., J. Virol. 86:930-946, 2012; R. Kong, et al., J. Virol. 86:947-960, 2012; G. Ozkaya Sahin, et al., J. Virol. 86:961-971, 2012). Here, we describe the envelope (Env) binding and neutralization properties of 15 anti-HIV-2 human monoclonal antibodies (MAbs), 14 of which were newly generated from 9 chronically infected subjects. All 15 MAbs bound specifically to HIV-2 gp120 monomers and neutralized heterologous primary virus strains HIV-2(7312A) and HIV-2(ST). Ten of 15 MAbs neutralized a third heterologous primary virus strain, HIV-2(UC1). The median 50% inhibitory concentrations (IC(50)s) for these MAbs were surprisingly low, ranging from 0.007 to 0.028 μg/ml. Competitive Env binding studies revealed three MAb competition groups: CG-I, CG-II, and CG-III. Using peptide scanning, site-directed mutagenesis, chimeric Env constructions, and single-cycle virus neutralization assays, we mapped the epitope of CG-I antibodies to a linear region in variable loop 3 (V3), the epitope of CG-II antibodies to a conformational region centered on the carboxy terminus of V4, and the epitope(s) of CG-III antibodies to conformational regions associated with CD4- and coreceptor-binding sites. HIV-2 Env is thus highly immunogenic in vivo and elicits antibodies having diverse epitope specificities, high potency, and wide breadth. In contrast to the HIV-1 Env trimer, which is generally well shielded from antibody binding and neutralization, HIV-2 is surprisingly vulnerable to broadly reactive NAbs. The availability of 15 human MAbs targeting diverse HIV-2 Env epitopes can facilitate comparative studies of HIV/SIV Env structure, function, antigenicity, and immunogenicity.

Slyker JA, Rowland-Jones SL, Dong T, Reilly M, Richardson B, Emery VC, Atzberger A, Mbori-Ngacha D, Lohman-Payne BL, John-Stewart GC. 2012. Acute cytomegalovirus infection is associated with increased frequencies of activated and apoptosis-vulnerable T cells in HIV-1-infected infants. J Virol, 86 (20), pp. 11373-11379. | Show Abstract | Read more

Cytomegalovirus (CMV) coinfection is associated with infant HIV-1 disease progression and mortality. In a cohort of Kenyan HIV-infected infants, the frequencies of activated (CD38(+) HLA-DR(+)) and apoptosis-vulnerable (CD95(+) Bcl-2(-)) CD4(+) and CD8(+) T cells increased substantially during acute CMV infection. The frequency of activated CD4(+) T cells was strongly associated with both concurrent CMV coinfection (P = 0.001) and HIV-1 viral load (P = 0.05). The frequency of apoptosis-vulnerable cells was also associated with CMV coinfection in the CD4 (P = 0.02) and CD8 (P < 0.001) T cell subsets. Similar observations were made in HIV-exposed uninfected infants. CMV-induced increases in T cell activation and apoptosis may contribute to the rapid disease progression in coinfected infants.

Blais ME, Zhang Y, Rostron T, Griffin H, Taylor S, Xu K, Yan H, Wu H, James I, John M et al. 2012. High frequency of HIV mutations associated with HLA-C suggests enhanced HLA-C-restricted CTL selective pressure associated with an AIDS-protective polymorphism. J Immunol, 188 (9), pp. 4663-4670. | Show Abstract | Read more

Delayed HIV-1 disease progression is associated with a single nucleotide polymorphism upstream of the HLA-C gene that correlates with differential expression of the HLA-C Ag. This polymorphism was recently shown to be a marker for a protective variant in the 3'UTR of HLA-C that disrupts a microRNA binding site, resulting in enhanced HLA-C expression at the cell surface. Whether individuals with "high" HLA-C expression show a stronger HLA-C-restricted immune response exerting better viral control than that of their counterparts has not been established. We hypothesized that the magnitude of the HLA-C-restricted immune pressure on HIV would be greater in subjects with highly expressed HLA-C alleles. Using a cohort derived from a unique narrow source epidemic in China, we identified mutations in HIV proviral DNA exclusively associated with HLA-C, which were used as markers for the intensity of the immune pressure exerted on the virus. We found an increased frequency of mutations in individuals with highly expressed HLA-C alleles, which also correlated with IFN-γ production by HLA-C-restricted CD8(+) T cells. These findings show that immune pressure on HIV is stronger in subjects with the protective genotype and highlight the potential role of HLA-C-restricted responses in HIV control. This is, to our knowledge, the first in vivo evidence supporting the protective role of HLA-C-restricted responses in nonwhites during HIV infection.

Walther M, De Caul A, Aka P, Njie M, Amambua-Ngwa A, Walther B, Predazzi IM, Cunnington A, Deininger S, Takem EN et al. 2012. HMOX1 gene promoter alleles and high HO-1 levels are associated with severe malaria in Gambian children. PLoS Pathog, 8 (3), pp. e1002579. | Show Abstract | Read more

Heme oxygenase 1 (HO-1) is an essential enzyme induced by heme and multiple stimuli associated with critical illness. In humans, polymorphisms in the HMOX1 gene promoter may influence the magnitude of HO-1 expression. In many diseases including murine malaria, HO-1 induction produces protective anti-inflammatory effects, but observations from patients suggest these may be limited to a narrow range of HO-1 induction, prompting us to investigate the role of HO-1 in malaria infection. In 307 Gambian children with either severe or uncomplicated P. falciparum malaria, we characterized the associations of HMOX1 promoter polymorphisms, HMOX1 mRNA inducibility, HO-1 protein levels in leucocytes (flow cytometry), and plasma (ELISA) with disease severity. The (GT)(n) repeat polymorphism in the HMOX1 promoter was associated with HMOX1 mRNA expression in white blood cells in vitro, and with severe disease and death, while high HO-1 levels were associated with severe disease. Neutrophils were the main HO-1-expressing cells in peripheral blood, and HMOX1 mRNA expression was upregulated by heme-moieties of lysed erythrocytes. We provide mechanistic evidence that induction of HMOX1 expression in neutrophils potentiates the respiratory burst, and propose this may be part of the causal pathway explaining the association between short (GT)(n) repeats and increased disease severity in malaria and other critical illnesses. Our findings suggest a genetic predisposition to higher levels of HO-1 is associated with severe illness, and enhances the neutrophil burst leading to oxidative damage of endothelial cells. These add important information to the discussion about possible therapeutic manipulation of HO-1 in critically ill patients.

Khalid M, Yu H, Sauter D, Usmani SM, Schmokel J, Feldman J, Gruters RA, van der Ende ME, Geyer M, Rowland-Jones S et al. 2012. Efficient Nef-mediated downmodulation of TCR-CD3 and CD28 is associated with high CD4+ T cell counts in viremic HIV-2 infection. J Virol, 86 (9), pp. 4906-4920. | Show Abstract | Read more

The role of the multifunctional accessory Nef protein in the immunopathogenesis of HIV-2 infection is currently poorly understood. Here, we performed comprehensive functional analyses of 50 nef genes from 21 viremic (plasma viral load, >500 copies/ml) and 16 nonviremic (<500) HIV-2-infected individuals. On average, nef alleles from both groups were equally active in modulating CD4, TCR-CD3, CD28, MHC-I, and Ii cell surface expression and in enhancing virion infectivity. Thus, many HIV-2-infected individuals efficiently control the virus in spite of efficient Nef function. However, the potency of nef alleles in downmodulating TCR-CD3 and CD28 to suppress the activation and apoptosis of T cells correlated with high numbers of CD4(+) T cells in viremic patients. No such correlations were observed in HIV-2-infected individuals with undetectable viral load. Further functional analyses showed that the Nef-mediated downmodulation of TCR-CD3 suppressed the induction of Fas, Fas-L, PD-1, and CTLA-4 cell surface expression as well as the secretion of gamma interferon (IFN-γ) by primary CD4(+) T cells. Moreover, we identified a single naturally occurring amino acid variation (I132T) in the core domain of HIV-2 Nef that selectively disrupts its ability to downmodulate TCR-CD3 and results in functional properties highly reminiscent of HIV-1 Nef proteins. Taken together, our data suggest that the efficient Nef-mediated downmodulation of TCR-CD3 and CD28 help viremic HIV-2-infected individuals to maintain normal CD4(+) T cell homeostasis by preventing T cell activation and by suppressing the induction of death receptors that may affect the functionality and survival of both virally infected and uninfected bystander cells.

Njie-Jobe J, Nyamweya S, Miles DJ, van der Sande M, Zaman S, Touray E, Hossin S, Adetifa J, Palmero M, Burl S et al. 2012. Immunological impact of an additional early measles vaccine in Gambian children: responses to a boost at 3 years. Vaccine, 30 (15), pp. 2543-2550. | Show Abstract | Read more

BACKGROUND: Measles vaccine in early infancy followed by a dose at 9 months of age protects against measles and enhances child survival through non-specific effects. Little is known of immune responses in the short or long term after booster doses. METHODS: Infants were randomized to receive measles vaccine at 9 months of age (group 1) or 4 and 9 months of age (group 2). Both groups received a boost at 36 months of age. T-cell effector and memory responses using IFN-γ ELIspot and cytokine assays and antibody titres using a haemagglutination-inhibition assay were compared at various times. RESULTS: Vaccination at 4 months of age elicited antibody and CD4 T-cell mediated immune responses .Two weeks after vaccination at 9 months of age group 2 had much higher antibody titres than group1 infants; cell-mediated effector responses were similar. At 36 months of age group 2 antibody titres exceeded protective levels but were 4-fold lower than group 1; effector and cytokine responses were similar. Re-vaccination resulted in similar rapid and high antibody titres in both groups (median 512); cellular immunity changed little. At 48 months of age group 2 antibody concentrations remained well above protective levels though 2-fold lower than group 1; T-cell memory was readily detectable and similar in both groups. CONCLUSIONS: An additional early measles vaccine given to children at 4 months of age induced a predominant CD4 T-cell response at 9 months and rapid development of high antibody concentrations after booster doses. However, antibody decayed faster in these children than in the group given primary vaccination at 9 months of age. Cellular responses after 9 months were generally insignificantly different.

Peterson K, Rowland-Jones S. 2012. Novel agents for the treatment of HIV-2 infection. Antivir Ther, 17 (3), pp. 435-438. | Show Abstract | Read more

Many of the antiretrovirals used against HIV-1 are either ineffective or less effective in HIV-2 infection. There is in vitro evidence of the potency of maraviroc and several investigational agents against HIV-2. We conclude that, whilst specific boosted protease inhibitors combined with nucleoside analogues should still be considered the mainstays of HIV-2 treatment, maraviroc, T-1249, TAK-779 and AMD3100, as well as raltegravir, could contribute to regimens for treatment-experienced individuals. Factors bearing on the use and timing of these alternative agents are discussed.

Sabbah S, Jagne YJ, Zuo J, de Silva T, Ahasan MM, Brander C, Rowland-Jones S, Flanagan KL, Hislop AD. 2012. T-cell immunity to Kaposi sarcoma-associated herpesvirus: recognition of primary effusion lymphoma by LANA-specific CD4+ T cells. Blood, 119 (9), pp. 2083-2092. | Show Abstract | Read more

T-cell immunity is important for controlling Kaposi sarcoma-associated herpesvirus (KSHV) diseases such as the endothelial cell malignancy Kaposi sarcoma, or the B-cell malignancy, primary effusion lymphoma (PEL). However, little is known about KSHV-specific T-cell immunity in healthy donors and immune control of disease. Using PBMCs from healthy KSHV-infected donors, we found weak ex vivo responses to the KSHV latent antigens LANA, vFLIP, vCyclin, and Kaposin, with LANA most frequently recognized. CD4(+) T-cell clones specific to LANA, a protein expressed in all KSHV-infected cells and malignancies, were established to determine whether they could recognize LANA-expressing cells. B-cell targets expressing or fed LANA protein were consistently recognized by the clones; however, most PEL cell lines were not. PELs express the KSHV protein vIRF3 that inhibits promoter function of the HLA class II transactivator, decreasing expression of genes controlled by this transactivator. Re-expressing the class II transactivator in the PELs increased expression of downstream targets such as HLA class II and restored recognition but not killing by the LANA-specific clones. We suggest that PELs are poorly controlled in vivo because of inefficient recognition and killing by T cells.

Moysi E, de Silva T, Rowland-Jones S. 2012. Immune Mechanisms of Viral Control in HIV-2 Infection pp. 293-315. | Show Abstract | Read more

Human immunodeficiency virus 2 (HIV-2) infection is a zoonosis in which simian immunodeficiency virus from a West African monkey species; the sooty mangabey is thought to have entered the human population on at least eight separate occasions. This has given rise to eight distinct HIV-2 groups, of which only groups A and B have continued to spread among humans; the other clades appear only to have led to single-person infections. Viral control in HIV-2 infection is associated with several distinct features-a high-magnitude cellular immune response directed toward conserved Gag epitopes, an earlier-differentiated CD8 + T cell phenotype with increased polyfunctionality and exceptionally high functional avidity, supported by polyfunctional virus-specific CD4 + T cells, against a background of substantially less extensive immune activation than is seen in human immunodeficiency virus 1 (HIV-1) infection. Emerging as one of the most striking differences from HIV-1 infection is the slower evolution and a possible lower frequency of adaptive immune escape in asymptomatic HIV-2-infected individuals. © 2012 Elsevier Inc. All rights reserved.

Slyker JA, Lohman-Payne B, John-Stewart GC, Dong T, Mbori-Ngacha D, Tapia K, Atzberger A, Taylor S, Rowland-Jones SL, Blish CA. 2012. The impact of HIV-1 infection and exposure on natural killer (NK) cell phenotype in Kenyan infants during the first year of life. Front Immunol, 3 (DEC), pp. 399. | Show Abstract | Read more

Natural killer (NK) cells play an important role in the containment of HIV replication during primary infection, though their functions are impaired during chronic HIV infection. Infants experience more rapid HIV disease progression than adults, but contributions of infant NK cells to containing HIV infection are unknown. The aim of this study was to determine the impact of HIV infection on infant NK cell phenotype by evaluating samples and data from a cohort study of women and their infants, conducted in Nairobi, Kenya between 1999 and 2003. The percentage and phenotype of NK cells was evaluated longitudinally by multi-parameter flow cytometry over the first year of life in HIV-infected (HIV+, = 16), HIV-exposed uninfected (HIV-EU, n = 6), and healthy unexposed controls (HIV-, n = 4). At birth, NK subset distributions based on expression of CD56 and CD16 did not differ between HIV+, HIV-EU, or HIV- infants. However, HIV infection was associated with a subsequent decline in NK cells as a percentage of total lymphocytes (p < 0.001), and an expanding proportion of CD56-CD16+ NK cells (p < 0.001). Activated CD38(bright)CD69+ NK cells were more frequent in the HIV+ infants, followed by HIV-EU and HIV- infants, in both CD56(dim) (p = 0.005) and CD56(bright) compartments (p = 0.03). HIV infection and exposure was also associated with a significant decline in the percentage of perforin-expressing NK cells in the CD56(dim) compartment over the first year of life, with HIV+ infants losing approximately 2.5% (p < 0.001) and HIV-EU infants losing 3.0% (p = 0.01) of perforin+ cells per month. Thus, infant HIV infection is associated with alterations in NK cell subsets, activation, and cytolytic potential that could contribute to their poor control over HIV infection. Furthermore, exposure to HIV infection in infants who escaped infection is also associated with alterations in NK cells that may contribute to the reduced ability to fight infections that is observed in HIV-EU infants.

Lee LY-H, Ha DLA, Simmons C, de Jong MD, Chau NVV, Schumacher R, Peng YC, McMichael AJ, Farrar JJ, Smith GL et al. 2012. Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals Journal of Clinical Investigation, 122 (11), pp. 4301-4301. | Read more

Lohman-Payne B, Slyker JA, Moore S, Maleche-Obimbo E, Wamalwa DC, Richardson BA, Rowland-Jones S, Mbori-Ngacha D, Farquhar C, Overbaugh J, John-Stewart G. 2012. Breast milk cellular HIV-specific interferon γ responses are associated with protection from peripartum HIV transmission AIDS, 26 (16), pp. 2007-2016. | Show Abstract | Read more

OBJECTIVE: Breast milk is a major route of infant HIV infection, yet the majority of breast-fed, HIV-exposed infants escape infection by unknown mechanisms. This study aimed to investigate the role of HIV-specific breast milk cells in preventing infant HIV infection. DESIGN: A prospective study was designed to measure associations between maternal breast milk HIV-specific interferon-γ (IFN-γ) responses and infant HIV-1 detection at 1 month of age. METHODS: In a Kenyan cohort of HIV-infected mothers, blood and breast milk HIV-gag IFN-γ ELISpot responses were measured. Logistic regression was used to measure associations between breast milk IFN-γ responses and infant HIV infection at 1 month of age. RESULTS: IFN-γ responses were detected in breast milk from 117 of 170 (69%) women. IFN-γ responses were associated with breast milk viral load, levels of macrophage inflammatory protein (MIP) 1α, MIP-1β, regulated upon activation, normal T-cell expressed, and secreted and stromal-cell derived factor 1 and subclinical mastitis. Univariate factors associated with infant HIV infection at 1 month postpartum included both detection and breadth of breast milk IFN-γ response (P=0.08, P=0.04, respectively), breast milk MIP-1β detection (P=0.05), and plasma (P=0.004) and breast milk (P=0.004) viral load. In multivariate analyses adjusting for breast milk viral load and MIP-1β, breast milk IFN-γ responses were associated with an approximately 70% reduction in infant HIV infection [adjusted odds ratio (aOR) 0.29, 95% confidence interval (CI) 0.092-0.91], and each additional peptide pool targeted was associated with an approximately 35% reduction in infant HIV (aOR 0.65, 95% CI 0.44-0.97). CONCLUSION: These data show breast milk HIV-gag-specific IFN-γ cellular immune responses are prevalent and may contribute to protection from early HIV transmission. More broadly, these data suggest breast milk cellular responses are potentially influential in decreasing mother-to-child transmission of viruses. Copyright © 2012 Lippincott Williams &Wilkins.

Nyamweya S, Townend J, Zaman A, Steele SJ, Jeffries D, Rowland-Jones S, Whittle H, Flanagan KL, Jaye A. 2012. Are plasma biomarkers of immune activation predictive of HIV progression: a longitudinal comparison and analyses in HIV-1 and HIV-2 infections? PLoS One, 7 (9), pp. e44411. | Show Abstract | Read more

BACKGROUND: Chronic immune activation is a hallmark of HIV infection and has been associated with disease progression. Assessment of soluble biomarkers indicating immune activation provide clues into pathogenesis and hold promise for the development of point-of-care monitoring of HIV in resource-poor-settings. Their evaluation in cohort resources is therefore needed to further their development and use in HIV research. METHODOLOGY/PRINCIPAL FINDINGS: Longitudinal evaluation of βeta-2 microglobulin (β-2 m), neopterin and suPAR soluble urokinase-type plasminogen activator receptor (suPAR) was performed with archived plasma samples to predict disease progression and provided the first direct comparison of levels in HIV-1 and HIV-2 infections. At least 2095 samples from 137 HIV-1 and 198 HIV-2 subjects with starting CD4% of ≥ 28 and median follow up of 4 years were analysed. All biomarkers were correlated negatively to CD4% and positively to viral load and to each other. Analyses in subjects living for ≥ 5 years revealed increases in median β-2 m and neopterin and decreases in CD4% over this period and the odds of death within 5 years were positively associated with baseline levels of β-2 m and neopterin. ROC analyses strengthened the evidence of elevation of biomarkers in patients approaching death in both HIV-1 and HIV-2 infections. Regression models showed that rates of biomarker fold change accelerated from 6-8 years before death with no significant differences between biomarker levels in HIV-1 and HIV-2 at equal time points prior to death.An 'immune activation index' analysis indicative of biomarker levels at equivalent viral loads also showed no differences between the two infections. CONCLUSIONS/SIGNIFICANCE: Our results suggest that β-2 m and neopterin are useful tools for disease monitoring in both HIV-1 and HIV-2 infections, whereas sUPAR performed less well. Levels of immune activation per amount of virus were comparable in HIV-1 and HIV-2 infected subjects.

Simpson PD, Moysi E, Wicks K, Sudan K, Rowland-Jones SL, McMichael AJ, Knight J, Gillespie GM. 2012. Functional differences exist between TNFα promoters encoding the common -237G SNP and the rarer HLA-B*5701-linked A variant. PLoS One, 7 (7), pp. e40100. | Show Abstract | Read more

A large body of functional and epidemiological evidence have previously illustrated the impact of specific MHC class I subtypes on clinical outcome during HIV-1 infection, and these observations have recently been re-iterated in genome wide association studies (GWAS). Yet because of the complexities surrounding GWAS-based approaches and the lack of knowledge relating to the identity of rarer single nucleotide polymorphism (SNP) variants, it has proved difficult to discover independent causal variants associated with favourable immune control. This is especially true of the candidate variants within the HLA region where many of the recently proposed disease influencing SNPs appear to reflect linkage with 'protective' MHC class I alleles. Yet causal MHC-linked SNPs may exist but remain overlooked owing to the complexities associated with their identification. Here we focus on the ancestral TNFα promoter -237A variant (rs361525), shown historically to be in complete linkage disequilibrium with the 'protective' HLA-B*5701 allele. Many of the ancestral SNPs within the extended TNFα promoter have been associated with both autoimmune conditions and disease outcomes, however, the direct role of these variants on TNFα expression remains controversial. Yet, because of the important role played by TNFα in HIV-1 infection, and given the proximity of the -237 SNP to the core promoter, its location within a putative repressor region previously characterized in mice, and its disruption of a methylation-susceptible CpG dinucleotide motif, we chose to carefully evaluate its impact on TNFα production. Using a variety of approaches we now demonstrate that carriage of the A SNP is associated with lower TNFα production, via a mechanism not readily explained by promoter methylation nor the binding of transcription factors or repressors. We propose that the -237A variant could represent a minor causal SNP that additionally contributes to the HLA-B*5701-mediated 'protective' effect during HIV-1 infection.

Zaidi I, Peterson K, Jeffries D, Whittle H, de Silva T, Rowland-Jones S, Jaye A, de Jong BC. 2012. Immune reconstitution inflammatory syndrome and the influence of T regulatory cells: a cohort study in The Gambia. PLoS One, 7 (6), pp. e39213. | Show Abstract | Read more

OBJECTIVE: The factors associated with the development of immune reconstitution inflammatory syndrome in HIV patients commencing antiretroviral therapy have not been fully elucidated. Using a longitudinal study design, this study addressed whether alteration in the levels of T regulatory cells contributed to the development of IRIS in a West African cohort of HIV-1 and HIV-2 patients. Seventy-one HIV infected patients were prospectively recruited to the study and followed up for six months. The patients were categorized as IRIS or non-IRIS cases following published clinical guidelines. The levels of T regulatory cells were measured using flow cytometry at baseline and all follow-up visits. Baseline cytokine levels of IL-2, IL-6, IFN-γ, TNF-α, MIP-1β, IL-1, IL-12, IL-13, and IL-10 were measured in all patients. RESULTS: Twenty eight percent of patients (20/71) developed IRIS and were predominantly infected with HIV-1. Patients developing IRIS had lower nadir CD4 T cells at baseline (p = 0.03) and greater CD4 T cell reconstitution (p = 0.01) at six months post-ART. However, the development of IRIS was not influenced by the levels of T regulatory cells. Similarly, baseline cytokine levels did not predict the onset of IRIS. CONCLUSION: The development of IRIS was not associated with differences in levels of T regulatory cells or baseline pro-inflammatory cytokines.

Gourlay AJ, van Tienen C, Dave SS, Vincent T, Rowland-Jones SL, Glynn JR, Whittle HC, van der Loeff MFS. 2012. Clinical predictors cannot replace biological predictors in HIV-2 infection in a community setting in West Africa International Journal of Infectious Diseases, 16 (5), | Show Abstract | Read more

Objective: To identify clinical predictors of mortality in HIV-2-infected individuals that may be used in place of CD4 count or plasma viral load (PVL) to guide treatment management in resource-limited settings. Methods: A prospective community cohort study of HIV-infected and HIV-negative individuals in a rural area of Guinea-Bissau has been ongoing since 1989. In 2003 participants were invited for a clinical examination and blood tests. They were followed-up for vital status until 2010. Antiretroviral treatment (ART) became available in 2007. Cox regression was used to examine the association of clinical measures (World Health Organization (WHO) stage, body mass index (BMI), mid-upper arm circumference (MUAC), and WHO performance scale) measured in 2003 with subsequent mortality. Results: In 2003, 146 HIV-2-infected individuals (68% women; mean age 56 years) were examined. Over the next 7 years, 44 (30%) died. BMI<18.5kg/m2 was associated with a crude mortality hazard ratio (HR) of 1.9 (95% confidence interval (CI) 1.0-3.9, p=0.08); adjusted for age and sex, HR 1.8 (95% CI 0.9-3.8, p=0.1). MUAC <230mm in women and <240mm in men was also associated with an elevated mortality HR, though statistical evidence was weak (crude HR 2.2, 95% CI 0.9-5.3, p=0.1). WHO clinical stage and WHO performance scale were not associated with mortality (p=0.6 and p=0.2, respectively, for crude associations). Conclusions: Baseline BMI, MUAC, WHO stage, and WHO performance scale were not strong or statistically significant predictors of mortality among HIV-2-infected individuals. CD4 count and PVL are more reliable tools, when available, for the management of HIV-2-infected patients in the community setting. © 2012 International Society for Infectious Diseases.

Njie-Jobe J, Nyamweya S, Miles DJC, van der Sande M, Zaman S, Touray E, Hossin S, Adetifa J, Palmero M, Burl S et al. 2012. Immunological impact of an additional early measles vaccine in Gambian children: Responses to a boost at 3 years Vaccine, 30 (15), pp. 2543-2550. | Show Abstract | Read more

Background: Measles vaccine in early infancy followed by a dose at 9 months of age protects against measles and enhances child survival through non-specific effects. Little is known of immune responses in the short or long term after booster doses. Methods: Infants were randomized to receive measles vaccine at 9 months of age (group 1) or 4 and 9 months of age (group 2). Both groups received a boost at 36 months of age. T-cell effector and memory responses using IFN-γ ELIspot and cytokine assays and antibody titres using a haemagglutination-inhibition assay were compared at various times. Results: Vaccination at 4 months of age elicited antibody and CD4 T-cell mediated immune responses .Two weeks after vaccination at 9 months of age group 2 had much higher antibody titres than group1 infants; cell-mediated effector responses were similar. At 36 months of age group 2 antibody titres exceeded protective levels but were 4-fold lower than group 1; effector and cytokine responses were similar. Re-vaccination resulted in similar rapid and high antibody titres in both groups (median 512); cellular immunity changed little. At 48 months of age group 2 antibody concentrations remained well above protective levels though 2-fold lower than group 1; T-cell memory was readily detectable and similar in both groups. Conclusions: An additional early measles vaccine given to children at 4 months of age induced a predominant CD4 T-cell response at 9 months and rapid development of high antibody concentrations after booster doses. However, antibody decayed faster in these children than in the group given primary vaccination at 9 months of age. Cellular responses after 9 months were generally insignificantly different. © 2012 Elsevier Ltd.

Lohman-Payne B, Slyker J, Rowland-Jones SL. 2012. Immune approaches for the prevention of breast milk transmission of HIV-1. Adv Exp Med Biol, 743 pp. 185-195. | Show Abstract | Read more

Mother-to-child transmission (MTCT) of HIV-1 infection remains a significant cause of new HIV-1 infections, despite the increasing implementation of prevention strategies using antiretroviral therapy (ART) and the resulting decline in infections across the developing world. In 2009, the UNAIDS global report estimated 370,000 children under the age of 15 years were newly infected with HIV-1 (refer UNAIDS Report on the global AIDS epidemic, 2010 http://www.unaids.org/globalreport/Global-report.htm), most of whom acquired the infection from their mothers in low- and middle-income countries. Even with substantial progress, challenges remain for poor countries in providing comprehensive screening programs for pregnant women and implementing the full range of prevention services for those identified as HIV-1-infected. Although antiretroviral regimens and risk reduction counseling have been successfully used for pregnant women and their infants in many parts of the developing world, full implementation of these programs remains a challenge in many countries, especially where antenatal clinical attendance and HIV-1 screening is not yet widespread. In addition, potential toxicities of and development of drug resistance to ART in both mother and child are concerns. Therefore, the development of a safe effective immunoprophylaxis regimen begun at birth and continuing during breastfeeding, perhaps alongside neonatal chemoprophylaxis, remains an area of active research interest. An ideal pediatric vaccine for prevention of MTCT (PMTCT) would combine the immediacy of passive immunization designed to protect the infant during the first vulnerable weeks of life with the durability of active immunization to protect against the repeated low-dose homologous virus exposure delivered multiple times a day via breastfeeding. © 2012 Springer Science+Business Media New York.

Jayasooriya S, Hislop A, Peng Y, Croom-Carter D, Jankey Y, Bell A, Dong T, Rowland-Jones S, Rickinson A, Walther M, Whittle H. 2012. Revisiting the effect of acute P. falciparum malaria on Epstein-Barr virus: host balance in the setting of reduced malaria endemicity. PLoS One, 7 (2), pp. e31142. | Show Abstract | Read more

Burkitt's lymphoma (BL), an EBV-associated tumour, occurs at high incidence in populations where malaria is holoendemic. Previous studies in one such population suggested that acute P.falciparum infection impairs EBV-specific T-cell surveillance, allowing expansion of EBV infected B-cells from which BL derives. We re-examined the situation in the same area, The Gambia, after a reduction in malaria endemicity. Cellular immune responses to EBV were measured in children with uncomplicated malaria before (day 0) and after treatment (day 28), comparing EBV genome loads in blood and EBV-specific CD8(+) T-cell numbers (assayed by MHC Class I tetramers and IFNγ ELISPOTS) with those seen in age- and sex-matched healthy controls. No significant changes were seen in EBV genome loads, percentage of EBV-specific CD8(+) T-cells and IFNγ producing T-cells in acute versus convalescent samples, nor any difference versus controls. Regression assays performed also no longer detected any impairment of EBV-specific T-cell surveillance. Acute uncomplicated malaria infection no longer alters EBV-specific immune responses in children in The Gambia. Given the recent decline in malaria incidence in that country, we hypothesise that gross disturbance of the EBV-host balance may be a specific effect of acute malaria only in children with a history of chronic/recurrent malaria challenge.

Stewart B, Jobarteh ML, Sarge-Njie R, Alabi A, de Silva T, Peterson K, Peterson I, Whittle H, Rowland-Jones S, Jaye A et al. 2011. Emergence of HBV resistance to lamivudine (3TC) in HIV/HBV co-infected patients in The Gambia, West Africa. BMC Res Notes, 4 (1), pp. 561. | Show Abstract | Read more

BACKGROUND: Lamivudine (3TC) is a potent inhibitor of both Hepatitis B virus (HBV) and Human Immunodeficiency Virus (HIV) replication and is part of first-line highly active antiretroviral therapy (HAART) in the Gambia. Unfortunately, the effectiveness of 3TC against HBV is limited by the emergence of resistant strains. AIM: The aim of this retrospective study was to characterise 3TC-resistant mutations in HBV from co-infected patients receiving HAART, by generating HBV polymerase sequence data and viral loads from HBV genotype E infected patients, both at initiation and during a course of 3TC therapy. METHOD: Samples from 21 HBV chronic carriers co-infected with HIV-1 (n = 18), HIV-2 (n = 2) and HIV-dual (n = 1) receiving HAART for a period of 6-52 months were analysed for the emergence of 3TC-resistance mutations. FINDINGS: Sixteen out of 21 HBV/HIV co-infected patients responded well to HAART treatment maintaining suppression of HBV viraemia to low (≤ 104 copies/mL) (n = 5) or undetectable levels (< 260 copies/ml) (n = 11). Out of the 5 non-responders, 3 had developed 3TC-resistant HBV strains showing mutations in the YMDD motif at position 204 of the RT domain of the HBV polymerase. One patient showed the M204V+ L180M+ V173L+ triple mutation associated with a vaccine escape phenotype, which could be of public health concern in a country with a national HBV vaccination programme. All except one patient was infected with HBV genotype E. CONCLUSIONS: Our findings confirm the risk of 3TC mutations in HAART patients following monotherapy. This is a novel study on 3TC resistance in HBV genotype E patients and encourage the use of tenofovir (in association with 3TC), which has not shown unequivocally documented HBV resistance to date, as part of first-line therapy in HIV/HBV co-infected patients in West Africa.HBV- hepatitis B infection; HIV- human immunodeficiency virus; HAART- antiretroviral therapy.

Powell TJ, Fox A, Peng Y, Quynh Mai LET, Lien VT, Hang NL, Wang L, Lee LY, Simmons CP, McMichael AJ et al. 2012. Identification of H5N1-specific T-cell responses in a high-risk cohort in vietnam indicates the existence of potential asymptomatic infections. J Infect Dis, 205 (1), pp. 20-27. | Show Abstract | Read more

BACKGROUND: Most reported human H5N1 viral infections have been severe and were detected after hospital admission. A case ascertainment bias may therefore exist, with mild cases or asymptomatic infections going undetected. We sought evidence of mild or asymptomatic H5N1 infection by examining H5N1-specific T-cell and antibody responses in a high-risk cohort in Vietnam. METHODS: Peripheral blood mononuclear cells were tested using interferon-γ enzyme-linked immunospot T assays measuring the response to peptides of influenza H5, H3, and H1 hemagglutinin (HA), N1 and N2 neuraminidase, and the internal proteins of H3N2. Horse erythrocyte hemagglutination inhibition assay was performed to detect antibodies against H5N1. RESULTS: Twenty-four of 747 individuals demonstrated H5-specific T-cell responses but little or no cross-reactivity with H3 or H1 HA peptides. H5N1 peptide-specific T-cell lines that did not cross-react with H1 or H3 influenza virus HA peptides were generated. Four individuals also had antibodies against H5N1. CONCLUSIONS: This is the first report of ex vivo H5 HA-specific T-cell responses in a healthy but H5N1-exposed population. Our results indicate that the presence of H5N1-specific T cells could be an additional diagnostic tool for asymptomatic H5N1 infection.

de Silva TI, Aasa-Chapman M, Cotten M, Hué S, Robinson J, Bibollet-Ruche F, Sarge-Njie R, Berry N, Jaye A, Aaby P et al. 2012. Potent autologous and heterologous neutralizing antibody responses occur in HIV-2 infection across a broad range of infection outcomes. J Virol, 86 (2), pp. 930-946. | Show Abstract | Read more

Few studies have explored the role of neutralizing antibody (NAb) responses in controlling HIV-2 viremia and disease progression. Using a TZM-bl neutralization assay, we assessed heterologous and autologous NAb responses from a community cohort of HIV-2-infected individuals with a broad range of disease outcomes in rural Guinea-Bissau. All subjects (n = 40) displayed exceptionally high heterologous NAb titers (50% inhibitory plasma dilution or 50% inhibitory concentration [IC(50)], 1:7,000 to 1:1,000,000) against 5 novel primary HIV-2 envelopes and HIV-2 7312A, whereas ROD A and 3 primary envelopes were relatively resistant to neutralization. Most individuals also showed high autologous NAb against contemporaneous envelopes (78% of plasma-envelope combinations in 69 envelopes from 21 subjects), with IC(50)s above 1:10,000. No association between heterologous or autologous NAb titer and greater control of HIV-2 was found. A subset of envelopes was found to be more resistant to neutralization (by plasma and HIV-2 monoclonal antibodies). These envelopes were isolated from individuals with greater intrapatient sequence diversity and were associated with changes in potential N-linked glycosylation sites but not CD4 independence or CXCR4 use. Plasma collected from up to 15 years previously was able to potently neutralize recent autologous envelopes, suggesting a lack of escape from NAb and the persistence of neutralization-sensitive variants over time, despite significant NAb pressure. We conclude that despite the presence of broad and potent NAb responses in HIV-2-infected individuals, these are not the primary forces behind the dichotomous outcomes observed but reveal a limited capacity for adaptive selection and escape from host immunity in HIV-2 infection.

Peterson I, Togun O, de Silva T, Oko F, Rowland-Jones S, Jaye A, Peterson K. 2011. Mortality and immunovirological outcomes on antiretroviral therapy in HIV-1 and HIV-2-infected individuals in the Gambia. AIDS, 25 (17), pp. 2167-2175. | Show Abstract | Read more

OBJECTIVES: This study's objective was to assess outcomes in HIV-1 and HIV-2 infected antiretroviral therapy (ART)-naïve patients starting ART in the Gambia, West Africa. DESIGN: A cohort design was used to estimate survival in ART patients and determine whether survival and time to virologic failure varied across patient subgroups. METHODS: Mortality, virologic failures and CD4(+) cell recovery were assessed in a clinical cohort of patients from the Genito-Urinary Medicine (GUM) clinic of the MRC Laboratories in the Gambia. Kaplan-Meier estimates of survival were determined for mortality and virologic failure. A Cox proportional hazards model was used to identify baseline demographic, clinical, immunologic and virologic factors associated with increased risk of death. RESULTS: The overall Kaplan-Meier estimate of survival to 36 months was 73.4% (66.5, 80.3). Survival was marginally higher in HIV-2-infected patients compared to HIV-1-infected patients; it was significantly higher in patients with a baseline CD4(+) lymphocyte cell count of greater than 50 cells/μl compared to those with a baseline CD4(+) count of less than 50 cells/μl. CD4(+) cell recovery was faster in HIV-1-infected individuals compared to HIV-2-infected patients up to 24 months, although this did not result higher mortality in the latter group. No differences in virologic failure were observed by HIV type. CONCLUSION: HIV-1 and HIV-2-infected patients receiving ART in a clinical setting in the Gambia had good survival to 36 months. HIV-2-infected patients did as well as HIV-1-infected patients in terms of long-term immunological and virological responses and overall survival.

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Zhang Y, Peng Y, Yan H, Xu K, Saito M, Wu H, Chen X, Ranasinghe S, Kuse N, Powell T et al. 2011. Multilayered Defense in HLA-B51-Associated HIV Viral Control JOURNAL OF IMMUNOLOGY, 187 (2), pp. 684-691. | Show Abstract | Read more

Polymorphism in the HLA region of a chromosome is the major source of host genetic variability in HIV-1 outcome, but there is limited understanding of the mechanisms underlying the beneficial effect of protective class I alleles such as HLA-B57, -B27, and -B51. Taking advantage of a unique cohort infected with clade B' HIV-1 through contaminated blood, in which many variables such as the length of infection, the infecting viral strain, and host genetic background are controlled, we performed a comprehensive study to understand HLA-B51-associated HIV-1 control.We focused on the T cell responses against three dominant HLA-B51-restricted epitopes: Gag327-345(NI9) NANPDCKTI, Pol743-751(LI9) LPPVVAKEI, and Pol283-289(TI8) TAFTIPSI. Mutations in all three dominant epitopes were significantly associated with HLA-B51 in the cohort. A clear hierarchy in selection of epitope mutations was observed through epitope sequencing. L743I in position 1 of epitope LI9 was seen in most B51+ individuals, followed by V289X in position 8 of the TI8, and then, A328S, in position 2 of the NI9 epitope, was also seen in some B51+ individuals. Good control of viral load and higher CD4+ counts were significantly associated with at least one detectable T cell response to unmutated epitopes, whereas lower CD4+ counts and higher viral loads were observed in patients who had developed escape mutations in all three epitopes or who lacked T cell responses specific to these epitope(s). We propose that patients with HLA-B51 benefit from having multiple layers of effective defense against the development of immune escape mutations. Copyright © 2011 by The American Association of Immunologists, Inc.

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Dong T, Zhang Y, Xu KY, Yan H, James I, Peng Y, Blais M-E, Gaudieri S, Chen X, Lun W et al. 2011. Extensive HLA-driven viral diversity following a narrow-source HIV-1 outbreak in rural China BLOOD, 118 (1), pp. 98-106. | Show Abstract | Read more

Obstacles to developing an HIV-1 vaccine include extensive viral diversity and lack of correlates of protective immunity. High mutation rates allow HIV-1 to adapt rapidly to selective forces such as antiretroviral therapy and immune pressure, including HIV-1-specific CTLs that select viral variants which escape T-cell recognition. Multiple factors contribute to HIV-1 diversity, making it difficult to disen-tangle the contribution of CTL selection without using complex analytical approaches. We describe an HIV-1 outbreak in 231 former plasma donors in China, where a narrow-source virus that had contaminated the donation system was apparently transmitted to many persons contemporaneously. The genetic divergence now evident in these subjects should uniquely reveal how much viral diversity at the population level is solely attributable to host factors. We found significant correlations between pair-wise divergence of viral sequences and HLA class I genotypes across epitope-length windows in HIV-1 Gag, reverse transcriptase, integrase, and Nef, corresponding to sites of 140 HLA class I allele-associated viral polymorphisms. Of all polymorphic sites across these 4 proteins, 24%-56% were sites of HLA-associated selection. These data confirm that CTL pressure has a major effect on inter-host HIV-1 viral diversity and probably represents a key element of viral control. © 2011 by The American Society of Hematology.

Ota MO, Odutola AA, Owiafe PK, Donkor S, Owolabi OA, Brittain NJ, Williams N, Rowland-Jones S, Hill AV, Adegbola RA, McShane H. 2011. Immunogenicity of the tuberculosis vaccine MVA85A is reduced by coadministration with EPI vaccines in a randomized controlled trial in Gambian infants. Sci Transl Med, 3 (88), pp. 88ra56. | Show Abstract | Read more

New tuberculosis vaccines are urgently needed to curtail the current epidemic. MVA85A is a subunit vaccine that could enhance immunity from BCG vaccination. To determine MVA85A safety and immunogenicity as well as interactions with other routine vaccines administered in infancy, we randomized healthy 4-month-old infants who had received Bacille Calmette-Guérin at birth to receive Expanded Program on Immunization (EPI) vaccines alone, EPI and MVA85A simultaneously, or MVA85A alone. Adverse events were monitored throughout. Blood samples obtained before vaccination and at 1, 4, and 20 weeks after vaccination were used to assess safety and immunogenicity. The safety profile of both low and standard doses was comparable, but the standard dose was more immunogenic and therefore was selected for the second stage of the study. In total, 72 (first stage) and 142 (second stage) infants were enrolled. MVA85A was safe and well tolerated and induced a potent cellular immune response. Coadministration of MVA85A with EPI vaccines was associated with a significant reduction in MVA85A immunogenicity, but did not affect humoral responses to the EPI vaccines. These results provide important information regarding timing of immunizations, which is required for the design of infant efficacy trials with MVA85A, and suggest that modifications to the standard EPI schedule may be required to incorporate a new generation of T cell-inducing vaccines.

Ranasinghe SRF, Kramer HB, Wright C, Kessler BM, di Gleria K, Zhang Y, Gillespie GM, Blais M-E, Culshaw A, Pichulik T et al. 2011. The Antiviral Efficacy of HIV-Specific CD8(+) T-Cells to a Conserved Epitope Is Heavily Dependent on the Infecting HIV-1 Isolate PLOS PATHOGENS, 7 (5), | Show Abstract | Read more

A major challenge to developing a successful HIV vaccine is the vast diversity of viral sequences, yet it is generally assumed that an epitope conserved between different strains will be recognised by responding T-cells. We examined whether an invariant HLA-B8 restricted Nef90-97 epitope FL8 shared between five high titre viruses and eight recombinant vaccinia viruses expressing Nef from different viral isolates (clades A-H) could activate antiviral activity in FL8-specific cytotoxic T-lymphocytes (CTL). Surprisingly, despite epitope conservation, we found that CTL antiviral efficacy is dependent on the infecting viral isolate. Only 23% of Nef proteins, expressed by HIV-1 isolates or as recombinant vaccinia-Nef, were optimally recognised by CTL. Recognition of the HIV-1 isolates by CTL was independent of clade-grouping but correlated with virus-specific polymorphisms in the epitope flanking region, which altered immunoproteasomal cleavage resulting in enhanced or impaired epitope generation. The finding that the majority of virus isolates failed to present this conserved epitope highlights the importance of viral variance in CTL epitope flanking regions on the efficiency of antigen processing, which has been considerably underestimated previously. This has important implications for future vaccine design strategies since efficient presentation of conserved viral epitopes is necessary to promote enhanced anti-viral immune responses. © 2011 Ranasinghe et al.

Blais ME, Dong T, Rowland-Jones S. 2011. HLA-C as a mediator of natural killer and T-cell activation: spectator or key player? Immunology, 133 (1), pp. 1-7. | Show Abstract | Read more

The biochemical properties of the HLA-C antigen differ substantially from those of HLA-A and -B molecules. For this reason, HLA-C diversity and expression at the cell surface are much lower than its counterparts and in consequence HLA-C-restricted responses have been infrequently detected and described. In this review we summarise the key differences between HLA-C and other class I molecules and provide an update on natural killer and T-cell responses restricted by HLA-C. We also discuss the different clinical settings associated with HLA-C alleles which mainly consist of autoimmune disorders, cancers and chronic infections.

Hodges-Mameletzis I, De Bree GJ, Rowland-Jones SL. 2011. An underestimated lentivirus model: what can HIV-2 research contribute to the development of an effective HIV-1 vaccine? Expert Rev Anti Infect Ther, 9 (2), pp. 195-206. | Show Abstract | Read more

The development of an HIV-1 vaccine that would be effective against all existing subtypes and circulating recombinant forms remains one of the great scientific and public health challenges of our generation. One of the major barriers to HIV-1 vaccine development is a lack of understanding of the correlates of protective immunity against the virus. In this context, research has focused on the rare phenomenon of spontaneous control of HIV-1 infection, in groups referred to as 'long-term nonprogressors' and 'elite controllers', together with models of nonprogressive sooty mangabey simian immunodeficiency (SIV) infection in African nonhuman primate hosts such as sooty mangabeys and African green monkeys, in which the majority of animals tolerate high levels of viral replication without development of immunodeficiency or disease. Much less attention has been given to humans infected with the nonpandemic strain HIV-2, derived from the SIV in West Africa, most of whom behave as long-term nonprogressors or viral controllers, while a minority develop disease clinically indistinguishable from AIDS caused by HIV-1. This apparent dichotomous outcome is, based on the evidence accumulated to date, more clearly related to the host immune response than the good clinical outcome of HIV-1 controllers. We propose that complementing research into HIV-1 controllers and nonpathogenic SIV models with the prioritization of HIV-2 research could enhance the HIV-1 vaccine research effort. The absence of disease progression or detectable plasma viral replication in the presence of an effective immune response in most patients living with HIV-2 represents an opportunity to unravel the virus' evolutionary adaptation in human hosts and to establish the correlates of such a protective response.

van Tienen C, Schim van der Loeff M, Peterson I, Cotten M, Andersson S, Holmgren B, Vincent T, de Silva T, Rowland-Jones S, Aaby P, Whittle H. 2011. HTLV-1 and HIV-2 infection are associated with increased mortality in a rural West African community. PLoS One, 6 (12), pp. e29026. | Show Abstract | Read more

BACKGROUND: Survival of people with HIV-2 and HTLV-1 infection is better than that of HIV-1 infected people, but long-term follow-up data are rare. We compared mortality rates of HIV-1, HIV-2, and HTLV-1 infected subjects with those of retrovirus-uninfected people in a rural community in Guinea-Bissau. METHODS: In 1990, 1997 and 2007, adult residents (aged ≥15 years) were interviewed, a blood sample was drawn and retroviral status was determined. An annual census was used to ascertain the vital status of all subjects. Cox regression analysis was used to estimate mortality hazard ratios (HR), comparing retrovirus-infected versus uninfected people. RESULTS: A total of 5376 subjects were included; 197 with HIV-1, 424 with HIV-2 and 325 with HTLV-1 infection. The median follow-up time was 10.9 years (range 0.0-20.3). The crude mortality rates were 9.6 per 100 person-years of observation (95% confidence interval 7.1-12.9) for HIV-1, 4.1 (3.4-5.0) for HIV-2, 3.6 (2.9-4.6) for HTLV-1, and 1.6 (1.5-1.8) for retrovirus-negative subjects. The HR comparing the mortality rate of infected to that of uninfected subjects varied significantly with age. The adjusted HR for HIV-1 infection varied from 4.0 in the oldest age group (≥60 years) to 12.7 in the youngest (15-29 years). The HR for HIV-2 infection varied from 1.2 (oldest) to 9.1 (youngest), and for HTLV-1 infection from 1.2 (oldest) to 3.8 (youngest). CONCLUSIONS: HTLV-1 infection is associated with significantly increased mortality. The mortality rate of HIV-2 infection, although lower than that of HIV-1 infection, is also increased, especially among young people.

Buranapraditkun S, Hempel U, Pitakpolrat P, Allgaier RL, Thantivorasit P, Lorenzen SI, Sirivichayakul S, Hildebrand WH, Altfeld M, Brander C et al. 2011. A novel immunodominant CD8+ T cell response restricted by a common HLA-C allele targets a conserved region of Gag HIV-1 clade CRF01_AE infected Thais. PLoS One, 6 (8), pp. e23603. | Show Abstract | Read more

BACKGROUND: CD8+ T cell responses play an important role in the control of HIV-1. The extensive sequence diversity of HIV-1 represents a critical hurdle to developing an effective HIV-1 vaccine, and it is likely that regional-specific vaccine strains will be required to overcome the diversity of the different HIV-1 clades distributed world-wide. Unfortunately, little is known about the CD8+ T cell responses against CRF01_AE, which is responsible for the majority of infections in Southeast Asia. METHODOLOGY/PRINCIPAL FINDINGS: To identify dominant CD8+ T cell responses recognized in HIV-1 clade CRF01_AE infected subjects we drew upon data from an immunological screen of 100 HIV-1 clade CRF01_AE infected subjects using IFN-gamma ELISpot to characterize a novel immunodominant CD8+ T cell response in HIV-1 Gag restricted by HLA-Cw*0102 (p24, (277)YSPVSILDI(285), YI9). Over 75% of Cw*0102+ve subjects targeted this epitope, representing the strongest response in more than a third of these individuals. This novel CD8 epitope was located in a highly conserved region of HIV-1 Gag known to contain immunodominant CD8 epitopes, which are restricted by HLA-B*57 and -B*27 in clade B infection. Nonetheless, viral escape in this epitope was frequently observed in Cw*0102+ve subjects, suggestive of strong selection pressure being exerted by this common CD8+ T cell response. CONCLUSIONS/SIGNIFICANCE: As HLA-Cw*0102 is frequently expressed in the Thai population (allelic frequency of 16.8%), this immunodominant Cw*0102-restricted Gag epitope may represent an attractive candidate for vaccines specific to CRF01_AE and may help facilitate further studies of immunopathogenesis in this understudied HIV-1 clade.

Peterson K, Jallow S, Rowland-Jones SL, de Silva TI. 2011. Antiretroviral Therapy for HIV-2 Infection: Recommendations for Management in Low-Resource Settings. AIDS Res Treat, 2011 pp. 463704. | Show Abstract | Read more

HIV-2 contributes approximately a third to the prevalence of HIV in West Africa and is present in significant amounts in several low-income countries outside of West Africa with historical ties to Portugal. It complicates HIV diagnosis, requiring more expensive and technically demanding testing algorithms. Natural polymorphisms and patterns in the development of resistance to antiretrovirals are reviewed, along with their implications for antiretroviral therapy. Nonnucleoside reverse transcriptase inhibitors, crucial in standard first-line regimens for HIV-1 in many low-income settings, have no effect on HIV-2. Nucleoside analogues alone are not sufficiently potent enough to achieve durable virologic control. Some protease inhibitors, in particular those without ritonavir boosting, are not sufficiently effective against HIV-2. Following review of the available evidence and taking the structure and challenges of antiretroviral care in West Africa into consideration, the authors make recommendations and highlight the needs of special populations.

Peterson I, Togun O, De Silva T, Oko F, Rowland-Jones S, Jaye A, Peterson K. 2011. Mortality and immunovirological outcomes on antiretroviral therapy in HIV-1 and HIV-2-infected individuals in the Gambia AIDS, 25 (17), pp. 2167-2175. | Show Abstract | Read more

OBJECTIVES:: This study's objective was to assess outcomes in HIV-1 and HIV-2 infected antiretroviral therapy (ART)-naïve patients starting ART in the Gambia, West Africa. DESIGN:: A cohort design was used to estimate survival in ART patients and determine whether survival and time to virologic failure varied across patient subgroups. METHODS:: Mortality, virologic failures and CD4 cell recovery were assessed in a clinical cohort of patients from the Genito-Urinary Medicine (GUM) clinic of the MRC Laboratories in the Gambia. Kaplan-Meier estimates of survival were determined for mortality and virologic failure. A Cox proportional hazards model was used to identify baseline demographic, clinical, immunologic and virologic factors associated with increased risk of death. RESULTS:: The overall Kaplan-Meier estimate of survival to 36 months was 73.4% (66.5, 80.3). Survival was marginally higher in HIV-2-infected patients compared to HIV-1-infected patients; it was significantly higher in patients with a baseline CD4 lymphocyte cell count of greater than 50 cells/μl compared to those with a baseline CD4 count of less than 50 cells/μl. CD4 cell recovery was faster in HIV-1-infected individuals compared to HIV-2-infected patients up to 24 months, although this did not result higher mortality in the latter group. No differences in virologic failure were observed by HIV type. CONCLUSION:: HIV-1 and HIV-2-infected patients receiving ART in a clinical setting in the Gambia had good survival to 36 months. HIV-2-infected patients did as well as HIV-1-infected patients in terms of long-term immunological and virological responses and overall survival. © 2011 Wolters Kluwer Health Lippincott Williams & Wilkins.

Slyker JA, John-Stewart GC, Dong T, Lohman-Payne B, Reilly M, Atzberger A, Taylor S, Maleche-Obimbo E, Mbori-Ngacha D, Rowland-Jones SL. 2011. Phenotypic characterization of HIV-specific CD8+ T cells during early and chronic infant HIV-1 infection. PLoS One, 6 (5), pp. e20375. | Show Abstract | Read more

Although CD8(+) T cells play an important role in the containment of adult HIV-1 replication, their role in infant HIV-1 infection is not as well understood. Impaired HIV-specific CD8(+) T cell responses may underlie the persistently high viral loads observed in infants. We examined the frequency and phenotype of infant HIV-specific CD8(+) T cells in 7 HIV-infected antiretroviral therapy-naïve infants during the first 2 years of life, using class I HLA tetramers and IFN-γ-ELISPOT. The frequency (0.088-3.9% of CD3(+)CD8(+) cells) and phenotype (CD27(+)CD28(-), CD45RA(+/-), CD57(+/-), HLA-DR(+), CD95(+)) of infant HIV-specific CD8(+) T cells were similar to reports in adults undergoing early infection. Unlike adults, at 23-24 months post-infection a high frequency of HIV-specific CD8(+) T cells expressed HLA-DR (mean 80%, range 68-85%) and CD95 (mean 88%, range 79-96%), suggesting sustained activation and vulnerability to apoptosis. Despite comparable expansion of HIV-specific CD8(+) T cells of a similar phenotype to adults during early infection, infant T cells failed to contain HIV-1 replication, and remained persistently activated and vulnerable to apoptosis during chronic infection.

Lohman-Payne B, Slyker J, Rowland-Jones SL. 2010. Immune-based approaches to the prevention of mother-to-child transmission of HIV-1: active and passive immunization. Clin Perinatol, 37 (4), pp. 787-ix. | Show Abstract | Read more

Despite more than 2 decades of research, an effective vaccine that can prevent HIV-1 infection in populations exposed to the virus remains elusive. In the pursuit of an HIV-1 vaccine, does prevention of exposure to maternal HIV-1 in utero, at birth or in early life through breast milk require special consideration? This article reviews what is known about the immune mechanisms of susceptibility and resistance to mother-to-child transmission (MTCT) of HIV-1 and summarizes studies that have used passive or active immunization strategies to interrupt MTCT of HIV-1. Potentially modifiable infectious cofactors that may enhance transmission and/or disease progression (especially in the developing world) are described. An effective prophylactic vaccine against HIV-1 infection needs to be deployed as part of the Extended Program of Immunization recommended by the World Health Organization for use in developing countries, so it is important to understand how the infant immune system responds to HIV-1 antigens, both in natural infection and presented by candidate vaccines.

de Silva TI, Turner R, Hué S, Trikha R, van Tienen C, Onyango C, Jaye A, Foley B, Whittle H, Rowland-Jones SL, Cotten M. 2010. HIV-1 subtype distribution in the Gambia and the significant presence of CRF49_cpx, a novel circulating recombinant form. Retrovirology, 7 (1), pp. 82. | Show Abstract | Read more

BACKGROUND: Detailed local HIV-1 sequence data are essential for monitoring the HIV epidemic, for maintaining sensitive sequence-based diagnostics, and to aid in designing vaccines. RESULTS: Reported here are full envelope sequences derived from 38 randomly selected HIV-1 infections identified at a Gambian clinic between 1991 and 2009. Special care was taken to generate sequences from circulating viral RNA as uncloned products, either by limiting dilution or single genome amplification polymerase chain reaction (PCR). Within these 38 isolates, eight were subtyped as A and 18 as CRF02_AG. A small number of subtype B, C, D viruses were identified. Surprising, however, was the identification of six isolates with subtype J-like envelopes, a subtype found normally in Central Africa and the Democratic Republic of the Congo (DRC), with gag p24 regions that clustered with subtype A sequences. Near full-length sequence from three of these isolates confirmed that these represent a novel circulating recombinant form of HIV-1, now named CRF49_cpx. CONCLUSIONS: This study expands the HIV-1 sequence database from the Gambia and will provide important data for HIV diagnostics, patient care, and vaccine development.

Burl S, Adetifa UJ, Cox M, Touray E, Ota MO, Marchant A, Whittle H, McShane H, Rowland-Jones SL, Flanagan KL. 2010. Delaying bacillus Calmette-Guérin vaccination from birth to 4 1/2 months of age reduces postvaccination Th1 and IL-17 responses but leads to comparable mycobacterial responses at 9 months of age. J Immunol, 185 (4), pp. 2620-2628. | Show Abstract | Read more

Bacillus Camette-Guérin (BCG) vaccine is the only licensed vaccine against tuberculosis, yet its protective efficacy is highly variable between different geographical regions. We hypothesized that exposure to nontuberculous mycobacteria attenuates BCG immunogenicity by inducing mycobacterial-specific regulatory T cells (Tregs). Gambian neonates were recruited at birth and randomized to receive BCG vaccination either at birth or at 4 1/2 mo. Mycobacterial immune responses were assessed at birth, 4 1/2, and 9 mo of age. At 4 1/2 mo of age the BCG naive individuals had detectable mycobacterial responses, including increased IL-10 production suggesting environmental priming. Vaccination at birth significantly enhanced Th1, Th2, IL-6, IL-17, and Treg responses in mycobacterial cultures at 4 1/2 mo compared with the BCG naive group. Analyzing results at 4 1/2 mo postvaccination revealed lower IFN-gamma, IL-6, and IL-17 responses in the delayed BCG vaccine group compared with those vaccinated at birth, but this did not relate to Treg levels prevaccination. When comparing responses pre- and post-BCG vaccination in the delayed vaccine group, there was no priming of mycobacterial IL-17. Mycobacterial responses waned over 9 mo in those vaccinated at birth, leading to comparable mycobacterial immunity in both groups at 9 mo of age. Overall, these data suggest that vaccination at birth induces a broad Th1/Th2/IL-17/Treg mycobacterial response but the Th1/Th-17 response was reduced when delaying the vaccine. The evidence did not suggest that mycobacterial specific naturally occurring Tregs accounted for this attenuated immunogenicity.

Leligdowicz A, Onyango C, Yindom LM, Peng Y, Cotten M, Jaye A, McMichael A, Whittle H, Dong T, Rowland-Jones S. 2010. Highly avid, oligoclonal, early-differentiated antigen-specific CD8+ T cells in chronic HIV-2 infection. Eur J Immunol, 40 (7), pp. 1963-1972. | Show Abstract | Read more

HIV-1-specific CD8(+) T cells are present in most HIV-1-infected people and play an important role in controlling viral replication, but the characteristics of an effective HIV-specific T-cell response are largely unknown. The majority of HIV-2-infected people behave as long-term non-progressors while those who progress to AIDS do so in a manner indistinguishable from HIV-1. A detailed study of HIV-2 infection may identify protective immune responses. Robust gag p26-specific T-cell responses are elicited during HIV-2 infection and correlate with control of viremia. In this study, we analyzed features of an HLA-B 3501-restricted T-cell response to HIV-2 p26 that may contribute to virus control. In contrast to HIV-1, HIV-2-specific T cells are at an early stage of differentiation (CD27(+)CD28(+)), a finding that relates directly to CD4(+) T-cell levels and inversely to immune activation. The cells demonstrate IFN-gamma secretion, oligoclonal T-cell receptor Vbeta gene segment usage, exceptional avidity and secretion of pro-inflammatory cytokines. Despite the potentially strong selection pressure imposed on the virus by these cells, there was no evidence of HIV-2 sequence evolution. We propose that in chronic HIV-2 infection, the maintenance of early-differentiated, highly avid CD8(+) T cells could account for the non-progressive course of disease. Such responses may be desirable from an HIV vaccine.

Kaul R, MacDonald KS, Nagelkerke NJ, Kimani J, Fowke K, Ball TB, Luo M, Kariri A, Jaoko W, Moses S et al. 2010. HIV viral set point and host immune control in individuals with HIV-specific CD8+ T-cell responses prior to HIV acquisition. AIDS, 24 (10), pp. 1449-1454. | Show Abstract | Read more

OBJECTIVE: Vaccine-induced CD8(+) T-cell responses in primates have been associated with a reduced simian immunodeficiency virus plasma viral load and enhanced T-cell responses, but cellular vaccines have shown limited success in human trials. We previously described HIV-specific T-cell responses in two groups of highly exposed, persistently seronegative Kenyan female sex workers, and a subset of these participants have subsequently acquired HIV. We examined the impact of pre-existing CD8(+) T-cell responses on post-acquisition outcomes. DESIGN AND METHODS: HIV-specific CD8(+) T-cell responses had been examined in highly exposed, persistently seronegative participants from the Pumwani and Kibera cohorts, using a combination of virus-specific lysis, proliferation, interferon-gamma production, or all. Plasma viral load set point and HIV-specific T-cell proliferation and cytokine production were now examined post hoc by blinded investigators in the subset of participants who acquired HIV. RESULTS: Pre-acquisition cellular immune assays and post-infection viral load were available for 46 participants, and HIV-specific CD8(+) T-cell responses had been detected in 25 of 46 (54%) participants. Pre-acquisition CD8(+) T-cell responses were associated with a lower post-acquisition HIV viral load set point in both cohorts (pooled analysis, 3.1 vs. 4.1 log(10) RNA copies/ml; P=0.0002) and with enhanced post-acquisition HIV-specific CD8(+) T-cell proliferation (3.8 vs. 1.0%, P=0.03), but with a trend to reduced post-acquisition CD8(+) T-cell interferon-gamma responses. CONCLUSION: HIV-specific CD8(+) T-cell responses prior to HIV acquisition were associated with a lower HIV viral load and an altered functional profile of post-acquisition CD8(+) T-cell responses.

Yindom LM, Leligdowicz A, Martin MP, Gao X, Qi Y, Zaman SM, van der Loeff MS, van Tienen C, Jaye A, Aveika A et al. 2010. Influence of HLA class I and HLA-KIR compound genotypes on HIV-2 infection and markers of disease progression in a Manjako community in West Africa. J Virol, 84 (16), pp. 8202-8208. | Show Abstract | Read more

Overall, the time to AIDS after HIV-2 infection is longer than with HIV-1, and many individuals infected with HIV-2 virus remain healthy throughout their lives. Multiple HLA and KIR gene products have been implicated in the control of HIV-1, but the effect of variation at these loci on HIV-2 disease is unknown. We show here for the first time that HLA-B*1503 is associated significantly with poor prognosis after HIV-2 infection and that HLA-B*0801 is associated with susceptibility to infection. Interestingly, previous data indicate that HLA-B*1503 is associated with low viral loads in HIV-1 clade B infection but has no significant effect on viral load in clade C infection. In general, alleles strongly associated with HIV-1 disease showed no effect in HIV-2 disease. These data emphasize the unique nature of the effects of HLA and HLA/KIR combinations on HIV-2 immune responses relative to HIV-1, which could be related to their distinct clinical course.

Onyango CO, Leligdowicz A, Yokoyama M, Sato H, Song H, Nakayama EE, Shioda T, de Silva T, Townend J, Jaye A et al. 2010. HIV-2 capsids distinguish high and low virus load patients in a West African community cohort. Vaccine, 28 Suppl 2 (SUPPL. 2), pp. B60-B67. | Show Abstract | Read more

HIV-2 causes AIDS similar to HIV-1, however a considerable proportion of HIV-2 infected patients show no disease and have low plasma virus load (VL). An analysis of HIV-2 capsid (p26) variation demonstrated that proline at p26 positions 119, 159 and 178 are more frequent in lower VL subjects while non-proline residues at all three sites are more frequent in subjects with high VL. In vitro replication levels of viruses bearing changes at the three sites suggested that these three residues influence virus replication by altering susceptibility to TRIM5alpha. These results provide new insights into HIV-2 pathogenesis.

Dung NT, Duyen HT, Thuy NT, Ngoc TV, Chau NV, Hien TT, Rowland-Jones SL, Dong T, Farrar J, Wills B, Simmons CP. 2010. Timing of CD8+ T cell responses in relation to commencement of capillary leakage in children with dengue. J Immunol, 184 (12), pp. 7281-7287. | Show Abstract | Read more

Immune activation is a feature of dengue hemorrhagic fever (DHF) and CD8+ T cell responses in particular have been suggested as having a role in the vasculopathy that characterizes this disease. By phenotyping CD8+ T cells (CD38+/HLA-DR+, CD38+/Ki-67+, or HLA-DR+/Ki-67+) in serial blood samples from children with dengue, we found no evidence of increased CD8+ T cell activation prior to the commencement of resolution of viremia or hemoconcentration. Investigations with MHC class I tetramers to detect NS3(133-142)-specific CD8+ T cells in two independent cohorts of children suggested the commencement of hemoconcentration and thrombocytopenia in DHF patients generally begins before the appearance of measurable frequencies of NS3(133-142)-specific CD8+ T cells. The temporal mismatch between the appearance of measurable surface activated or NS3(133-142)-specific CD8+ T cells suggests that these cells are sequestered at sites of infection, have phenotypes not detected by our approach, or that other mechanisms independent of CD8+ T cells are responsible for early triggering of capillary leakage in children with DHF.

Sutherland JS, Young JM, Peterson KL, Sanneh B, Whittle HC, Rowland-Jones SL, Adegbola RA, Jaye A, Ota MO. 2010. Polyfunctional CD4(+) and CD8(+) T cell responses to tuberculosis antigens in HIV-1-infected patients before and after anti-retroviral treatment. J Immunol, 184 (11), pp. 6537-6544. | Show Abstract | Read more

Tuberculosis (TB) kills 2 million people per year and infection with HIV is the most potent known risk factor for progression to active TB. An understanding of the immune response to TB Ags in HIV-infected patients is required to develop optimal TB vaccines and diagnostics. We assessed polyfunctional (IFN-gamma(+)IL-2(+)TNF-alpha(+)) T cell responses to TB Ags in three groups of HIV-1-infected patients dependent on their TB status, CD4 counts, and anti-retroviral exposure. We found that although the proportion of IFN-gamma cells in response to TB Ags was higher in patients with low CD4 counts, the responding cells changed from a polyfunctional CD4(+) to a monofunctional CD8(+) response. The overall polyfunctionality of the cells was restored by 12 mo of anti-retroviral therapy and primarily involved CD4(+) T cells with an effector memory phenotype. These findings have major implications for diagnosis of TB and in vaccine development strategies for TB in HIV-1-infected patients.

Flanagan KL, Halliday A, Burl S, Landgraf K, Jagne YJ, Noho-Konteh F, Townend J, Miles DJ, van der Sande M, Whittle H, Rowland-Jones S. 2010. The effect of placental malaria infection on cord blood and maternal immunoregulatory responses at birth. Eur J Immunol, 40 (4), pp. 1062-1072. | Show Abstract | Read more

Placental malaria (PM), a frequent infection of pregnancy, provides an ideal opportunity to investigate the impact on immune development of exposure of the foetal immune system to foreign Ag. We investigated the effect of PM on the regulatory phenotype and function of cord blood cells from healthy Gambian newborns and peripheral blood cells from their mothers, and analyzed for effects on the balance between regulatory and effector responses. Using the gold standard for classifying PM we further distinguished between resolved infection and acute or chronic PM active at the time of delivery. We show that exposure to malarial Ag in utero results in the expansion of malaria-specific FOXP3(+) Treg and more generalized FOXP3(+) CD4(+) Treg in chronic and resolved PM, alongside increased Th1 pro-inflammatory responses (IFN-gamma, TNF-alpha, IFN-gamma:IL-10) in resolved PM infection only. These observations demonstrate a clear effect of exposure to malarial Ag in foetal life on the immune environment at birth, with a regulatory response dominating in the newborns with ongoing chronic PM, while those with resolved infection produce both regulatory and inflammatory responses. The findings might explain some of the adverse effects on the health of babies born to women with PM.

Tienen CV, van der Loeff MS, Zaman SM, Vincent T, Sarge-Njie R, Peterson I, Leligdowicz A, Jaye A, Rowland-Jones S, Aaby P, Whittle H. 2010. Two distinct epidemics: the rise of HIV-1 and decline of HIV-2 infection between 1990 and 2007 in rural Guinea-Bissau. J Acquir Immune Defic Syndr, 53 (5), pp. 640-647. | Show Abstract | Read more

OBJECTIVES: To assess changes in HIV incidence and prevalence in Caió, a rural area of Guinea-Bissau, between 1990 and 2007. DESIGN: Three cross-sectional community surveys. METHODS: In 1990, 1997, and 2007, surveys were conducted among adults. The prevalence of HIV-1 and of HIV-2 was estimated for each survey, and incidence rates were calculated for the first (1990-1997) and second period (1997-2007). RESULTS: The HIV-1 incidence was approximately 4.5/1000 person-years in the two periods, whereas the HIV-2 incidence decreased from 4.7 (95% confidence interval 3.6-6.2) in the first to 2.0 (95% confidence interval 1.4-3.0) per 1000 person-years in the second period (P < 0.001). HIV-1 prevalence rose from 0.5% in 1990 to 3.6% in 2007, and HIV-2 prevalence decreased from 8.3% in 1990 to 4.7% in 2007. HIV-1 prevalence was less than 2% in 15 to 24 year olds in all surveys and was highest (7.2%) in 2007 among 45 to 54 year olds. The HIV-2 prevalence was fivefold higher in older subjects (> or =45 yr) compared with those less than 45 years in both sexes in 2007. CONCLUSIONS: HIV-1 incidence is stable, and its prevalence is increasing, whereas HIV-2 incidence and prevalence are both declining. In contrast with what has been observed in other sub-Saharan countries, HIV-1 prevalence is lower in younger age groups than older age groups.

Mendy ME, Welzel T, Lesi OA, Hainaut P, Hall AJ, Kuniholm MH, McConkey S, Goedert JJ, Kaye S, Rowland-Jones S et al. 2010. Hepatitis B viral load and risk for liver cirrhosis and hepatocellular carcinoma in The Gambia, West Africa. J Viral Hepat, 17 (2), pp. 115-122. | Show Abstract | Read more

The main objectives of this study were to define the occurrence and levels of hepatitis B virus (HBV) DNA in asymptomatic HBV carriers, cirrhosis patients and hepatocellular carcinoma (HCC) cases from The Gambia, and to evaluate the risk for cirrhosis or HCC associated with HBV viremia. We used sensitive real-time quantitative PCR assays to measure HBV DNA in samples from a case-control study consisting of 60 asymptomatic HBV carriers, 53 cirrhotic patients and 129 HCC cases. Logistic regression was used to estimate the risks of cirrhosis and HCC associated with HBV-DNA levels and HBV e antigenemia (HBeAg) detection (a surrogate marker for viral replication). Detectable HBV viremia and HBeAg positivity were both significantly associated with cirrhosis (increasing risk by fourfold and 11-fold respectively) and with HCC (increasing risk by sixfold and threefold respectively). HBV-DNA levels were significantly higher in both HCC cases and cirrhotic patients compared to asymptomatic carriers (P < 0.01 for both). High-level HBV DNA (>10,000 copies/mL) was strongly associated with both HCC and cirrhosis (17- and 39-fold increased risk). Lower level HBV viremia (200-10,000 copies/mL) conferred a significant risk of HCC, although the association with cirrhosis was not significant. In conclusion, we find that high HBV-DNA levels are strongly associated with the serious sequelae of HBV infection, independent of HBeAg status. While risk for cirrhosis and for HCC notably increases at HBV-DNA levels >or=10,000 copies/mL, low-level viremia was also associated with significant risk for HCC.

Makadzange AT, Gillespie G, Dong T, Kiama P, Bwayo J, Kimani J, Plummer F, Easterbrook P, Rowland-Jones SL. 2010. Characterization of an HLA-C-restricted CTL response in chronic HIV infection. Eur J Immunol, 40 (4), pp. 1036-1041. | Show Abstract | Read more

HIV-specific CTL play an important role in the host control of HIV infection. HIV-nef may facilitate escape of HIV-infected cells from CTL recognition by selectively downregulating the expression of HLA-A and HLA-B molecules, while surface expression of HLA-C is unaffected. The HLA-C-restricted CTL responses have previously been largely ignored and poorly characterized. We examined the frequency, function, and phenotype of HLA-C-restricted CTL in ten antiretroviral therapy-naïve Caucasian and African individuals with chronic HIV-1 infection (for at least 8 years; CD4 cell counts in the range of 50-350) who carried the HLA-Cw04 allele. HLA-Cw04-restricted CTL that recognize a conserved epitope within HIV-1 envelope (aa 375-383 SF9) were analyzed using IFN-gamma ELISPOT assays and phenotypic analysis was carried out by flow cytometry. HLA-C-restricted CTL play an important role in the HIV-specific response, and can account for as much as 54% of the total response. HLA-C-restricted CTL are functionally and phenotypically identical to HLA-A- and HLA-B-restricted CTL. HLA-C-restricted CTL in chronic HIV infection are memory cells of an intermediate phenotype, characterized by high CD27 and low CD28 expression and lack of perforin production.

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Leligdowicz A, Feldmann J, Jaye A, Cotten M, Dong T, McMichael A, Whittle H, Rowland-Jones S. 2010. Direct relationship between virus load and systemic immune activation in HIV-2 infection Journal of Infectious Diseases, 201 (1), pp. 114-122. | Show Abstract | Read more

Immune activation is a hallmark of disease progression in human immunodeficiency virus (HIV) type 1 (HIV1) and HIV type 2 (HIV-2) infection. However, the relationship between viremia and systemic immune activation is unclear. We assessed the relationship between HIV-2 plasma virus load and immune system activation in a cross-sectional study in a community cohort of HIV-1-positive, HIV-2-positive, and HIV-negative patients, in which many HIV-2-positive patients had nonprogressing infection. HLA-DR and CD38 expression on CD4+ and CD8+ T cells was measured, as were plasma β2-microglobulin levels. These markers were related to clinical (virus load and CD4+ cell count) and immunological (HIV-2-specific interferon γ secretion) correlates of delayed disease progression. A consistent positive correlation was identified between the level of HIV-2 viremia and immune activation. We propose that increasing virus load may contribute to systemic immune activation in HIV-2 infection. © 2009 by the Infectious Diseases Society of America. All rights reserved.

Holder B, Miles DJ, Kaye S, Crozier S, Mohammed NI, Duah NO, Roberts E, Ojuola O, Palmero MS, Touray ES et al. 2010. Epstein-Barr virus but not cytomegalovirus is associated with reduced vaccine antibody responses in Gambian infants. PLoS One, 5 (11), pp. e14013. | Show Abstract | Read more

BACKGROUND: Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are persistent herpesviruses that have various immunomodulatory effects on their hosts. Both viruses are usually acquired in infancy in Sub-Saharan Africa, a region where childhood vaccines are less effective than in high income settings. To establish whether there is an association between these two observations, we tested the hypothesis that infection with one or both viruses modulate antibody responses to the T-cell independent meningococcal polysaccharide vaccine and the T-cell dependent measles vaccines. METHODOLOGY/PRINCIPAL FINDINGS: Infection with EBV and CMV was diagnosed by the presence of virus-specific IgM in the peripheral blood or by the presence of IgG at higher levels than that found in umbilical cord blood. Anti-meningococcus IgG and IgM were quantified by ELISA. Anti-measles antibody responses were quantified by haemagglutinin antibody inhibition assay. Infants infected with EBV had reduced IgG and IgM antibody responses to meningococcal polysaccharides and to measles vaccine. Infection with CMV alone predicted no changes in the response to meningococcal polysaccharide. While CMV alone had no discernable effect on the antibody response to measles, the response of infants infected with both CMV and EBV was similar to that of infants infected with neither, suggesting that the effects of CMV infection countered the effects of EBV on measles antibody responses. CONCLUSIONS: The results of this exploratory study indicate that infection with EBV is associated with reduced antibody responses to polysaccharides and to measles vaccine, but suggest that the response to T-cell dependent antigens such as measles haemagglutinin may be restored by infection with CMV.

van Tienen C, van der Loeff MF, Peterson I, Cotten M, Holmgren B, Andersson S, Vincent T, Sarge-Njie R, Rowland-Jones S, Jaye A et al. 2010. HTLV-1 in rural Guinea-Bissau: prevalence, incidence and a continued association with HIV between 1990 and 2007. Retrovirology, 7 (1), pp. 50. | Show Abstract | Read more

BACKGROUND: HTLV-1 is endemic in Guinea-Bissau, and the highest prevalence in the adult population (5.2%) was observed in a rural area, Caió, in 1990. HIV-1 and HIV-2 are both prevalent in this area as well. Cross-sectional associations have been reported for HTLV-1 with HIV infection, but the trends in prevalence of HTLV-1 and HIV associations are largely unknown, especially in Sub Saharan Africa. In the current study, data from three cross-sectional community surveys performed in 1990, 1997 and 2007, were used to assess changes in HTLV-1 prevalence, incidence and its associations with HIV-1 and HIV-2 and potential risk factors. RESULTS: HTLV-1 prevalence was 5.2% in 1990, 5.9% in 1997 and 4.6% in 2007. Prevalence was higher among women than men in all 3 surveys and increased with age. The Odds Ratio (OR) of being infected with HTLV-1 was significantly higher for HIV positive subjects in all surveys after adjustment for potential confounding factors. The risk of HTLV-1 infection was higher in subjects with an HTLV-1 positive mother versus an uninfected mother (OR 4.6, CI 2.6-8.0). The HTLV-1 incidence was stable between 1990-1997 (Incidence Rate (IR) 1.8/1,000 pyo) and 1997-2007 (IR 1.6/1,000 pyo) (Incidence Rate Ratio (IRR) 0.9, CI 0.4-1.7). The incidence of HTLV-1 among HIV-positive individuals was higher compared to HIV negative individuals (IRR 2.5, CI 1.0-6.2), while the HIV incidence did not differ by HTLV-1 status (IRR 1.2, CI 0.5-2.7). CONCLUSIONS: To our knowledge, this is the largest community based study that has reported on HTLV-1 prevalence and associations with HIV. HTLV-1 is endemic in this rural community in West Africa with a stable incidence and a high prevalence. The prevalence increases with age and is higher in women than men. HTLV-1 infection is associated with HIV infection, and longitudinal data indicate HIV infection may be a risk factor for acquiring HTLV-1, but not vice versa. Mother to child transmission is likely to contribute to the epidemic.

Walther B, Miles DJ, Crozier S, Waight P, Palmero MS, Ojuola O, Touray E, Sande MVD, Whittle H, Rowland-Jones S, Flanagan KL. 2010. Placental Malaria is associated with reduced early life weight development of affected children independent of low birth weight Malaria Journal, 9 (1), | Show Abstract | Read more

Background: Infection with Plasmodium falciparum during pregnancy contributes substantially to the disease burden in both mothers and offspring. Placental malaria may lead to intrauterine growth restriction or preterm delivery resulting in low birth weight (LBW), which, in general, is associated with increased infant morbidity and mortality. However, little is known about the possible direct impact of the specific disease processes occurring in PM on longer term outcomes such as subsequent retarded growth development independent of LBW. Methods. In an existing West-African cohort, 783 healthy infants with a birth weight of at least 2,000 g were followed up during their first year of life. The aim of the study was to investigate if Plasmodium falciparum infection of the placenta, assessed by placental histology, has an impact on several anthropometric parameters, measured at birth and after three, six and 12 months using generalized estimating equations models adjusting for moderate low birth weight. Results. Independent of LBW, first to third born infants who were exposed to either past, chronic or acute placental malaria during pregnancy had significantly lower weight-for-age (-0.43, 95% CI: -0.80;-0.07), weight-for-length (-0.47, 95% CI: -0.84; -0.10) and BMI-for-age z-scores (-0.57, 95% CI: -0.84; -0.10) compared to infants born to mothers who were not diagnosed with placental malaria (p = 0.019, 0.013, and 0.012, respectively). Interestingly, the longitudinal data on histology-based diagnosis of PM also document a sharp decline of PM prevalence in the Sukuta cohort from 16.5% in 2002 to 5.4% in 2004. Conclusions. It was demonstrated that PM has a negative impact on the infant's subsequent weight development that is independent of LBW, suggesting that the longer term effects of PM have been underestimated, even in areas where malaria transmission is declining. © 2010 Walther et al; licensee BioMed Central Ltd.

Jobarteh M, Malfroy M, Peterson I, Jeng A, Sarge-Njie R, Alabi A, Peterson K, Cotten M, Hall A, Rowland-Jones S et al. 2010. Seroprevalence of hepatitis B and C virus in HIV-1 and HIV-2 infected Gambians. Virol J, 7 (1), pp. 230. | Show Abstract | Read more

BACKGROUND: The prevalence of HIV/hepatitis co-infection in sub-Saharan Africa is not well documented, while both HIV and HBV are endemic in this area. OBJECTIVE: The aim of this study is to determine the seroprevalence of HBV and HCV virus in HIV-infected subjects in the Gambia. METHODS: Plasma samples from HIV infected patients (190 individuals with clinically defined AIDS and 382 individuals without AIDS) were tested retrospectively for the presence of HBV sero-markers and for serum HBV DNA, screened for HCV infection by testing for anti-HCV antibody and HCV RNA. RESULTS: HBsAg prevalence in HIV-positive individuals is 12.2%. HIV/HBV co-infected individuals with CD4 count of <200 cells µL⁻¹ have a higher HBV DNA viral load than patients with higher CD4 count (log 4.0 vs. log 2.0 DNA copies/ml, p < 0.05). Males (OR = 1.8, 95% CI: 1.0, 3.2) were more likely to be HBsAg positive than female. HCV seroprevalence was 0.9% in HIV-positive individuals. CONCLUSION: The prevalence of HBsAg carriage in HIV- infected Gambians is similar to that obtained in the general population. However co-infected individuals with reduced CD4 levels, indicative of AIDS had higher prevalence of HBeAg retention and elevated HBV DNA levels compared to non-AIDS patients with higher CD4 count.

Burl S, Adetifa UJ, Cox M, Touray E, Whittle H, McShane H, Rowland-Jones SL, Flanagan KL. 2010. The tuberculin skin test (TST) is affected by recent BCG vaccination but not by exposure to non-tuberculosis mycobacteria (NTM) during early life. PLoS One, 5 (8), pp. e12287. | Show Abstract | Read more

The tuberculin skin test (TST) is widely used in TB clinics to aid Mycobacterium tuberculosis (M.tb) diagnosis, but the definition and the significance of a positive test in very young children is still unclear. This study compared the TST in Gambian children at 4(1/2) months of age who either received BCG vaccination at birth (Group 1) or were BCG naïve (Group 2) in order to examine the role of BCG vaccination and/or exposure to environmental mycobacteria in TST reactivity at this age. Nearly half of the BCG vaccinated children had a positive TST (>or=5 mm) whereas all the BCG naïve children were non-reactive, confirming that recent BCG vaccination affects TST reactivity. The BCG naïve children demonstrated in vitro PPD responses in peripheral blood in the absence of TST reactivity, supporting exposure to and priming by environmental mycobacterial antigens. Group 2 were then vaccinated at 4(1/2) months of age and a repeat TST was performed at 20-28 months of age. Positive reactivity (>or=5 mm) was evident in 11.1% and 12.5% infants from Group 1 and Group 2 respectively suggesting that the timing of BCG vaccination had little effect by this age. We further assessed for immune correlates in peripheral blood at 4(1/2) months of age. Mycobacterial specific IFNgamma responses were greater in TST responders than in non-responders, although the size of induration did not correlate with IFNgamma. However the IFNgamma: IL-10 ratio positively correlated with TST induration suggesting that the relationship between PPD induced IFNgamma and IL-10 in the peripheral blood may be important in controlling TST reactivity. Collectively these data provide further insights into how the TST is regulated in early life, and how a positive response might be interpreted.

Feldmann J, Leligdowicz A, Jaye A, Dong T, Whittle H, Rowland-Jones SL. 2009. Downregulation of the T-cell receptor by human immunodeficiency virus type 2 Nef does not protect against disease progression. J Virol, 83 (24), pp. 12968-12972. | Show Abstract | Read more

Chronic immune activation is thought to play a major role in human immunodeficiency virus (HIV) pathogenesis, but the relative contributions of multiple factors to immune activation are not known. One proposed mechanism to protect against immune activation is the ability of Nef proteins from some HIV and simian immunodeficiency virus strains to downregulate the T-cell receptor (TCR)-CD3 complex of the infected cell, thereby reducing the potential for deleterious activation. HIV type 1 (HIV-1) Nef has lost this property. In contrast to HIV-1, HIV-2 infection is characterized by a marked disparity in the disease course, with most individuals maintaining a normal life span. In this study, we examined the relationship between the ability of HIV-2 Nef proteins to downregulate the TCR and immune activation, comparing progressors and nonprogressors. Representative Nef variants were isolated from 28 HIV-2-infected individuals. We assessed their abilities to downregulate the TCR from the surfaces of CD4 T cells. In the same individuals, the activation of peripheral lymphocytes was evaluated by measurement of the expression levels of HLA-DR and CD38. We observed a striking correlation of the TCR downregulation efficiency of HIV-2 Nef variants with immune activation in individuals with a low viral load. This strongly suggests that Nef expression can influence the activation state of the immune systems of infected individuals. However, the efficiency of TCR downregulation by Nef was not reduced in progressing individuals, showing that TCR downregulation does not protect against progression in HIV-2 infection.

Webster DP, Farrar J, Rowland-Jones S. 2009. Progress towards a dengue vaccine. Lancet Infect Dis, 9 (11), pp. 678-687. | Show Abstract | Read more

The spread of dengue virus throughout the tropics represents a major, rapidly growing public health problem with an estimated 2.5 billion people at risk of dengue fever and the life-threatening disease, severe dengue. A safe and effective vaccine for dengue is urgently needed. The pathogenesis of severe dengue results from a complex interaction between the virus, the host, and, at least in part, immune-mediated mechanisms. Vaccine development has been slowed by fears that immunisation might predispose individuals to the severe form of dengue infection. A pipeline of candidate vaccines now exists, including live attenuated, inactivated, chimeric, DNA, and viral-vector vaccines, some of which are at the stage of clinical testing. In this Review, we present what is understood about dengue pathogenesis and its implications for vaccine design, the progress that is being made in the development of a vaccine, and the future challenges.

Slyker JA, Lohman-Payne BL, John-Stewart GC, Maleche-Obimbo E, Emery S, Richardson B, Dong T, Iversen AK, Mbori-Ngacha D, Overbaugh J et al. 2009. Acute cytomegalovirus infection in Kenyan HIV-infected infants. AIDS, 23 (16), pp. 2173-2181. | Show Abstract | Read more

OBJECTIVE: Cytomegalovirus (CMV) coinfection may influence HIV-1 disease progression during infancy. Our aim was to describe the incidence of CMV infection and the kinetics of viral replication in Kenyan HIV-infected and HIV-exposed uninfected infants. METHODS: HIV-1 and CMV plasma viral loads were serially measured in 20 HIV-exposed uninfected and 44 HIV-infected infants born to HIV-infected mothers. HIV-infected children were studied for the first 2 years of life, and HIV-exposed uninfected infants were studied for 1 year. RESULTS: CMV DNA was detected frequently during the first months of life; by 3 months of age, CMV DNA was detected in 90% of HIV-exposed uninfected infants and 93% of infants who had acquired HIV-1 in utero. CMV viral loads were highest in the 1-3 months following the first detection of virus and declined rapidly thereafter. CMV peak viral loads were significantly higher in the HIV-infected infants compared with the HIV-exposed uninfected infants (mean 3.2 versus 2.7 log10 CMV DNA copies/ml, respectively, P = 0.03). The detection of CMV DNA persisted to 7-9 months post-CMV infection in both the HIV-exposed uninfected (8/17, 47%) and HIV-infected (13/18, 72%, P = 0.2) children. Among HIV-infected children, CMV DNA was detected in three of the seven (43%) surviving infants tested between 19 and 21 months post-CMV infection. Finally, a strong correlation was found between peak CMV and HIV-1 viral loads (rho = 0.40, P = 0.008). CONCLUSION: Acute CMV coinfection is common in HIV-infected Kenyan infants. HIV-1 infection was associated with impaired containment of CMV replication.

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Sharma D, Bastard K, Guethlein LA, Norman PJ, Yawata N, Yawata M, Pando M, Thananchai H, Dong T, Rowland-Jones S et al. 2009. Dimorphic Motifs in D0 and D1+D2 Domains of Killer Cell Ig-Like Receptor 3DL1 Combine to Form Receptors with High, Moderate, and No Avidity for the Complex of a Peptide Derived from HIV and HLA-A*2402 JOURNAL OF IMMUNOLOGY, 183 (7), pp. 4569-4582. | Read more

Jallow S, Alabi A, Sarge-Njie R, Peterson K, Whittle H, Corrah T, Jaye A, Cotten M, Vanham G, McConkey SJ et al. 2009. Virological response to highly active antiretroviral therapy in patients infected with human immunodeficiency virus type 2 (HIV-2) and in patients dually infected with HIV-1 and HIV-2 in the Gambia and emergence of drug-resistant variants. J Clin Microbiol, 47 (7), pp. 2200-2208. | Show Abstract | Read more

Drug design, antiretroviral therapy (ART), and drug resistance studies have focused almost exclusively on human immunodeficiency virus type 1 (HIV-1), resulting in limited information for patients infected with HIV-2 and for those dually infected with HIV-1 and HIV-2. In this study, 20 patients, 12 infected with HIV-2 and 8 dually infected with HIV-1 and HIV-2, all treated with zidovudine (ZDV), lamivudine (3TC), and lopinavir-ritonavir (LPV/r), were followed up longitudinally for about 3 years. For 19/20 patients, viral loads were reduced to undetectable levels; the patient whose viral load remained detectable reported adverse effects associated with LPV/r that had caused him to stop taking all the drugs. HIV-2 strains containing mutations in both the protease and the reverse transcriptase gene that may confer drug resistance were observed in two patients with viral rebound, as early as 130 days (4.3 months) after the initiation of therapy. We conclude that the combination of ZDV, 3TC, and LPV/r is able to provide efficient and durable suppression of HIV-1 and HIV-2 for as long as 3 years in HIV-2-infected and dually infected patients. However, the emergence of HIV-1 and HIV-2 strains containing drug-resistant mutations can compromise the efficacy of this highly active ART.

Jallow S, Vincent T, Leligdowicz A, De Silva T, Van Tienen C, Alabi A, Sarge-Njie R, Aaby P, Corrah T, Whittle H et al. 2009. Presence of a multidrug-resistance mutation in an HIV-2 variant infecting a treatment-naive individual in Caio, Guinea Bissau. Clin Infect Dis, 48 (12), pp. 1790-1793. | Show Abstract | Read more

We report the possible transmission of drug-resistant human immunodeficiency virus type 2. A 66-year-old woman from rural Guinea Bissau who had no obvious antiretroviral exposure was found to harbor a variant with the multidrug-resistance mutation Q151M. Finding this mutation among a drug-naive population presents an important public health issue that needs to be addressed for treatment to be effective.

Mabuka JM, Mackelprang RD, Lohman-Payne B, Majiwa M, Bosire R, John-Stewart G, Rowland-Jones S, Overbaugh J, Farquhar C. 2009. CCR2-64I polymorphism is associated with lower maternal HIV-1 viral load and reduced vertical HIV-1 transmission. J Acquir Immune Defic Syndr, 51 (2), pp. 235-237. | Read more

Lohman-Payne B, Slyker JA, Richardson BA, Farquhar C, Majiwa M, Maleche-Obimbo E, Mbori-Ngacha D, Overbaugh J, Rowland-Jones S, John-Stewart G. 2009. Infants with late breast milk acquisition of HIV-1 generate interferon-gamma responses more rapidly than infants with early peripartum acquisition. Clin Exp Immunol, 156 (3), pp. 511-517. | Show Abstract | Read more

Infants infected with HIV-1 after the first month of life have a lower viral set-point and slower disease progression than infants infected before 1 month. We investigated the kinetics of HIV-1-specific CD8(+) T lymphocyte secretion of interferon (IFN)-gamma in infants infected before 1 month of life compared with those infected between months 1 and 12 (late infection). HIV-1 infection was assessed at birth and at months 1, 3, 6, 9 and 12 and timing of infection was determined by HIV-1 gag DNA from dried blood spots and verified by plasma HIV-1 RNA levels. HIV-1 peptide-specific IFN-gamma responses were measured by enzyme-linked immunospot at months 1, 3, 6, 9 and 12. Timing of development of IFN-gamma responses was compared using the log-rank test and Kaplan-Meier survival curves. Infants infected late developed HIV-1-specific CD8(+) T cell responses 2.8 months sooner than infants infected peripartum: 2.3 versus 5.1 months after HIV-1 infection (n = 52, P = 0.04). Late-infected infants had more focused epitope recognition than early-infected infants (median 1 versus 2 peptides, P = 0.03); however, there were no differences in the strength of IFN-gamma responses. In infants infected with HIV-1 after the first month of life, emergence of HIV-1-specific CD8(+) IFN-gamma responses is coincident with the decline in viral load, nearly identical to what is observed in adults and more rapid than in early-infected infants.

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John-Stewart GC, Mbori-Ngacha D, Payne BL, Farquhar C, Richardson BA, Emery S, Otieno P, Obimbo E, Dong T, Slyker J et al. 2009. HIV-1-Specific Cytotoxic T Lymphocytes and Breast Milk HIV-1 Transmission JOURNAL OF INFECTIOUS DISEASES, 199 (6), pp. 889-898. | Show Abstract | Read more

Background. Breast-feeding by infants exposed to human immunodeficiency virus type 1 (HIV-1) provides an opportunity to assess the role played by repeated HIV-1 exposure in eliciting HIV-1-specific immunity and in defining whether immune responses correlate with protection from infection. Methods. Breast-feeding infants born to HIV-1-seropositive women were assessed for HLA-selected HIV-1 peptide-specific cytotoxic T lymphocyte interferon (IFN)-γ responses by means of enzyme-linked immunospot (ELISpot) assays at 1, 3, 6, 9, and 12 months of age. Responses were deemed to be positive when they reached ≥50 HIV-1-specific sfu/1 × 106 peripheral blood mononuclear cells (PBMCs) and were at least twice those of negative controls. Results. A total of 807 ELISpot assays were performed for 217 infants who remained uninfected with HIV-1 at ̃12 months of age; 101 infants (47%) had at least 1 positive ELISpot result (median, 78-170 sfu/1 × 106 PBMCs). The prevalence and magnitude of responses increased with age (P = .01 and P = .007, respectively); the median log10 value for HIV-1-specific IFN-γ responses increased by 1.0 sfu/1 × 106 PBMCs/month (P < .001) between 1 and 12 months of age. Of 141 HIV-1-uninfected infants with 1-month ELISpot results, 10 (7%) acquired HIV-1 infection (0/16 with positive vs. 10/125 [8%] with negative ELISpot results; P = .6). Higher values for log10 HIV-1-specific spot-forming units at 1 month of age were associated with a decreased risk of HIV-1 infection, adjusted for maternal HIV-1 RNA level (adjusted hazard ratio, 0.09 [95% confidence interval, 0.01- 0.72]). Conclusions. Breast-feeding HIV-1-exposed uninfected infants frequently had HIV-1-specific IFN-γ responses. Greater early HIV-1-specific IFN-γ responses were associated with decreased HIV-1 acquisition. © 2009 by the Infectious Diseases Society of America.

Thananchai H, Makadzange T, Maenaka K, Kuroki K, Peng Y, Conlon C, Rowland-Jones S, Dong T. 2009. Reciprocal recognition of an HLA-Cw4-restricted HIV-1 gp120 epitope by CD8+ T cells and NK cells. AIDS, 23 (2), pp. 189-193. | Show Abstract | Read more

OBJECTIVES: The HIV-1 Nef protein selectively downregulates human leukocyte antigen (HLA)-A and HLA-B but not HLA-C molecules on the surface of infected cells. This allows HIV-infected cells to evade recognition by most cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. We investigated the recognition of an HLA-Cw4-restricted HIV-1 gp120 epitope SFNCGGEFF (SF9) and its variant SFNCGGEFL (SL9) by T cells and NK receptors. DESIGN AND METHOD: Recognition of HIV-1 gp120 peptides (SF9 and SL9) by T-cell clones was measured by staining with HLA-Cw4-peptide tetrameric complexes and cytolytic assays using target cell pulsed with either peptides. KIR2DL1 binding to these two peptides was measured using surface plasmon resonance and tetramer staining of an NK cell line. RESULT: : CTLs could recognize SF9 better than the variant SL9, as shown by both tetramer staining and cytolytic assays. Intriguingly, an HLA-Cw4 tetramer folded with the 'escape' variant SL9 could bind to KIR2DL1 on NK cell lines with higher affinity than HLA-Cw4-SF9. The binding of KIR2DL1 to its ligand results in inhibition of NK cell function. Our results indicate that the HIV-1 gp120 variant peptide SL9 could potentially escape both from NK cell and CTL recognition by increasing its affinity for KIR2DL1 binding. CONCLUSION: These data suggest that HIV-1 can acquire mutations that are capable of escaping from both CTL and NK cell recognition, a phenomenon we have termed 'double escape'.

Slyker JA, Lohman-Payne BL, Rowland-Jones SL, Otieno P, Maleche-Obimbo E, Richardson B, Farquhar C, Mbori-Ngacha D, Emery VC, John-Stewart GC. 2009. The detection of cytomegalovirus DNA in maternal plasma is associated with mortality in HIV-1-infected women and their infants. AIDS, 23 (1), pp. 117-124. | Show Abstract | Read more

OBJECTIVE: Cytomegalovirus (CMV) is an important pathogen in healthy neonates and individuals with human immunodeficiency virus (HIV-1). The objective of this study was to determine whether the detection of CMV DNA (CMV DNAemia) in maternal plasma was associated with mortality in HIV-1-infected women or their infants. METHODS: A longitudinal study was designed to examine the relationship between maternal CMV DNAemia and maternal-infant mortality during 2 years postpartum. Sixty-four HIV-1-infected women and their infants were studied. CMV DNA loads were quantified in plasma from the mothers near the time of delivery. Baseline maternal CD4 cell counts, CD4%, HIV-1 RNA, and CMV DNAemia were evaluated as covariates of subsequent maternal or infant mortality in univariate and multivariate Cox regression. RESULTS: CMV DNA was detected in 11/64 (17%) of the HIV-1-infected women. HIV-1 and CMV viral load were strongly correlated in CMV DNAemic women (rho = 0.84, P = 0.001). Detection of CMV DNAemia was associated with decreased maternal survival at 24 months postpartum (log-rank P = 0.006). Additionally, HIV-1-infected infants born to CMV DNAemic women had a four-fold increased risk of mortality during 24 months of follow-up. Maternal CMV DNAemia remained a significant risk factor for mortality in HIV-1-infected infants after adjusting for maternal CD4 cells/microl [adjusted hazard ratio (HR) = 4.3, confidence interval (CI) = 1.4-13], CD4% (HR = 3.2, CI = 1.0-10), HIV-1 viral load (HR = 4.1, CI = 1.4-12) or maternal death (HR = 3.7, CI = 1.0-13). CONCLUSION: Maternal plasma CMV DNAemia identified a subgroup of Kenyan women and infants at high risk for death in the 2 years following delivery.

Blais ME, Rowland-Jones S. 2009. Lessons from the failure of the adenovector HIV vaccine. F1000 Biol Rep, 1 pp. 50. | Show Abstract | Read more

The much-publicised halting of the joint Merck/HIV Vaccine Trials Network phase IIB candidate HIV-1 vaccine trial in 2007 has led to an unprecedented degree of discussion and introspection amongst the HIV research community. In this commentary, we will summarise the lessons learned from the trial and examine the current state of HIV vaccine research.

Ondondo BO, Rowland-Jones SL, Dorrell L, Peterson K, Cotten M, Whittle H, Jaye A. 2008. Comprehensive analysis of HIV Gag-specific IFN-gamma response in HIV-1- and HIV-2-infected asymptomatic patients from a clinical cohort in The Gambia. Eur J Immunol, 38 (12), pp. 3549-3560. | Show Abstract | Read more

Majority of HIV-2-infected individuals meet the criteria of long-term non-progressors. This has been linked to superior qualitative HIV-2-specific cellular immune responses that correlate with viral control. However, it is unknown whether this is due to frequent targeting of immunodominant Gag epitopes in HIV-2 than HIV-1 infection. We describe a comprehensive comparison of the magnitude, breadth and frequency of Gag responses and the degree of cross-recognition of frequently targeted, immunodominant Gag peptides in a cross-sectional study of asymptomatic HIV-1- and HIV-2-infected individuals. Fresh PBMC from 20 HIV-1- and 20 HIV-2-infected patients with similar CD4(+) T-cell counts (p=0.36) were stimulated with pools of HIV-1 and/or HIV-2 Gag peptides in an IFN-gamma ELISPOT assay. We found no difference in the cumulative magnitude of IFN-gamma responses (p=0.75) despite significantly lower plasma viral loads in HIV-2-infected people (p<0.0001). However, Gag211-290 was targeted with significantly higher magnitude in HIV-2-infected subjects (p=0.03) although this did not correlate with viral control. There was no difference in frequently targeted Gag peptides, the breadth, immunodominance or cross-recognition of Gag peptide pools between the two infections. This suggests that other factors may control viral replication in HIV-2 infection.

de Silva TI, Cotten M, Rowland-Jones SL. 2008. HIV-2: the forgotten AIDS virus. Trends Microbiol, 16 (12), pp. 588-595. | Show Abstract | Read more

HIV type 2 (HIV-2), a closely related retrovirus discovered a few years after HIV type 1, causes AIDS in only a minority of infected individuals. Determining why HIV-2 causes asymptomatic infection in most patients could further our understanding of HIV immunopathogenesis. Studies to date have suggested that both enhanced immune responses and lower viral replication could play a role. We summarize the important findings to date and highlight areas that warrant further exploration.

Gottlieb GS, Eholié SP, Nkengasong JN, Jallow S, Rowland-Jones S, Whittle HC, Sow PS. 2008. A call for randomized controlled trials of antiretroviral therapy for HIV-2 infection in West Africa. AIDS, 22 (16), pp. 2069-2072. | Read more

Lee LY, Ha DOLA, Simmons C, de Jong MD, Chau NV, Schumacher R, Peng YC, McMichael AJ, Farrar JJ, Smith GL et al. 2008. Memory T cells established by seasonal human influenza A infection cross-react with avian influenza A (H5N1) in healthy individuals. J Clin Invest, 118 (10), pp. 3478-3490. | Show Abstract | Read more

The threat of avian influenza A (H5N1) infection in humans remains a global health concern. Current influenza vaccines stimulate antibody responses against the surface glycoproteins but are ineffective against strains that have undergone significant antigenic variation. An alternative approach is to stimulate pre-existing memory T cells established by seasonal human influenza A infection that could cross-react with H5N1 by targeting highly conserved internal proteins. To determine how common cross-reactive T cells are, we performed a comprehensive ex vivo analysis of cross-reactive CD4+ and CD8+ memory T cell responses to overlapping peptides spanning the full proteome of influenza A/Viet Nam/CL26/2005 (H5N1) and influenza A/New York/232/2004 (H3N2) in healthy individuals from the United Kingdom and Viet Nam. Memory CD4+ and CD8+ T cells isolated from the majority of participants exhibited human influenza-specific responses and showed cross-recognition of at least one H5N1 internal protein. Participant CD4+ and CD8+ T cells recognized multiple synthesized influenza peptides, including peptides from the H5N1 strain. Matrix protein 1 (M1) and nucleoprotein (NP) were the immunodominant targets of cross-recognition. In addition, cross-reactive CD4+ and CD8+ T cells recognized target cells infected with recombinant vaccinia viruses expressing either H5N1 M1 or NP. Thus, vaccine formulas inducing heterosubtypic T cell-mediated immunity may confer broad protection against avian and human influenza A viruses.

Mendy ME, Kaye S, Le Roux E, Kirk GD, Jeng-Barry A, McConkey S, Cotten M, Kuniholm MH, Leligdowicz A, Hainaut P et al. 2008. Application of a novel, rapid, and sensitive oligonucleotide ligation assay for detection of cancer-predicting mutations in the precore and basal core promoter of hepatitis B virus. J Clin Microbiol, 46 (8), pp. 2723-2730. | Show Abstract | Read more

Hepatocellular carcinoma (HCC) and cirrhosis are important causes of mortality worldwide. Persistent hepatitis B virus (HBV) infection is a major cause of these diseases. Double mutations in the basal core promoter (BCP) (A1762T and G1764A) and precore (pre-C) (G1896A) regions of the virus are associated with progression to HCC. The current study is aimed at developing a simple method for screening and detecting BCP and pre-C mutations in HBV carriers. We have developed and validated an oligonucleotide ligation assay (OLA) to detect point mutations in the HBV core gene. We have applied OLA methods to samples from HBV-infected carriers recruited from the Gambia Liver Cancer Study (GLCS) comprising asymptomatic HBsAg carriers, patients with cirrhosis, and patients with HCC. We observed an 89.3% and 95.8% concordance between the OLA and DNA sequencing for BCP and pre-C mutations, respectively. OLA detected the mutations in single-strain infections and in infections with mixtures of wild-type and mutant viruses under conditions where sequencing detected only the single dominant strains. BCP mutations were detected in 75.7% of patients with advanced liver disease (cirrhosis/HCC) compared to 47.6% of asymptomatic carriers, while pre-C mutations were detected in 34.5% of advanced liver disease patients and in 47.6% of asymptomatic HBsAg carriers. There was a significant association between the presence of BCP mutations and advanced liver disease. In conclusion, OLA is a simple, economical, and reliable assay for detection of pre-C and BCP mutations. Its application can lead to improvement in diagnosis and clinical care in regions where HBV is endemic.

Voelter V, Rufer N, Reynard S, Greub G, Brookes R, Guillaume P, Grosjean F, Fagerberg T, Michelin O, Rowland-Jones S et al. 2008. Characterization of Melan-A reactive memory CD8+ T cells in a healthy donor. Int Immunol, 20 (8), pp. 1087-1096. | Show Abstract | Read more

Melan-A specific CD8+ T cells are thought to play an important role against the development of melanoma. Their in vivo expansion is often observed with advanced disease. In recent years, low levels of Melan-A reactive CD8+ T cells have also been found in HLA-A2 healthy donors, but these cells harbor naive characteristics and are thought to be mostly cross-reactive for the Melan-A antigen. Here, we report on a large population of CD8+ T cells reactive for the Melan-A antigen, identified in one donor with no evidence of melanoma. Interestingly, this population is oligoclonal and displays a clear memory phenotype. However, a detailed study of these cells indicated that they are unlikely to be directly specific for melanoma, so that their in vivo expansion may have been driven by an exogenous antigen. Screening of a Melan-A cross-reactive peptide library suggested that these cells may be specific for an epitope derived from a Mycobacterium protein, which would provide a further example of CD8+ T cell cross-reactivity between a pathogen antigen and a tumor antigen. Finally, we discuss potential perspectives regarding the role of such cells in heterologous immunity, by influencing the balance between protective immunity and pathology, e.g. in the case of melanoma development.

Walton RT, Rowland-Jones SL. 2008. HIV and chemokine binding to red blood cells--DARC matters. Cell Host Microbe, 4 (1), pp. 3-5. | Show Abstract | Read more

A mutation in the Duffy antigen (DARC) that abrogates receptor expression and gives profound protection against some malaria species has become almost universal in African populations. He et al. (2008) show that this polymorphism also leads to significantly increased susceptibility to HIV-1 infection but, paradoxically, to prolonged survival in HIV-1-infected subjects.

Miles DJ, Sanneh M, Holder B, Crozier S, Nyamweya S, Touray ES, Palmero MS, Zaman SM, Rowland-Jones S, van der Sande M, Whittle H. 2008. Cytomegalovirus infection induces T-cell differentiation without impairing antigen-specific responses in Gambian infants. Immunology, 124 (3), pp. 388-400. | Show Abstract | Read more

Cytomegalovirus (CMV) infection induces profound differentiation of T cells, and is associated with impaired responses to other immune challenges. We therefore considered whether CMV infection and the consequent T-cell differentiation in Gambian infants was associated with impaired specific responses to measles vaccination or polyclonal responses to the superantigen staphylococcal enterotoxin B (SEB). While the concentration of undifferentiated (CD27(+) CD28(+) CCR7(+)) T-cells in peripheral blood was unaffected by CMV, there was a large increase in differentiated (CD28(-) CD57(+)) CD8 T-cells and a smaller increase in differentiated CD4 cells. One week post-vaccination, the CD4 cell interferon-gamma (IFN-gamma) response to measles was lower among CMV-infected infants, but there were no other differences between the cytokine responses, or between the cytokine or proliferative responses 4 months post-vaccination. However, the CD8 T cells of CMV-infected infants proliferated more in response to SEB and the antibody response to measles correlated with the IFN-gamma response to CMV, indicating that CMV infection actually enhances some immune responses in infancy.

Abidi SH, Dong T, Vuong MT, Sreenu VB, Rowland-Jones SL, Evans EJ, Davis SJ. 2008. Differential remodeling of a T-cell transcriptome following CD8- versus CD3-induced signaling. Cell Res, 18 (6), pp. 641-648. | Show Abstract | Read more

CD8 engagement with class I major histocompatibility antigens greatly enhances T-cell activation, but it is not clear how this is achieved. We address the question of whether or not the antibody-mediated ligation of CD8 alone induces transcriptional remodeling in a T-cell clone, using serial analysis of gene expression. Even though it fails to induce overt phenotypic changes, we find that CD8 ligation profoundly alters transcription in the T-cell clone, at a scale comparable to that induced by antibody-mediated ligation of CD3. The character of the resulting changes is distinct, however, with the net effect of CD8 ligation being substantially inhibitory. We speculate that ligating CD8 induces weak, T-cell receptor (TCR)-mediated inhibitory signals reminiscent of the effects of TCR antagonists. Our results imply that CD8 ligation alone is incapable of activating the T-cell clone because it fails to fully induce NFAT-dependent transcription.

Miles DJ, van der Sande M, Crozier S, Ojuola O, Palmero MS, Sanneh M, Touray ES, Rowland-Jones S, Whittle H, Ota M, Marchant A. 2008. Effects of antenatal and postnatal environments on CD4 T-cell responses to Mycobacterium bovis BCG in healthy infants in the Gambia. Clin Vaccine Immunol, 15 (6), pp. 995-1002. | Show Abstract | Read more

The Mycobacterium bovis BCG vaccine has a poor record of efficacy in low-income tropical settings. Against this background, we evaluated the immune response of infants to mycobacterial antigens over the 2 years following BCG vaccination at birth by measuring the gamma interferon (IFN-gamma), interleukin-2 (IL-2), and CD154 responses of CD4 T cells. Similar numbers of cells expressed IFN-gamma in infants, 4- to 5-year-old children, and adults, while CD154 was not expressed at comparable levels until the second year of infancy. The IL-2 response remained relatively low in infants, children, and adults but correlated negatively with mother's body mass index and was highest among infants born to Mandinka mothers. Similarly, infants born in the wet season had a stronger CD154 response than those born in the dry season throughout the 2 years of the study. We conclude that the prenatal and perinatal environments have a lasting effect on the response of infants to the BCG vaccine.

Rowland-Jones S, de Silva T. 2008. Resisting immune exhaustion in HIV-1 infection (vol 5, pg e134, 2008) PLOS MEDICINE, 5 (6), pp. 1005-1005. | Read more

Kaye S, Miles D, Antoine P, Burny W, Ojuola B, Kaye P, Rowland-Jones S, Whittle H, van der Sande M, Marchant A. 2008. Virological and immunological correlates of mother-to-child transmission of cytomegalovirus in The Gambia. J Infect Dis, 197 (9), pp. 1307-1314. | Show Abstract | Read more

BACKGROUND: Cytomegalovirus (CMV) is the most common congenital infection and can follow primary and recurrent maternal infection. We studied correlates of vertical transmission of CMV in The Gambia, where most children acquire CMV during the first year of life. METHODS: A cohort of 281 mothers and infants was recruited at birth. Infants were prospectively followed up for CMV infection during the first year of life. Excretion of CMV and antiviral immune response were studied at birth in mothers of children infected in utero, early during infancy, or late during infancy or not infected at 1 year of age. RESULTS: Congenital infection was diagnosed in 3.9% of newborns, and 85% of children were infected by 1 year. Excretion of CMV in colostrum or in the genital tract was more common in mothers of congenitally (100%) or early infected children (48%) than in mothers of late-infected (20%) or uninfected children (27%). Higher rates of viral excretion were associated with significantly higher levels of serum anti-CMV immunoglobulin G and higher frequencies of CMV-specific CD4+ T cells. CONCLUSION: In the context of recurrent maternal infection, transmission of CMV in utero and during early postnatal life is associated with excretion of the virus in colostrum and the genital tract.

Mackelprang RD, John-Stewart G, Carrington M, Richardson B, Rowland-Jones S, Gao X, Mbori-Ngacha D, Mabuka J, Lohman-Payne B, Farquhar C. 2008. Maternal HLA homozygosity and mother-child HLA concordance increase the risk of vertical transmission of HIV-1. J Infect Dis, 197 (8), pp. 1156-1161. | Show Abstract | Read more

BACKGROUND: Mother-child human leukocyte antigen (HLA) concordance and maternal HLA homozygosity may increase the risk of vertical transmission of human immunodeficiency virus type 1 (HIV-1) risk by reducing infant immune responses. METHODS: We analyzed mother-child HLA concordance and maternal HLA homozygosity in a Kenyan perinatal cohort receiving antenatal zidovudine. HLA concordance was scored as the number of shared class I alleles, and relative risk estimates were adjusted for maternal HIV-1 load. RESULTS: Among 277 mother-infant pairs, HIV-1 transmission occurred in 58 infants (21%), with in utero transmission in 21 (36%), peripartum transmission in 26 (45%), and transmission via breast-feeding in 11 (19%). With increased concordance, we observed a significant increase in the risk of transmission overall (adjusted hazard ratio [aHR], 1.3 [95% confidence interval {CI}, 1.0-1.7]; P = .04 in utero (adjusted odds ratio, 1.72 [95% CI, 1.0-1.7]; P = .04), and via breast-feeding (aHR, 1.6 [95% CI, 1.0-2.5]; P = .04). Women with homozygosity had higher plasma HIV-1 RNA levels at 32 weeks of gestation (5.1 vs. 4.8 log(10) copies/mL; P = .03) and an increased risk of transmission overall (aHR, 1.7 [95% CI, 1.1-2.7]; P = .03) and via breast-feeding (aHR, 5.8 [95% CI, 1.9-17.7]; P = .002). CONCLUSION: The risks of overall, in utero, and breast milk HIV-1 transmission increased with HLA concordance and homozygosity. The increased risk may be due to reduced alloimmunity or less diverse protective immune responses.

Moran E, Simmons C, Vinh Chau N, Luhn K, Wills B, Dung NP, Thao LETT, Hien TT, Farrar J, Rowland-Jones S, Dong T. 2008. Preservation of a critical epitope core region is associated with the high degree of flaviviral cross-reactivity exhibited by a dengue-specific CD4+ T cell clone. Eur J Immunol, 38 (4), pp. 1050-1057. | Show Abstract | Read more

Dengue is a member of the Flaviviridae, a large group of related viruses some of which co-circulate in certain regions (e.g. dengue and Yellow fever in South America). Immune responses cross-reactive between different dengue serotypes are important in the pathogenesis of dengue disease but it is not known whether previous infection with one flavivirus might affect the clinical course of subsequent infections with other members of the family. CD4+ T cells have been shown to be important in the production of cytokines in response to dengue infection and can demonstrate significant epitope cross-reactivity. Here, we describe the generation and characterisation of CD4+ T cell clones from a patient experiencing acute dengue infection. These clones were DRB1*15+ and recognised epitope variants not only within other dengue viruses but certain other flaviviruses. This cross-reactivity was dependent upon the presence of a five-amino acid core region, consistent with structural observations of class II MHC binding to TCR demonstrating that only a subset of residues within an epitope bound to a class II molecule are "read out" by the TCR. This capacity of CD4+ T cell clones to recognise a given epitope despite considerable variation between viruses may be of pathological significance, particularly in regions where related viruses co-circulate.

Leligdowicz A, Rowland-Jones S. 2008. Tenets of protection from progression to AIDS: lessons from the immune responses to HIV-2 infection. Expert Rev Vaccines, 7 (3), pp. 319-331. | Show Abstract | Read more

In the past 25 years, life survival curves of many countries have been remodeled owing to HIV infection. Both HIV-1 and HIV-2 can cause AIDS, yet patients infected with HIV-2 fare much better clinically and most will never experience detrimental effects of the infection. Despite over two decades of comprehensive research into vaccine development, a prophylactic vaccine is not yet realized. An essential missing link in the innovation of a successful vaccine strategy is the description of a favorable immune response that abolishes virus replication. Lessons learned from studying the role of the immune system in the long-term nonprogression characteristic of HIV-2 infection will offer insight into how a balanced immune response can protect from the destruction of the immune system associated with chronic HIV-1 infection.

Miles DJ, Sande MV, Kaye S, Crozier S, Ojuola O, Palmero MS, Sanneh M, Touray ES, Waight P, Rowland-Jones S et al. 2008. CD4(+) T cell responses to cytomegalovirus in early life: a prospective birth cohort study. J Infect Dis, 197 (5), pp. 658-662. | Show Abstract | Read more

We compared cytomegalovirus (CMV)-specific interferon-gamma (IFN-gamma), interleukin 2 (IL-2), and CD154 CD4(+) T cell responses of infants to those from chronically infected adults and from children aged 4-5 years. Magnitudes of the responses were similar, although coexpression of IFN-gamma plus CD154 occurred more than coexpression of IFN-gamma plus IL-2 or IL-2 plus CD154. Responses remained constant during infancy, although the proportion of IFN-gamma-producing cells increased from infancy to adulthood. Most responding cells in infants were undifferentiated (i.e., CD27(+)CD28(+)), although IFN-gamma-producing cells were disproportionately CD27(-). By 12 months after diagnosis, viremia was rarely detectable, indicating that CMV was controlled despite the slow development of CMV-specific CD4(+) T cell responses.

Duvall MG, Precopio ML, Ambrozak DA, Jaye A, McMichael AJ, Whittle HC, Roederer M, Rowland-Jones SL, Koup RA. 2008. Polyfunctional T cell responses are a hallmark of HIV-2 infection. Eur J Immunol, 38 (2), pp. 350-363. | Show Abstract | Read more

HIV-2 is distinguished clinically and immunologically from HIV-1 infection by delayed disease progression and maintenance of HIV-specific CD4(+) T cell help in most infected subjects. Thus, HIV-2 provides a unique natural human model in which to investigate correlates of immune protection against HIV disease progression. Here, we report a detailed assessment of the HIV-2-specific CD4(+) and CD8(+) T cell response compared to HIV-1, using polychromatic flow cytometry to assess the quality of the HIV-specific T cell response by measuring IFN-gamma, IL-2, TNF-alpha, MIP-1beta, and CD107a mobilization (degranulation) simultaneously following Gag peptide stimulation. We find that HIV-2-specific CD4(+) and CD8(+) T cells are more polyfunctional that those specific for HIV-1 and that polyfunctional HIV-2-specific T cells produce more IFN-gamma and TNF-alpha on a per-cell basis than monofunctional T cells. Polyfunctional HIV-2-specific CD4(+) T cells were generally more differentiated and expressed CD57, while there was no association between function and phenotype in the CD8(+) T cell fraction. Polyfunctional HIV-specific T cell responses are a hallmark of non-progressive HIV-2 infection and may be related to good clinical outcome in this setting.

Hammond AS, McConkey SJ, Hill PC, Crozier S, Klein MR, Adegbola RA, Rowland-Jones S, Brookes RH, Whittle H, Jaye A. 2008. Mycobacterial T cell responses in HIV-infected patients with advanced immunosuppression. J Infect Dis, 197 (2), pp. 295-299. | Show Abstract | Read more

Antimycobacterial T cell reactivity at different stages of HIV infection was investigated. Subjects were screened with purified protein derivative (PPD), early secreted antigenic target (ESAT)-6, and culture filtrate protein (CFP)-10 antigens for interferon (IFN)-gamma-producing effector T cell responses by direct ex vivo enzyme-linked immunospot (ELISpot) assay. The proportion of responders to PPD tuberculin decreased with a reduction in CD4 T cell count, whereas the proportion of responder to ESAT-6 and CFP-10 did not. The main sources of IFN-gamma secretion were CD4 cells, and the relative responses to ESAT-6 and CFP-10 significantly increased in HIV-infected patients with decreasing CD4 cell count. This may reflect early signs of reactivation, reinfection, or a restricted, inefficient immune response to Mycobacterium tuberculosis.

Rowland-Jones S. 2008. A winding road towards an HIV vaccine. Eur J Immunol, 38 (1), pp. 13-14. | Read more

Seale AC, de Jong BC, Zaidi I, Duvall M, Whittle H, Rowland-Jones S, Jaye A. 2008. Effects of cryopreservation on CD4+ CD25+ T cells of HIV-1 infected individuals. J Clin Lab Anal, 22 (3), pp. 153-158. | Show Abstract | Read more

The role of T regulatory cells (Tregs) in human immunodeficiency virus (HIV)-1 infection, although not entirely clear, has recently been highlighted. Despite their lack of specificity, fluorochrome-labeled CD4 and CD25 antibodies are common flow cytometric reagents used to identify these cells with immunosuppressive potential. Cryopreservation has previously been shown to alter the proportions of lymphocytes with certain phenotypes expressed in peripheral blood mononuclear cells (PBMCs). The aim of this study was to assess the effect of cryopreservation on CD4+ CD25+ T cells in PBMCs from HIV-1+ individuals to guide the design of future studies on Tregs. We recruited 30 HIV-1+ individuals and nine healthy controls. CD25 expression in CD4+ T cells was compared between fresh and frozen/thawed PBMC samples from the same time point. In this study, cryopreservation significantly decreased the proportion of CD4+ CD25+ T cells in PBMC samples from HIV-1 infected subjects. This finding suggests that studies of CD4+ CD25+ T cells should be carried out on fresh samples to avoid bias introduced by cryopreservation.

Miles DJ, van der Sande M, Jeffries D, Kaye S, Ojuola O, Sanneh M, Cox M, Palmero MS, Touray ES, Waight P et al. 2008. Maintenance of large subpopulations of differentiated CD8 T-cells two years after cytomegalovirus infection in Gambian infants. PLoS One, 3 (8), pp. e2905. | Show Abstract | Read more

BACKGROUND: In a previously published study, we found that large differentiated subpopulations of CD8 T-cells emerged rapidly after CMV infection in young infants and persisted throughout the following year. Here we describe a follow-up study conducted on the same infants to establish whether the differentiated subpopulations continued through the second year post-infection. METHODOLOGY / PRINCIPAL FINDINGS: CMV-specific cells identified using tetramers remained more activated and differentiated than the overall CD8 population. The large subpopulation of differentiated cytotoxic (CD28(-)CD62L(-)Bcl-2(low)CD95(+)perforin(+)) cells that emerged rapidly after infection remained stable after two years. No similar subpopulation was found in CMV-uninfected infants indicating that two years after infection, CMV remained a major factor in driving CD8 T-cell differentiation. Although markers of activation (CD45R0 and HLA-D) declined throughout the first year, HLA-D expression continued to decline during the second year and CD45R0 expression increased slightly. The age-related increase in IFNgamma response observed during the first year continued but was non-significant during the second year, indicating that the rate of functional improvement had slowed substantially. CONCLUSIONS / SIGNIFICANCE: The large differentiated subpopulations of CD8 T-cells that had emerged immediately after CMV infection persisted through the second year post-infection, while levels of activation and functional capacity remained fairly constant.

Duvall MG, Loré K, Blaak H, Ambrozak DA, Adams WC, Santos K, Geldmacher C, Mascola JR, McMichael AJ, Jaye A et al. 2007. Dendritic cells are less susceptible to human immunodeficiency virus type 2 (HIV-2) infection than to HIV-1 infection. J Virol, 81 (24), pp. 13486-13498. | Show Abstract | Read more

Human immunodeficiency virus type 1 (HIV-1) infection of dendritic cells (DCs) has been documented in vivo and may be an important contributor to HIV-1 transmission and pathogenesis. HIV-1-specific CD4(+) T cells respond to HIV antigens presented by HIV-1-infected DCs and in this process become infected, thereby providing a mechanism through which HIV-1-specific CD4(+) T cells could become preferentially infected in vivo. HIV-2 disease is attenuated with respect to HIV-1 disease, and host immune responses are thought to be contributory. Here we investigated the susceptibility of primary myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) to infection by HIV-2. We found that neither CCR5-tropic primary HIV-2 isolates nor a lab-adapted CXCR4-tropic HIV-2 strain could efficiently infect mDCs or pDCs, though these viruses could infect primary CD4(+) T cells in vitro. HIV-2-exposed mDCs were also incapable of transferring virus to autologous CD4(+) T cells. Despite this, we found that HIV-2-specific CD4(+) T cells contained more viral DNA than memory CD4(+) T cells of other specificities in vivo. These data suggest that either infection of DCs is not an important contributor to infection of HIV-2-specific CD4(+) T cells in vivo or that infection of DCs by HIV-2 occurs at a level that is undetectable in vitro. The frequent carriage of HIV-2 DNA within HIV-2-specific CD4(+) T cells, however, does not appear to be incompatible with preserved numbers and functionality of HIV-2-specific CD4(+) T cells in vivo, suggesting that additional mechanisms contribute to maintenance of HIV-2-specific CD4(+) T-cell help in vivo.

Rowland-Jones S, Dong T. 2007. Dying T cells trigger autoimmunity in HIV NATURE MEDICINE, 13 (12), pp. 1413-1415. | Read more

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Leligdowicz A, Yindom L-M, Onyango C, Sarge-Njie R, Alabi A, Cotten M, Vincent T, da Costa C, Aaby P, Jaye A et al. 2007. Robust gag-specific T cell responses characterize viremia control in HIV-2 infection JOURNAL OF CLINICAL INVESTIGATION, 117 (10), pp. 3067-3074. | Read more

Miles DJ, van der Sande M, Jeffries D, Kaye S, Ismaili J, Ojuola O, Sanneh M, Touray ES, Waight P, Rowland-Jones S et al. 2007. Cytomegalovirus infection in Gambian infants leads to profound CD8 T-cell differentiation. J Virol, 81 (11), pp. 5766-5776. | Show Abstract | Read more

Cytomegalovirus (CMV) infection is endemic in Gambian infants, with 62% infected by 3 months and 85% by 12 months of age. We studied the CD8 T-cell responses of infants to CMV following primary infection. CMV-specific CD8 T cells, identified with tetramers, showed a fully differentiated phenotype (CD28(-) CD62L(-) CD95(+) perforin(+) granzyme A(+) Bcl-2(low)). Strikingly, the overall CD8 T-cell population developed a similar phenotype following CMV infection, which persisted for at least 12 months. In contrast, primary infection was accompanied by up-regulation of markers of activation (CD45R0 and HLA-D) on both CMV-specific cells and the overall CD8 T-cell population and division (Ki-67) of specific cells, but neither pattern persisted. At 12 months of age, the CD8 T-cell population of CMV-infected infants was more differentiated than that of uninfected infants. Although the subpopulation of CMV-specific cells remained constant, the CMV peptide-specific gamma interferon response was lower in younger infants and increased with age. As the CD8 T-cell phenotype induced by CMV is indicative of immune dysfunction in the elderly, the existence of a similar phenotype in large numbers of Gambian infants raises the question of whether CMV induces a similarly deleterious effect.

Lühn K, Simmons CP, Moran E, Dung NT, Chau TN, Quyen NT, Thao LETT, Van Ngoc T, Dung NM, Wills B et al. 2007. Increased frequencies of CD4+ CD25(high) regulatory T cells in acute dengue infection. J Exp Med, 204 (5), pp. 979-985. | Show Abstract | Read more

Dengue virus infection is an increasingly important tropical disease, causing 100 million cases each year. Symptoms range from mild febrile illness to severe hemorrhagic fever. The pathogenesis is incompletely understood, but immunopathology is thought to play a part, with antibody-dependent enhancement and massive immune activation of T cells and monocytes/macrophages leading to a disproportionate production of proinflammatory cytokines. We sought to investigate whether a defective population of regulatory T cells (T reg cells) could be contributing to immunopathology in severe dengue disease. CD4(+)CD25(high)FoxP3(+) T reg cells of patients with acute dengue infection of different severities showed a conventional phenotype. Unexpectedly, their capacity to suppress T cell proliferation and to secrete interleukin-10 was not altered. Moreover, T reg cells suppressed the production of vasoactive cytokines after dengue-specific stimulation. Furthermore, T reg cell frequencies and also T reg cell/effector T cell ratios were increased in patients with acute infection. A strong indication that a relative rise of T reg cell/effector T cell ratios is beneficial for disease outcome comes from patients with mild disease in which this ratio is significantly increased (P < 0.0001) in contrast to severe cases (P = 0.2145). We conclude that although T reg cells expand and function normally in acute dengue infection, their relative frequencies are insufficient to control the immunopathology of severe disease.

Jallow S, Kaye S, Schutten M, Brandin E, Albert J, McConkey SJ, Corrah T, Whittle H, Vanham G, Rowland-Jones S, Janssens W. 2007. Development and evaluation of an oligonucleotide ligation assay for detection of drug resistance-associated mutations in the human immunodeficiency virus type 2 pol gene. J Clin Microbiol, 45 (5), pp. 1565-1571. | Show Abstract | Read more

Human immunodeficiency virus type 2 (HIV-2) is naturally resistant to several antiretroviral drugs, including all of the non-nucleoside reverse transcriptase inhibitors and the entry inhibitor T-20, and may have reduced susceptibility to some protease inhibitors. These resistance properties make treatment of HIV-2 patients difficult, with very limited treatment options. Therefore, early detection of resistance mutations is important for understanding treatment failures and guiding subsequent therapy decisions. With the Global Fund Initiative, a substantial number of HIV-2 patients in West Africa will receive antiretroviral therapy. Therefore, development of cheaper and more sustainable resistance assays, such as the oligonucleotide ligation assay (OLA), is a priority. In this study, we designed oligonucleotide probes to detect the Q151M mutation, associated with phenotypic resistance to zidovudine, didanosine, zalcitabine, and stavudine, and the M184V mutation, associated with phenotypic resistance to lamivudine and emtricitabine, in HIV-2. The assay was successfully developed and evaluated with 122 samples from The Gambia, Guinea Bissau, The Netherlands, and Sweden. The overall sensitivity of the assay was 98.8%, with 99.2% for Q151M and 98.4% for M184V. OLA results were compared with sequencing to give high concordances of 98.4% (Q151M) and 97.5% (M184V). OLA demonstrated a higher sensitivity for detection of minor variants as a mixture of wild-type and mutant viruses in cases when sequencing detected only the major population. In conclusion, we have developed a simple, easy-to-use, and economical assay for genotyping of drug resistance in HIV-2 that is more sustainable for use in resource-poor settings than is consensus sequencing.

Molyneux M. 2007. UK doctors are already put off by changes in training. BMJ, 334 (7596), pp. 709-710. | Read more

Rowland-Jones SL, Whittle HC. 2007. Out of Africa: what can we learn from HIV-2 about protective immunity to HIV-1? Nat Immunol, 8 (4), pp. 329-331. | Show Abstract | Read more

Most people infected with human immunodeficiency virus 2 (HIV-2) do not progress to disease, even though the minority who do cannot be distinguished clinically from HIV-1-infected patients. Here we review what is known about the basis of viral control in HIV-2 infection.

Gillespie GM, Bashirova A, Dong T, McVicar DW, Rowland-Jones SL, Carrington M. 2007. Lack of KIR3DS1 binding to MHC class I Bw4 tetramers in complex with CD8+ T cell epitopes. AIDS Res Hum Retroviruses, 23 (3), pp. 451-455. | Show Abstract | Read more

In HIV-1 infection, the synergistic association of a subset of Bw4 MHC class I molecules and the activating killer inhibitory receptor (KIR), KIR3DS1, with prolonged AIDS-free survival has been reported. As KIRs represent a diverse group of MHC class I receptors, we questioned whether Bw4 MHC class I molecules expressing isoleucine at position 80 (Bw4Ile80) and in complex with HIV-1-derived T cell epitopes represented KIR3DS1 ligands. MHC class I tetramers are powerful tools for the detection of T cell receptor-MHC class I interactions, and have recently been used to evaluate KIR-MHC class I binding ex vivo. Specifically, this approach has been successfully utilized to assess binding of Bw4 MHC class I tetramers to KIR3DL1, an inhibitory KIR and allele of KIR3DS1. In this study we generated a diverse panel of HIV-1-specific Bw4Ile80 MHC class I tetramers and tested its ability to bind transiently expressed KIR3DS1 on 293-T cells. Using flow cytometry analysis, the expression of KIR3DS1 on 293-T cells was confirmed by anti-FLAG BioM2 staining, prior to incubation with PE-conjugated MHC class I tetramers. Despite choosing a broad array of peptide epitopes and diverse Bw4Ile80 MHC class I molecules, we were unable to detect tetramer binding to KIR3DS1. We speculate that our negative finding may be a consequence of the MHC class I molecules and peptide epitopes chosen, but could also relate to key amino acid differences that distinguish KIR3DS1 from KIR3DL1.

Reinis M, Weiser B, Kuiken C, Dong T, Lang D, Nachman S, Zhang Y, Rowland-Jones S, Burger H. 2007. Genomic analysis of HIV type 1 strains derived from a mother and child pair of long-term nonprogressors AIDS RESEARCH AND HUMAN RETROVIRUSES, 23 (2), pp. 309-315. | Read more

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Scopus

Thananchai H, Gillespie G, Martin MP, Bashirova A, Yawata N, Yawata M, Easterbrook P, McVicar DW, Maenaka K, Parham P et al. 2007. Cutting edge: Allele-specific and peptide-dependent interactions between KIR3DL1 and HLA-A and HLA-B Journal of Immunology, 178 (1), pp. 33-37. | Show Abstract

Although it is clear that KIR3DL1 recognizes Bw4+ HLA-B, the role of Bw4+ HLA-A allotypes as KIR3DL1 ligands is controversial. We therefore examined the binding of tetrameric HLA-A and -B complexes, including HLA*2402, a common Bw4+ HLA-A allotype, to KIR3DL1*001, *005, *007, and *1502 allotypes. Only Bw4+ tetramers bound KIR3DL1. Three of four HLA-A*2402 tetramers bound one or more KIR3DL1 allotypes and all four KIR3DL1 allotypes bound to one or more HLA-A*2402 tetramers, but with different binding specificities. Only KIR3DL1*005 bound both HLA-A*2402 and HLA-B*5703 tetramers. HLA-A*2402-expressing target cells were resistant to lysis by NK cells expressing KIR3DL1*001 or *005. This study shows that HLAA*2402 is a ligand for KIR3DL1 and demonstrates how the binding of KIR3DL1 to Bw4+ ligands depends upon the bound peptide as well as HLA and KIR3DL1 polymorphism.

Hene L, Sreenu VB, Vuong MT, Abidi SH, Sutton JK, Rowland-Jones SL, Davis SJ, Evans EJ. 2007. Deep analysis of cellular transcriptomes - LongSAGE versus classic MPSS. BMC Genomics, 8 (1), pp. 333. | Show Abstract | Read more

BACKGROUND: Deep transcriptome analysis will underpin a large fraction of post-genomic biology. 'Closed' technologies, such as microarray analysis, only detect the set of transcripts chosen for analysis, whereas 'open' e.g. tag-based technologies are capable of identifying all possible transcripts, including those that were previously uncharacterized. Although new technologies are now emerging, at present the major resources for open-type analysis are the many publicly available SAGE (serial analysis of gene expression) and MPSS (massively parallel signature sequencing) libraries. These technologies have never been compared for their utility in the context of deep transcriptome mining. RESULTS: We used a single LongSAGE library of 503,431 tags and a "classic" MPSS library of 1,744,173 tags, both prepared from the same T cell-derived RNA sample, to compare the ability of each method to probe, at considerable depth, a human cellular transcriptome. We show that even though LongSAGE is more error-prone than MPSS, our LongSAGE library nevertheless generated 6.3-fold more genome-matching (and therefore likely error-free) tags than the MPSS library. An analysis of a set of 8,132 known genes detectable by both methods, and for which there is no ambiguity about tag matching, shows that MPSS detects only half (54%) the number of transcripts identified by SAGE (3,617 versus 1,955). Analysis of two additional MPSS libraries shows that each library samples a different subset of transcripts, and that in combination the three MPSS libraries (4,274,992 tags in total) still only detect 73% of the genes identified in our test set using SAGE. The fraction of transcripts detected by MPSS is likely to be even lower for uncharacterized transcripts, which tend to be more weakly expressed. The source of the loss of complexity in MPSS libraries compared to SAGE is unclear, but its effects become more severe with each sequencing cycle (i.e. as MPSS tag length increases). CONCLUSION: We show that MPSS libraries are significantly less complex than much smaller SAGE libraries, revealing a serious bias in the generation of MPSS data unlikely to have been circumvented by later technological improvements. Our results emphasize the need for the rigorous testing of new expression profiling technologies.

Dong T, Moran E, Vinh Chau N, Simmons C, Luhn K, Peng Y, Wills B, Phuong Dung N, Thi Thu Thao L, Hien TT et al. 2007. High pro-inflammatory cytokine secretion and loss of high avidity cross-reactive cytotoxic T-cells during the course of secondary dengue virus infection. PLoS One, 2 (12), pp. e1192. | Show Abstract | Read more

BACKGROUND: Dengue is one of the most important human diseases transmitted by an arthropod vector and the incidence of dengue virus infection has been increasing - over half the world's population now live in areas at risk of infection. Most infections are asymptomatic, but a subset of patients experience a potentially fatal shock syndrome characterised by plasma leakage. Severe forms of dengue are epidemiologically associated with repeated infection by more than one of the four dengue virus serotypes. Generally attributed to the phenomenon of antibody-dependent enhancement, recent observations indicate that T-cells may also influence disease phenotype. METHODS AND FINDINGS: Virus-specific cytotoxic T lymphocytes (CTL) showing high level cross reactivity between dengue serotypes could be expanded from blood samples taken during the acute phase of secondary dengue infection. These could not be detected in convalescence when only CTL populations demonstrating significant serotype specificity were identified. Dengue cross-reactive CTL clones derived from these patients were of higher avidity than serotype-specific clones and produced much higher levels of both type 1 and certain type 2 cytokines, many previously implicated in dengue pathogenesis. CONCLUSION: Dengue serotype cross-reactive CTL clones showing high avidity for antigen produce higher levels of inflammatory cytokines than serotype-specific clones. That such cells cannot be expanded from convalescent samples suggests that they may be depleted, perhaps as a consequence of activation-induced cell death. Such high avidity cross-reactive memory CTL may produce inflammatory cytokines during the course of secondary infection, contributing to the pathogenesis of vascular leak. These cells appear to be subsequently deleted leaving a more serotype-specific memory CTL pool. Further studies are needed to relate these cellular observations to disease phenotype in a large group of patients. If confirmed they have significant implications for understanding the role of virus-specific CTL in pathogenesis of dengue disease.

van der Sande MA, Kaye S, Miles DJ, Waight P, Jeffries DJ, Ojuola OO, Palmero M, Pinder M, Ismaili J, Flanagan KL et al. 2007. Risk factors for and clinical outcome of congenital cytomegalovirus infection in a peri-urban West-African birth cohort. PLoS One, 2 (6), pp. e492. | Show Abstract | Read more

BACKGROUND: Congenital cytomegalovirus (CMV) infection is the most prevalent congenital infection worldwide. Epidemiology and clinical outcomes are known to vary with socio-economic background, but few data are available from developing countries, where the overall burden of infectious diseases is frequently high. METHODOLOGY/PRINCIPAL FINDINGS: As part of an ongoing birth cohort study in The Gambia among term infants, urine samples were collected at birth and tested by PCR for the presence of CMV DNA. Risk factors for transmission and clinical outcome were assessed, including placental malaria infection. Babies were followed up at home monthly for morbidity and anthropometry, and at one year of age a clinical evaluation was performed. The prevalence of congenital CMV infection was 5.4% (40/741). A higher prevalence of hepatomegaly was the only significant clinical difference at birth. Congenitally infected children were more often first born babies (adjusted odds ratio (OR) 5.3, 95% confidence interval (CI) 2.0-13.7), more frequently born in crowded compounds (adjusted OR 2.9, 95%CI 1.0-8.3) and active placental malaria was more prevalent (adjusted OR 2.9, 95%CI 1.0-8.4). These associations were corrected for maternal age, bed net use and season of birth. During the first year of follow up, mothers of congenitally infected children reported more health complaints for their child. CONCLUSIONS/SIGNIFICANCE: In this study, the prevalence of congenital CMV among healthy neonates was much higher than previously reported in industrialised countries, and was associated with active placental malaria infection. There were no obvious clinical implications during the first year of life. The effect of early life CMV on the developing infant in the Gambia could be mitigated by environmental factors, such as the high burden of other infections.

Rowland-Jones S. 2006. Protective immunity against HIV infection: lessons from HIV-2 infection. Future Microbiol, 1 (4), pp. 427-433. | Show Abstract | Read more

Despite two decades of intensive research, the correlates of protective immunity to HIV-1 infection remain elusive. Much less attention has been paid to the related human virus strain, HIV-2, which can cause AIDS, but does not usually do so in the majority of infected people. What can be learned from HIV-2 infection about how the human host can peacefully coexist with a pathogenic retrovirus?

Ondondo BO, Yang H, Dong T, di Gleria K, Suttill A, Conlon C, Brown D, Williams P, Rowland-Jones SL, Hanke T et al. 2006. Immunisation with recombinant modified vaccinia virus Ankara expressing HIV-1 gag in HIV-1-infected subjects stimulates broad functional CD4+ T cell responses. Eur J Immunol, 36 (10), pp. 2585-2594. | Show Abstract | Read more

Virus-specific CD4+ T cells with IL-2-secreting and/or proliferative capacity are detected readily in HIV-1-infected long-term nonprogressors and rarely in persons with untreated progressive infection. The contribution of these cells to viraemia control is uncertain, but this question might be addressed in clinical therapeutic vaccination studies. However, the quality of T helper responses induced by currently available HIV-1 vaccine candidates has not been explored in depth. We determined the effect of vaccination with modified vaccinia virus Ankara (MVA) expressing HIV-1 gag p24/p17 (MVA.HIVA) on HIV-1-specific CD4+ T cell responses in 16 chronically infected, highly active antiretroviral therapy (HAART)-treated subjects using CD8-depleted IFN-gamma ELISPOT assays, intracellular cytokine staining assays for IL-2 and IFN-gamma, and a CFSE-based proliferation assay. Gag-specific CD4+ T cell responses were significantly increased in magnitude and breadth after vaccination and targeted both known and new epitopes, several of which were also recognised by healthy HIV-uninfected volunteers immunised with the same vaccines. The frequencies of CD4+ T cells expressing IL-2 or IFN-gamma, alone or simultaneously, were also augmented. These findings indicate that functional virus-specific T helper cells can be boosted by vaccination in chronic HIV-1 infection. Further evaluation of their role in viraemia control is warranted.

Rowland-Jones S, Dong T. 2006. HIV - Tired T cells turn around NATURE, 443 (7109), pp. 282-283. | Read more

Gillespie GM, Stewart-Jones G, Rengasamy J, Beattie T, Bwayo JJ, Plummer FA, Kaul R, McMichael AJ, Easterbrook P, Dong T et al. 2006. Strong TCR conservation and altered T cell cross-reactivity characterize a B*57-restricted immune response in HIV-1 infection. J Immunol, 177 (6), pp. 3893-3902. | Show Abstract

HLA-B*57 is associated with slower disease progression to AIDS, and CD8+ T cell responses to B*57-restricted epitopes are thought to contribute to this protective effect. In this study, we evaluate the B*57-restricted p24 KAFSPEVIPMF (KF11) immune response which is immunodominant during chronic infection. Previously, we observed that the KF11 clade variants KGFNPEVIPMF [A2G,S4N] and KAFNPEIIMPF [S4N,V7I], sharing a position 4 mutation, are differentially recognized by KF11-specific T cells. By combining structural and cellular studies, we now demonstrate that the KF11 and [A2G,S4N] epitopes induce distinct functional responses in [A2G,S4N] and KF11-specific T cells, respectively, despite minimal structural differences between the individual B*57-peptide complexes. Recently, we also elucidated the highly distinct structure of KF11 in complex with B*5703, and have now characterized the CD8+ T cell repertoire recognizing this epitope. We now report striking features of TCR conservation both in terms of TCR Valpha and Vbeta chain usage, and throughout the hypervariable region. Collectively, our findings highlight unusual features of the B*5701/B*5703-KF11-specific immune responses which could influence disease progression and that might be important to consider when designing future vaccine regimens.

Jallow S, Kaye S, Alabi A, Aveika A, Sarge-Njie R, Sabally S, Corrah T, Whittle H, Vanham G, Rowland-Jones S et al. 2006. Virological and immunological response to Combivir and emergence of drug resistance mutations in a cohort of HIV-2 patients in The Gambia. AIDS, 20 (10), pp. 1455-1458. | Read more

Duvall MG, Jaye A, Dong T, Brenchley JM, Alabi AS, Jeffries DJ, van der Sande M, Togun TO, McConkey SJ, Douek DC et al. 2006. Maintenance of HIV-specific CD4+ T cell help distinguishes HIV-2 from HIV-1 infection. J Immunol, 176 (11), pp. 6973-6981. | Show Abstract

Unlike HIV-1-infected people, most HIV-2-infected subjects maintain a healthy CD4+ T cell count and a strong HIV-specific CD4+ T cell response. To define the cellular immunological correlates of good prognosis in HIV-2 infection, we conducted a cross-sectional study of HIV Gag-specific T cell function in HIV-1- and HIV-2-infected Gambians. Using cytokine flow cytometry and lymphoproliferation assays, we show that HIV-specific CD4+ T cells from HIV-2-infected individuals maintained proliferative capacity, were not terminally differentiated (CD57-), and more frequently produced IFN-gamma or IL-2 than CD4+ T cells from HIV-1-infected donors. Polyfunctional (IFN-gamma+/IL-2+) HIV-specific CD4+ T cells were found exclusively in HIV-2+ donors. The disparity in CD4+ T cell responses between asymptomatic HIV-1- and HIV-2-infected subjects was not associated with differences in the proliferative capacity of HIV-specific CD8+ T cells. This study demonstrates that HIV-2-infected donors have a well-preserved and functionally heterogeneous HIV-specific memory CD4+ T cell response that is associated with delayed disease progression in the majority of infected people.

Dorrell L, Yang H, Ondondo B, Dong T, di Gleria K, Suttill A, Conlon C, Brown D, Williams P, Bowness P et al. 2006. Expansion and diversification of virus-specific T cells following immunization of human immunodeficiency virus type 1 (HIV-1)-infected individuals with a recombinant modified vaccinia virus Ankara/HIV-1 Gag vaccine. J Virol, 80 (10), pp. 4705-4716. | Show Abstract | Read more

Affordable therapeutic strategies that induce sustained control of human immunodeficiency virus type 1 (HIV-1) replication and are tailored to the developing world are urgently needed. Since CD8(+) and CD4(+) T cells are crucial to HIV-1 control, stimulation of potent cellular responses by therapeutic vaccination might be exploited to reduce antiretroviral drug exposure. However, therapeutic vaccines tested to date have shown modest immunogenicity. In this study, we performed a comprehensive analysis of the changes in virus-specific CD8(+) and CD4(+) T-cell responses occurring after vaccination of 16 HIV-1-infected individuals with a recombinant modified vaccinia virus Ankara-vectored vaccine expressing the consensus HIV-1 clade A Gag p24/p17 sequences and multiple CD8(+) T-cell epitopes during highly active antiretroviral therapy. We observed significant amplification and broadening of CD8(+) and CD4(+) gamma interferon responses to vaccine-derived epitopes in the vaccinees, without rebound viremia, but not in two unvaccinated controls followed simultaneously. Vaccine-driven CD8(+) T-cell expansions were also detected by tetramer reactivity, predominantly in the CD45RA(-) CCR7(+) or CD45RA(-) CCR7(-) compartments, and persisted for at least 1 year. Expansion was associated with a marked but transient up-regulation of CD38 and perforin within days of vaccination. Gag-specific CD8(+) and CD4(+) T-cell proliferation also increased postvaccination. These data suggest that immunization with MVA.HIVA is a feasible strategy to enhance potentially protective T-cell responses in individuals with chronic HIV-1 infection.

Nuvor SV, van der Sande M, Rowland-Jones S, Whittle H, Jaye A. 2006. Natural killer cell function is well preserved in asymptomatic human immunodeficiency virus type 2 (HIV-2) infection but similar to that of HIV-1 infection when CD4 T-cell counts fall. J Virol, 80 (5), pp. 2529-2538. | Show Abstract | Read more

Natural killer (NK) cells are potent effectors of natural immunity and their activity prevents human immunodeficiency virus type 1 (HIV-1) viral entry and viral replication. We sought to determine whether NK immune responses are associated with different clinical course of HIV-1 and HIV-2 infections. A cross-sectional analysis of NK cell responses was undertaken in 30 HIV-1 and 30 HIV-2 subjects in each of three categories of CD4(+)-T-cell counts (>500, 200 to 500, and <200 cells/microl) and in 50 HIV-uninfected control subjects. Lytic activity and gamma interferon (IFN-gamma) secretion were measured by chromium release and enzyme-linked immunospot assays, respectively. Flow cytometry was used to assess intracellular cytokines and chemokines. Levels of NK cytotoxicity were significantly higher in HIV-2 than in HIV-1 infections in subjects with high CD4(+)-T-cell counts and were similar to that of the healthy controls. In these HIV-2 subjects, cytolytic activity was positively correlated to NK cell count and inversely related to plasma viremia. Levels of intracellular MIP-1beta, RANTES, tumor necrosis factor alpha, and IFN-gamma produced by NK CD56(bright) cells were significantly higher in HIV-2- than HIV-1-infected subjects with high CD4(+)-T-cell counts but fell to similar levels as CD4 counts dropped. The data suggest efficient cytolytic and chemokine-suppressive activity of NK cells early in HIV-2 infection, which is associated with high CD4(+) T-cell counts. Enhancement of these functions may be important in immune-based therapy to control HIV disease.

Chakraborty R, Reinis M, Rostron T, Philpott S, Dong T, D'Agostino A, Musoke R, Silva E, Stumpf M, Weiser B et al. 2006. nef gene sequence variation among HIV-1-infected African children. HIV Med, 7 (2), pp. 75-84. | Show Abstract | Read more

BACKGROUND: There are few data on African children infected with nonclade B HIV-1 in endemic settings, which limits generalizations about pathogenesis and progression. Genotypic and phenotypic variations in host immunogenetics and HIV-1 negative factor (nef) accessory protein may influence disease progression and have frequently been characterized in subjects infected with clade B HIV-1. METHODS: In this descriptive study, we report nef gene sequence variation and host genetic polymorphisms in 32 Kenyan children, including 12 slow progressors. RESULTS: Phylogenetic analysis identified HIV-1 clades A, C and D and a recombinant A/D subtype. Grossly defective nef genes or significant changes from relevant clade reference sequences were not identified in children with delayed disease progression. CONCLUSIONS: nef sequence variations may not be common in perinatally infected African children. Further studies are warranted in HIV-1-infected subjects in settings where infection is endemic.

Makadzange AT, Gillespie G, Kimani J, Kiama P, Easterbrook P, Bwayo JJ, Rowland-Jones SL. 2006. Identification of a novel HLA B*57 restricted cytotoxic T-lymphocyte epitope within HIV-1 rev. AIDS, 20 (3), pp. 462-464. | Show Abstract | Read more

HLA-B5701 and its related allele B5703 have been shown to be strongly associated with slow HIV-1 disease progression. To elucidate the effect of these alleles fully on disease progression it is essential to identify key HIV-1 epitopes that are restricted by these alleles. Here we describe the identification of a novel HLA-B5701, B5703 restricted epitope within HIV-1 rev, which accounted for up to 25 and 40% of the total cytotoxic T-lymphocyte responses in two patients.

Cebere I, Dorrell L, McShane H, Simmons A, McCormack S, Schmidt C, Smith C, Brooks M, Roberts JE, Darwin SC et al. 2006. Phase I clinical trial safety of DNA- and modified virus Ankara-vectored human immunodeficiency virus type 1 (HIV-1) vaccines administered alone and in a prime-boost regime to healthy HIV-1-uninfected volunteers. Vaccine, 24 (4), pp. 417-425. | Show Abstract | Read more

DNA- and modified virus Ankara (MVA)-vectored candidate vaccines expressing human immunodeficiency virus type 1 (HIV-1) clade A-derived p24/p17 gag fused to a string of HLA class I epitopes, called HIVA, were tested in phase I trials in healthy, HIV-1/2-uninfected adults in Oxford, United Kingdom. Eighteen volunteers were vaccinated with pTHr.HIVA DNA (IAVI-001) alone, 8 volunteers received MVA.HIVA (IAVI-003) alone and 9 volunteers from study IAVI-001 were boosted with MVA.HIVA 9-14 months after DNA priming (IAVI-005). Immunogenicity results observed in these trials was published previously [Mwau M, Cebere I, Sutton J, Chikoti P, Winstone N, Wee EG-T, et al. An HIV-1 clade A vaccine in clinical trials: stimulation of HIV-specific T cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans. J Gen Virol 2004;85:911-9]. Here, we report on the safety of the two vaccines and the vaccine regimes. Overall, both candidate vaccines were safe and well tolerated. There were no reported vaccine-related adverse events over the 6-month period of the study and up to 2 years after the last vaccination. There were no moderate or severe local symptoms recorded after the pTHr.HIVA DNA intramuscular administration. Almost all participants experienced local reactogenicity events such as redness and induration after MVA.HIVA intradermal injection. Thus, the results from these initial small phase I trials administering the pTHr.HIVA DNA and MVA.HIVA vaccines either alone or in a prime-boost regime to healthy HIV-1/2-negative adults indicated that the vaccines were safe and warranted further testing of this approach in larger phase I/II studies.

Boutboul F, Puthier D, Appay V, Pellé O, Ait-Mohand H, Combadière B, Carcelain G, Katlama C, Rowland-Jones SL, Debré P et al. 2005. Modulation of interleukin-7 receptor expression characterizes differentiation of CD8 T cells specific for HIV, EBV and CMV. AIDS, 19 (17), pp. 1981-1986. | Show Abstract | Read more

OBJECTIVES: To further understand differentiation and homeostasis of CD8 T cells specific for HIV, Epstein-Barr Virus (EBV) and cytomegalovirus (CMV) during HIV infection, we investigated interleukin-7 receptor alpha (IL-7Ralpha) expression on those virus-specific T cells. METHODS: Microarrays and cytometry analyses were performed on peripheral blood mononuclear cells (PBMC), total and tetramer-binding virus-specific CD8 T cells from 66 HIV-infected patients. RESULTS: Microarray analysis revealed reduced levels of IL-7Ralpha and increased levels of perforin with disease progression in total PBMC. This loss of IL-7Ralpha expression was observed on CD8 T cells and was inversely related to perforin expression. The relative expression of both molecules defined three new subsets: IL-7Ralpha(pos)Perforin(neg); IL-7Ralpha(loneg)Perforin(lo); and IL-7Ralpha(loneg)Perforin(hi) corresponding to naive and effector-memory CD8 differentiation, as assessed by CD45RA/CD11a. The IL-7Ralpha expression decreased along the CD8 differentiation pathway defined by CD27 and CD28. In contrast, IL-7Ralpha expression was down-modulated on all the CD8 T cells specific for HIV, EBV and CMV that were almost exclusively IL-7Ralpha(lo/neg)Perforin(lo) and was parallel with the CD27 expression. In addition, this low IL-7Ralpha expression on HIV-specific CD8 T cells was independent of virus load and T-cell activation and remained stable during the first 6 months of antiretroviral therapy despite successful control of HIV replication. CONCLUSION: The relative expression of IL-7Ralpha, perforin reveals new aspects of virus-specific CD8 T cell differentiation, independently of T-cell activation and virus load. This opens new perspectives for understanding homeostasis of those cells and immune-based therapeutic strategies.

Thimme R, Appay V, Koschella M, Panther E, Roth E, Hislop AD, Rickinson AB, Rowland-Jones SL, Blum HE, Pircher H. 2005. Increased expression of the NK cell receptor KLRG1 by virus-specific CD8 T cells during persistent antigen stimulation. J Virol, 79 (18), pp. 12112-12116. | Show Abstract | Read more

The killer cell lectin-like receptor G1 (KLRG1) is a natural killer cell receptor expressed by T cells that exhibit impaired proliferative capacity. Here, we determined the KLRG1 expression by virus-specific T cells. We found that repetitive and persistent antigen stimulation leads to an increase in KLRG1 expression of virus-specific CD8+ T cells in mice and that virus-specific CD8+ T cells are mostly KLRG1+ in chronic human viral infections (human immunodeficiency virus, cytomegalovirus, and Epstein-Barr virus) but not in resolved infection (influenza virus). Thus, by using KLRG1 as a T-cell marker, our results suggest that the differentiation status and function of virus-specific CD8+ T cells are directly influenced by persistent antigen stimulation.

Stewart-Jones GB, Gillespie G, Overton IM, Kaul R, Roche P, McMichael AJ, Rowland-Jones S, Jones EY. 2005. Structures of three HIV-1 HLA-B*5703-peptide complexes and identification of related HLAs potentially associated with long-term nonprogression. J Immunol, 175 (4), pp. 2459-2468. | Show Abstract

Long-term nonprogression during acute HIV infection has been strongly associated with HLA-B*5701 or HLA-B*5703. In this study, we present the high resolution crystal structures of HLA-B*5703 complexes with three HIV-1 epitopes: ISPRTLNAW (ISP), KAFSPEVIPMF (KAF-11), and KAFSPEVI (KAF-8). These reveal peptide anchoring at position 2 and their C termini. The different peptide lengths and primary sequences are accommodated by variation in the specific contacts made to the HLA-B*5703, flexibility in water structure, and conformational adjustment of side chains within the peptide-binding groove. The peptides adopt markedly different conformations, and trap variable numbers of water molecules, near a cluster of tyrosine side chains located in the central region of the peptide-binding groove. The KAF-11 epitope completely encompasses the shorter KAF-8 epitope but the peptides are presented in different conformations; the KAF-11 peptide arches out of the peptide-binding groove, exposing a significant main chain surface area. Bioinformatic analysis of the MHC side chains observed to contribute to the peptide anchor specificity, and other specific peptide contacts, reveals HLA alleles associated with long-term nonprogression and a number of related HLA alleles that may share overlapping peptide repertoires with HLA-B*5703 and thus may display a similar capacity for efficient immune control of HIV-1 infection.

Dorrell L, Yang H, Iversen AK, Conlon C, Suttill A, Lancaster M, Dong T, Cebere I, Edwards A, Rowland-Jones S et al. 2005. Therapeutic immunization of highly active antiretroviral therapy-treated HIV-1-infected patients: safety and immunogenicity of an HIV-1 gag/poly-epitope DNA vaccine. AIDS, 19 (12), pp. 1321-1323. | Show Abstract | Read more

In view of the global emergency posed by lack of access to highly active antiretroviral therapy (HAART) and the limitations of current drug regimens, alternative therapeutic strategies are urgently needed. Cellular immune responses elicited by HIV-1 exert some control over virus replication, therefore the enhancement of HIV-1-specific responses by therapeutic vaccination might lead to viral containment without HAART. We evaluated the safety and immunogenicity, in HIV-1-infected individuals under HAART suppression, of a DNA vaccine, pTHr.HIVA.

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Lohman BL, Slyker JA, Richardson BA, Farquhar C, Mabuka JM, Crudder C, Dong T, Obimbo E, Mbori-Ngacha D, Overbaugh J et al. 2005. Longitudinal assessment of human immunodeficiency virus type 1 (HIV-1)-specific gamma interferon responses during the first year of life in HIV-1-infected infants JOURNAL OF VIROLOGY, 79 (13), pp. 8121-8130. | Show Abstract | Read more

Human immunodeficiency virus type 1 (HIV-1) infection results in different patterns of viral replication in pediatric compared to adult populations. The role of early HIV-1-specific responses in viral control has not been well defined, because most studies of HIV-1-infected infants have been retrospective or cross-sectional. We evaluated the association between HIV-1-specific gamma interferon (IFN-γ) release from the cells of infants of 1 to 3 months of age and peak viral loads and mortality in the first year of life among 61 Kenyan HIV-1-infected infants. At 1 month, responses were detected in 7/12 (58%) and 6/21 (29%) of infants infected in utero and peripartum, respectively (P = 0.09), and in ∼50% of infants thereafter. Peaks of HIV-specific spot-forming units (SFU) increased significantly with age in all infants, from 251/106 peripheral blood mononuclear cells (PBMC) at 1 month of age to 501/10 6 PBMC at 12 months of age (P = 0.03), although when limited to infants who survived to 1 year, the increase in peak HIV-specific SFU was no longer significant (P = 0.18). Over the first year of life, infants with IFN-γ responses at 1 month had peak plasma viral loads, rates of decline of viral load, and mortality risk similar to those of infants who lacked responses at 1 month. The strength and breadth of IFN-γ responses at 1 month were not significantly associated with viral containment or mortality. These results suggest that, in contrast to HIV-1-infected adults, in whom strong cytotoxic T lymphocyte responses in primary infection are associated with reductions in viremia, HIV-1-infected neonates generate HIV-1-specific CD8 +-T-cell responses early in life that are not clearly associated with improved clinical outcomes. Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Chakraborty R, Morel AS, Sutton JK, Appay V, Ripley RM, Dong T, Rostron T, Ogola S, Palakudy T, Musoke R et al. 2005. Correlates of delayed disease progression in HIV-1-infected Kenyan children. J Immunol, 174 (12), pp. 8191-8199. | Show Abstract

Without treatment most HIV-1-infected children in Africa die before their third birthday (>89%) and long-term nonprogressors are rare. The mechanisms underlying nonprogression in HIV-1-infected children are not well understood. In the present study, we examined potential correlates of delayed HIV disease progression in 51 HIV-1-infected African children. Children were assigned to progression subgroups based on clinical characterization. HIV-1-specific immune responses were studied using a combination of ELISPOT assays, tetramer staining, and FACS analysis to characterize the magnitude, specificity, and functional phenotype of HIV-1-specific CD8(+) and CD4(+) T cells. Host genetic factors were examined by genotyping with sequence-specific primers. HIV-1 nef gene sequences from infecting isolates from the children were examined for potential attenuating deletions. Thymic output was measured by T cell rearrangement excision circle assays. HIV-1-specific CD8(+) T cell responses were detected in all progression groups. The most striking attribute of long-term survivor nonprogressors was the detection of HIV-1-specific CD4(+) Th responses in this group at a magnitude substantially greater than previously observed in adult long-term nonprogressors. Although long-term survivor nonprogressors had a significantly higher percentage of CD45RA(+)CD4(+) T cells, nonprogression was not associated with higher thymic output. No protective genotypes for known coreceptor polymorphisms or large sequence deletions in the nef gene associated with delayed disease progression were identified. In the absence of host genotypes and attenuating mutations in HIV-1 nef, long-term surviving children generated strong CD4(+) T cell responses to HIV-1. As HIV-1-specific helper cells support anti-HIV-1 effector responses in active disease, their presence may be important in delaying disease progression.

Gillespie GM, Pinheiro S, Sayeid-Al-Jamee M, Alabi A, Kaye S, Sabally S, Sarge-Njie R, Njai H, Joof K, Jaye A et al. 2005. CD8+ T cell responses to human immunodeficiency viruses type 2 (HIV-2) and type 1 (HIV-1) gag proteins are distinguishable by magnitude and breadth but not cellular phenotype. Eur J Immunol, 35 (5), pp. 1445-1453. | Show Abstract | Read more

The mechanisms underlying the relatively slow progression of human immunodeficiency virus type 2 (HIV-2) compared with HIV-1 infection are undefined and could be a result of more effective immune responses. We used HIV-2 and HIV-1 IFN-gamma enzyme-linked immunospot assays to evaluate CD8(+) T cell responses in antiretroviral-naive HIV-2- ('HIV-2(+)') and HIV-1-infected ('HIV-1(+)') individuals. Gag-specific responses were detected in the majority of HIV-2(+) and HIV-1(+) subjects. Overlapping gag peptide analysis indicated a significantly greater magnitude and breadth of responses in the HIV-1(+) cohort, and this difference was attributable to low responses in HIV-2(+) subjects with undetectable viral load (medians 2107 and 512 spot-forming units per 10(6) PBMC, respectively, p=0.007). We investigated the phenotype of viral epitope-specific CD8(+) T cells identified with HLA-B53- and HLA-B58-peptide tetramers (8 HIV-2(+), 11 HIV-1(+) subjects). HIV-2-specific CD8(+) T cells were predominantly CD27(+) CD45RA(-), and only a minority expressed perforin. The limited breadth and low frequency of CD8(+) T cell responses to HIV-2 gag in aviremic HIV-2(+) subjects suggests that these responses reflect antigen load in plasma, as is the case in HIV-1 infection. Immune control of HIV-2 does not appear to be related to the frequency of perforin-expressing virus-specific CD8(+) T cells.

Simmons CP, Dong T, Chau NV, Dung NT, Chau TN, Thao LETT, Dung NT, Hien TT, Rowland-Jones S, Farrar J. 2005. Early T-cell responses to dengue virus epitopes in Vietnamese adults with secondary dengue virus infections. J Virol, 79 (9), pp. 5665-5675. | Show Abstract | Read more

T-cell responses to dengue viruses may be important in both protective immunity and pathogenesis. This study of 48 Vietnamese adults with secondary dengue virus infections defined the breadth and magnitude of peripheral T-cell responses to 260 overlapping peptide antigens derived from a dengue virus serotype 2 (DV2) isolate. Forty-seven different peptides evoked significant gamma interferon enzyme-linked immunospot (ELISPOT) assay responses in 39 patients; of these, 34 peptides contained potentially novel T-cell epitopes. NS3 and particularly NS3200-324 were important T-cell targets. The breadth and magnitude of ELISPOT responses to DV2 peptides were independent of the infecting dengue virus serotype, suggesting that cross-reactive T cells dominate the acute response during secondary infection. Acute ELISPOT responses were weakly correlated with the extent of hemoconcentration in individual patients but not with the nadir of thrombocytopenia or overall clinical disease grade. NS3556-564 and Env414-422 were identified as novel HLA-A*24 and B*07-restricted CD8+ T-cell epitopes, respectively. Acute T-cell responses to natural variants of Env414-422 and NS3556-564 were largely cross-reactive and peaked during disease convalescence. The results highlight the importance of NS3 and cross-reactive T cells during acute secondary infection but suggest that the overall breadth and magnitude of the T-cell response is not significantly related to clinical disease grade.

Dong T, Stewart-Jones G, Chen N, Easterbrook P, Xu X, Papagno L, Appay V, Weekes M, Conlon C, Spina C et al. 2004. HIV-specific cytotoxic T cells from long-term survivors select a unique T cell receptor. J Exp Med, 200 (12), pp. 1547-1557. | Show Abstract | Read more

HIV-specific cytotoxic T lymphocytes (CTL) are important in controlling HIV replication, but the magnitude of the CTL response does not predict clinical outcome. In four donors with delayed disease progression we identified Vbeta13.2 T cell receptors (TCRs) with very similar and unusually long beta-chain complementarity determining region 3 (CDR3) regions in CTL specific for the immunodominant human histocompatibility leukocyte antigens (HLA)-B8-restricted human immunodeficiency virus-1 (HIV-1) nef epitope, FLKEKGGL (FL8). CTL expressing Vbeta13.2 TCRs tolerate naturally arising viral variants in the FL8 epitope that escape recognition by other CTL. In addition, they expand efficiently in vitro and are resistant to apoptosis, in contrast to FL8-specific CTL using other TCRs. Selection of Vbeta13.2 TCRs by some patients early in the FL8-specific CTL response may be linked with better clinical outcome.

Missale G, Papagno L, Penna A, Pilli M, Zerbini A, Vitali P, Pieroni G, Urbani S, Uggeri J, Pinheiro S et al. 2004. Parenteral exposure to high HIV viremia leads to virus-specific T cell priming without evidence of infection. Eur J Immunol, 34 (11), pp. 3208-3215. | Show Abstract | Read more

Previous studies on CTL responses in HIV-exposed uninfected individuals assumed that the patients were exposed to replicating HIV, but the possibility that the immune responses detected were primed by exposure to a defective virus or viral antigen could not be excluded. Epidemiological and laboratory analysis of a nosocomial outbreak of acute hepatitis B unequivocally allowed the identification of an HIV-1- and HBV-co-infected patient with high plasma levels of both viruses, as the source case of the epidemics. This clinical setting provided a natural model for testing the HIV-specific T cell response in patients exposed to blood from a patient with highly replicating HIV. Parenteral exposure to both viruses led to acute hepatitis B in five subjects without evidence of HIV-1 infection. Cryopreserved lymphocytes derived from three exposed patients were tested ex vivo in an ELISPOT assay for IFN-gamma release upon stimulation with peptides from structural and non-structural HIV proteins; one of the patients was also tested with four HLA/class I tetramers. Circulating HIV-specific CD8 cells were detected by tetramer staining and a high frequency of T cells were able to release IFN-gamma upon stimulation with HIV peptides, showing in vivo T cell priming by HIV. These results unequivocally demonstrate a HIV-specific cell-mediated immune response in the absence of infection after exposure to highly replicating HIV.

Kaul R, Rutherford J, Rowland-Jones SL, Kimani J, Onyango JI, Fowke K, MacDonald K, Bwayo JJ, McMichael AJ, Plummer FA. 2004. HIV-1 Env-specific cytotoxic T-lymphocyte responses in exposed, uninfected Kenyan sex workers: a prospective analysis. AIDS, 18 (15), pp. 2087-2089. | Show Abstract | Read more

The prospective significance of HIV-specific cytotoxic T lymphocyte (CTL) responses in highly exposed, persistently seronegative populations is unknown. In 1996-1997 we screened for CTL responses against HIV clade B Env in 39 recently enrolled Kenyan female sex workers, and followed these women prospectively. Annual HIV incidence was 5.8%. CTL were independently associated with age and recent HIV-1 exposure,but were not prospectively associated with protection in a multivariable model that included HIV-1 exposure and duration of sex work.

Shi B, Philpott SM, Weiser B, Kuiken C, Brunner C, Fang G, Fowke KR, Plummer FA, Rowland-Jones S, Bwayo J et al. 2004. Construction of an infectious HIV type 1 molecular clone from an African patient with a subtype D/C Recombinant Virus. AIDS Res Hum Retroviruses, 20 (9), pp. 1015-1018. | Show Abstract | Read more

The majority of HIV-1 infections worldwide occur in Africa, where subtype B viruses are rare and intersubtype recombinants are common. Pathogenesis and vaccine studies need to focus on viruses derived from African patients, and infectious HIV-1 molecular clones can be useful tools. To clone non-B subtypes and recombinant viruses from patients, we cultivated HIV-1 from the plasma of a Kenyan long-term survivor. Viral DNA was cloned into a plasmid, which was transfected into COS cells; progeny virus was propagated in PBMCs. Sequence analyses revealed that both the patient's plasma HIV-1 RNA and the cloned DNA genomes were recombinants between subtypes D and C; subtype C sequences comprised the nef and LTR regions. The cloned virus used the CCR5 coreceptor and did not form syncytia in vitro. This infectious HIV-1 subtype D/C recombinant molecular clone obtained from a Kenyan long-term survivor promises to be useful to study pathogenesis and vaccine design.

Fang G, Kuiken C, Weiser B, Rowland-Jones S, Plummer F, Chen CH, Kaul R, Anzala AO, Bwayo J, Kimani J et al. 2004. Long-term survivors in Nairobi: complete HIV-1 RNA sequences and immunogenetic associations. J Infect Dis, 190 (4), pp. 697-701. | Show Abstract | Read more

To investigate African long-term survivors (LTSs) infected with non-subtype B human immunodeficiency virus type 1 (HIV-1), we obtained full-length HIV-1 RNA sequences and immunogenetic profiles from 6 untreated women enrolled in the Pumwani Sex Worker Cohort in Nairobi, Kenya. There were no discernible sequence changes likely to cause attenuation. CCR2-V64I, an immunogenetic polymorphism linked to LTSs, was detected in 4 women, all of whom carried the HLA B58 allele. Further investigation of 99 HIV-1-infected Nairobi women found an association between CCR2-V64I and HLA B58 (P=.0048). Studying the interaction among immunogenetics, immune responses, and viral sequences from all HIV-1 subtypes may increase our understanding of slow HIV-1 disease progression.

Beattie T, Kaul R, Rostron T, Dong T, Easterbrook P, Jaoko W, Kimani J, Plummer F, McMichael A, Rowland-Jones S. 2004. Screening for HIV-specific T-cell responses using overlapping 15-mer peptide pools or optimized epitopes. AIDS, 18 (11), pp. 1595-1598. | Show Abstract | Read more

The IFN-y enzyme-linked immunospot (ELI-Spot) assay is often used to map HIV-specific CD8 T-cell responses. We compared overlapping 15-mer pools with optimized CD8 epitopes to screen ELISpot responses in HIV-infected individuals. The 15-mer pools detected responses to previously undefined epitopes, but often missed low-level responses to predefined epitopes, particularly when the epitope was central in the 15-mer, rather than at the N-terminus or C-terminus. These factors should be considered in the monitoring of HIV vaccine trials.

Farquhar C, Rowland-Jones S, Mbori-Ngacha D, Redman M, Lohman B, Slyker J, Otieno P, Obimbo E, Rostron T, Ochieng J et al. 2004. Human leukocyte antigen (HLA) B*18 and protection against mother-to-child HIV type 1 transmission. AIDS Res Hum Retroviruses, 20 (7), pp. 692-697. | Show Abstract | Read more

Human leukocyte antigen (HLA) molecules regulate the cellular immune system and may be determinants of infant susceptibility to human immunodeficiency virus type 1 (HIV-1) infection. Molecular HLA typing for class I alleles was performed on infants followed in a Kenyan perinatal cohort. Early HIV-1 infection status was defined as infection occurring at birth or month 1, while late infection via breast milk was defined as first detection of HIV-1 after 1 month of age. Likelihood ratio tests based on a proportional hazards model adjusting for maternal CD4 T cell count and HIV-1 viral load at 32 weeks of gestation were used to test associations between infant allelic variation and incident HIV-1 infection. Among 433 infants, 76 (18%) were HIV-1 infected during 12 months of follow-up. HLA B*18 was associated with a significantly lower risk of early HIV-1 transmission [relative risk (RR) = 0.26; 95% confidence interval (CI) 0.04-0.82], and none of the 24 breastfeeding infants expressing HLA B*18 who were uninfected at month 1 acquired HIV-1 late via breast milk. We observed a trend toward increased early HIV-1 acquisition for infants presenting HLA A*29 (RR = 2.0; 95% CI 1.0-3.8) and increased late HIV-1 acquisition via breast milk for both Cw*07 and Cw*08 (RR = 4.0; 95% CI 1.0-17.8 and RR = 7.2; 95% CI 1.2-37.3, respectively). HLA B*18 may protect breast-feeding infants against both early and late HIV-1 acquisition, a finding that could have implications for the design and monitoring of HIV-1 vaccines targeting cellular immune responses against HIV-1.

Appay V, Rowland-Jones SL. 2004. Lessons from the study of T-cell differentiation in persistent human virus infection. Semin Immunol, 16 (3), pp. 205-212. | Show Abstract | Read more

Confusion surrounds the current classification of memory and effector T-cell subsets and there is a lack of consistency in the use of these terms between human and murine studies. The development of peptide-HLA tetrameric complexes ("tetramers") that accurately identify virus-specific T cells and can be used with a range of cell surface and intra-cellular markers has provided further insights in our understanding of the process of T-cell differentiation, or post-thymic development. We propose that T-cell differentiation subsets in human viral infection should be regarded as distinct from the current definitions of memory and effector cells; further work is needed to reveal the role of the differentiation process in anti-viral immunity.

Hansasuta P, Dong T, Thananchai H, Weekes M, Willberg C, Aldemir H, Rowland-Jones S, Braud VM. 2004. Recognition of HLA-A3 and HLA-A11 by KIR3DL2 is peptide-specific. Eur J Immunol, 34 (6), pp. 1673-1679. | Show Abstract | Read more

The recognition of MHC class I molecules by killer cell immunoglobulin-like receptors (KIR) is central to the control of NK cell function and can also modulate the CTL activation threshold. Among KIR receptors, KIR3DL2 is thought to interact with HLA-A3 and -A11, although direct evidence has been lacking. In this study, we show that HLA-A3 and -A11 tetramers specifically bind to KIR3DL2*001 transfectants and that this recognition is peptide-specific. Single amino acid substitutions in the nonamer peptide underline a critical role for residue 8 in recognition of KIR3DL2. However, the role of this interaction in vivo still remains to be established.

Mwau M, Cebere I, Sutton J, Chikoti P, Winstone N, Wee EG, Beattie T, Chen YH, Dorrell L, McShane H et al. 2004. A human immunodeficiency virus 1 (HIV-1) clade A vaccine in clinical trials: stimulation of HIV-specific T-cell responses by DNA and recombinant modified vaccinia virus Ankara (MVA) vaccines in humans. J Gen Virol, 85 (Pt 4), pp. 911-919. | Show Abstract | Read more

The immunogenicities of candidate DNA- and modified vaccinia virus Ankara (MVA)-vectored human immunodeficiency virus (HIV) vaccines were evaluated on their own and in a prime-boost regimen in phase I clinical trials in healthy uninfected individuals in the United Kingdom. Given the current lack of approaches capable of inducing broad HIV-neutralizing antibodies, the pTHr.HIVA DNA and MVA.HIVA vaccines focus solely on the induction of cell-mediated immunity. The vaccines expressed a common immunogen, HIVA, which consists of consensus HIV-1 clade A Gag p24/p17 proteins fused to a string of clade A-derived epitopes recognized by cytotoxic T lymphocytes (CTLs). Volunteers' fresh peripheral blood mononuclear cells were tested for HIV-specific responses in a validated gamma interferon enzyme-linked immunospot (ELISPOT) assay using four overlapping peptide pools across the Gag domain and three pools of known CTL epitopes present in all of the HIVA protein. Both the DNA and the MVA vaccines alone and in a DNA prime-MVA boost combination were safe and induced HIV-specific responses in 14 out of 18, seven out of eight and eight out of nine volunteers, respectively. These results are very encouraging and justify further vaccine development.

Papagno L, Spina CA, Marchant A, Salio M, Rufer N, Little S, Dong T, Chesney G, Waters A, Easterbrook P et al. 2004. Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS Biol, 2 (2), pp. E20. | Show Abstract | Read more

Progress in the fight against the HIV/AIDS epidemic is hindered by our failure to elucidate the precise reasons for the onset of immunodeficiency in HIV-1 infection. Increasing evidence suggests that elevated immune activation is associated with poor outcome in HIV-1 pathogenesis. However, the basis of this association remains unclear. Through ex vivo analysis of virus-specific CD8(+) T-cells and the use of an in vitro model of naïve CD8(+) T-cell priming, we show that the activation level and the differentiation state of T-cells are closely related. Acute HIV-1 infection induces massive activation of CD8(+) T-cells, affecting many cell populations, not only those specific for HIV-1, which results in further differentiation of these cells. HIV disease progression correlates with increased proportions of highly differentiated CD8(+) T-cells, which exhibit characteristics of replicative senescence and probably indicate a decline in T-cell competence of the infected person. The differentiation of CD8(+) and CD4(+) T-cells towards a state of replicative senescence is a natural process. It can be driven by excessive levels of immune stimulation. This may be part of the mechanism through which HIV-1-mediated immune activation exhausts the capacity of the immune system.

Fang G, Weiser B, Kuiken C, Philpott SM, Rowland-Jones S, Plummer F, Kimani J, Shi B, Kaul R, Bwayo J et al. 2004. Recombination following superinfection by HIV-1. AIDS, 18 (2), pp. 153-159. | Show Abstract | Read more

BACKGROUND: There is increasing recognition of recombinant HIV-1 strains globally, but it has been unclear whether recombination results from superinfection during untreated, chronic infection. OBJECTIVE: To search for evidence of recombination and superinfection in Africa, where multiple HIV-1 subtypes facilitate identification of strains. METHODS: Serial blood samples from highly exposed, chronically infected women in Nairobi's Pumwani sex workers cohort were examined. Serial, complete HIV-1 RNA sequence analyses were performed for seven untreated long-term survivors. Sequences were subjected to computational analysis. RESULTS: One woman had evidence of both superinfection and recombination. Complete HIV-1 RNA sequences were first derived from plasma obtained in 1986, when the woman had been HIV seropositive for at least 21 months; this sequence was entirely subtype A. The sequences obtained from plasma in 1995 and 1997, however, were subtype A/C recombinants with a SimPlot demonstrating that the subtype A fragment in 1995 and 1997 was derived from the original 1986 A sequence. Heteroduplex tracking assays demonstrated that the subtype C sequences were not detectable as minor species in 1986. CONCLUSION: Intersubtype recombination took place between the original non-recombinant subtype A strain and the superinfecting subtype C strain in an untreated, chronically infected woman. This finding helps to explain the rising prevalence of recombinant HIV-1 worldwide. Recombination resulting from superinfection with diverse strains may pose problems for eliciting broad immune responses necessary for an effective vaccine.

Lohman BL, Slyker J, Mbori-Ngacha D, Bosire R, Farquhar C, Obimbo E, Otieno P, Nduati R, Rowland-Jones S, John-Stewart G. 2003. Prevalence and magnitude of human immunodeficiency virus (HIV) type 1-specific lymphocyte responses in breast milk from HIV-1-seropositive women. J Infect Dis, 188 (11), pp. 1666-1674. | Show Abstract | Read more

Human immunodeficiency virus (HIV) type 1-specific cell-mediated immunity of breast milk may influence the likelihood of mother-to-child transmission of HIV-1 via breast-feeding. In breast-milk specimens collected during the first month postpartum from HIV-1-seropositive women in Nairobi, HIV-1 gag-specific cellular responses were detected in 17 (47%) of 36, and env-specific cellular responses were present in 20 (40%) of 50. Peripheral blood lymphocyte responses against either gag or env were detected in 35 (66%) of the 53 subjects, 18 (51%) of whom had positive gag or env responses in their breast milk. In paired analyses of blood and breast milk, the mean magnitude of responses to env or gag stimulation in breast milk was significantly higher than that in blood and remained higher in breast milk after normalization of responses according to CD8+ lymphocyte count. These results suggest that CD8+ lymphocytes present in breast milk have the capacity to recognize HIV-1-infected cells and may be selectively transported to breast milk to reduce either viral replication or transmission in breast milk.

Whelan KT, Lin CL, Cella M, McMichael AJ, Austyn JM, Rowland-Jones SL. 2003. The HIV protease inhibitor indinavir reduces immature dendritic cell transendothelial migration. Eur J Immunol, 33 (9), pp. 2520-2530. | Show Abstract | Read more

Indinavir (IDV) is a protease inhibitor that successfully suppresses HIV-1 replication as part of anti-retroviral therapy. There is evidence to suggest that IDV may also act non-specifically upon host proteases. In this study we investigated whether IDV could modulate protease-dependent molecules involved in dendritic cell (DC) migration - a pivotal process in immunoregulation. Human monocyte-derived DC were exposed to IDV (IDV-DC) and transendothelial migration (TEM) to inflammatory chemokines was determined. TEM of IDV-DC was significantly impaired compared to non-treated DC (p<0.01). Phenotypic analysis revealed that IDV-DC had reduced DC-SIGN expression, correlating with reduced adhesion to immobilized ICAM-2. Nevertheless, the reduction in migration following exposure to IDV could not be fully attributable to DC-SIGN interactions alone. Investigation of IDV-DC interactions with the underlying matrix protein, fibronectin, demonstrated that IDV significantly impaired DC binding to immobilized fibronectin (p<0.01). IDV appeared to act upon VLA-4 and VLA-5 since addition of antagonist monoclonal antibodies (mAb) similarly reduced adhesion of non-treated DC to fibronectin. Combined blockade of DC using anti-VLA-4, VLA-5 and anti-DC-SIGN mAb inhibited TEM to a similar extent as IDV. Our results strongly suggest that IDV inhibits host proteases necessary for DC migration and may, therefore, affect DC immunoregulation in HIV-1-infected patients.

Evans EJ, Hene L, Sparks LM, Dong T, Retiere C, Fennelly JA, Manso-Sancho R, Powell J, Braud VM, Rowland-Jones SL et al. 2003. The T cell surface--how well do we know it? Immunity, 19 (2), pp. 213-223. | Show Abstract | Read more

The overall degree of complexity of the T cell surface has been unclear, constraining our understanding of its biology. Using global gene expression analysis, we show that 111 of 374 genes encoding well-characterized leukocyte surface antigens are expressed by a resting cytotoxic T cell. Unexpectedly, of 97 stringently defined, T cell-specific transcripts with unknown functions that we identify, none encode proteins with the modular architecture characteristic of 80% of leukocyte surface antigens. Only two encode proteins with membrane topologies found exclusively in cell surface molecules. Our analysis indicates that the cell type-specific composition of the resting CD8+ T cell surface is now largely defined, providing an insight into the overall compositional complexity of the mammalian cell surface and a framework for formulating systematic models of T cell surface-dependent processes, such as T cell receptor triggering.

Shiroishi M, Tsumoto K, Amano K, Shirakihara Y, Colonna M, Braud VM, Allan DS, Makadzange A, Rowland-Jones S, Willcox B et al. 2003. Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proc Natl Acad Sci U S A, 100 (15), pp. 8856-8861. | Show Abstract | Read more

Ig-like transcript 4 (ILT4) (also known as leukocyte Ig-like receptor 2, CD85d, and LILRB2) is a cell surface receptor expressed mainly on myelomonocytic cells, whereas ILT2 (also known as leukocyte Ig-like receptor 1, CD85j, and LILRB1) is expressed on a wider range of immune cells including subsets of natural killer and T cells. Both ILTs contain immunoreceptor tyrosine-based inhibitory receptor motifs in their cytoplasmic tails that inhibit cellular responses by recruiting phosphatases such as SHP-1 (Src homology 2 domain containing tyrosine phosphatase 1). Although these ILTs have been shown to recognize a broad range of classical and nonclassical human MHC class I molecules (MHCIs), their precise binding properties remain controversial. We have used surface plasmon resonance to analyze the interaction of soluble forms of ILT4 and ILT2 with several MHCIs. Although the range of affinities measured was quite broad (Kd = 2-45 microM), some interesting differences were observed. ILT2 generally bound with a 2- to 3-fold higher affinity than ILT4 to the same MHCI. Furthermore, ILT2 and ILT4 bound to HLA-G with a 3- to 4-fold higher affinity than to classical MHCIs, suggesting that ILT/HLA-G recognition may play a dominant role in the regulation of natural killer, T, and myelomonocytic cell activation. Finally, we show that ILT2 and ILT4 effectively compete with CD8 for MHCI binding, raising the possibility that ILT2 modulates CD8+ T cell activation by blocking the CD8 binding as well as by recruiting inhibitory molecules through its immunoreceptor tyrosine-based inhibitory receptor motif.

Mongkolsapaya J, Dejnirattisai W, Xu XN, Vasanawathana S, Tangthawornchaikul N, Chairunsri A, Sawasdivorn S, Duangchinda T, Dong T, Rowland-Jones S et al. 2003. Original antigenic sin and apoptosis in the pathogenesis of dengue hemorrhagic fever. Nat Med, 9 (7), pp. 921-927. | Show Abstract | Read more

Dengue virus presents a growing threat to public health in the developing world. Four major serotypes of dengue virus have been characterized, and epidemiological evidence shows that dengue hemorrhagic fever (DHF), the more serious manifestation of the disease, occurs more frequently upon reinfection with a second serotype. We have studied dengue virus-specific T-cell responses in Thai children. During acute infection, few dengue-responsive CD8+ T cells were recovered; most of those present showed an activated phenotype and were undergoing programmed cell death. Many dengue-specific T cells were of low affinity for the infecting virus and showed higher affinity for other, probably previously encountered strains. Profound T-cell activation and death may contribute to the systemic disturbances leading to DHF, and original antigenic sin in the T-cell responses may suppress or delay viral elimination, leading to higher viral loads and increased immunopathology.

Marchant A, Appay V, Van Der Sande M, Dulphy N, Liesnard C, Kidd M, Kaye S, Ojuola O, Gillespie GM, Vargas Cuero AL et al. 2003. Mature CD8(+) T lymphocyte response to viral infection during fetal life. J Clin Invest, 111 (11), pp. 1747-1755. | Show Abstract | Read more

Immunization of newborns against viral infections may be hampered by ineffective CD8(+) T cell responses. To characterize the function of CD8(+) T lymphocytes in early life, we studied newborns with congenital human cytomegalovirus (HCMV) infection. We demonstrate that HCMV infection in utero leads to the expansion and the differentiation of mature HCMV-specific CD8(+) T cells, which have similar characteristics to those detected in adults. High frequencies of HCMV-specific CD8(+) T cells were detected by ex vivo tetramer staining as early as after 28 weeks of gestation. During the acute phase of infection, these cells had an early differentiation phenotype (CD28(-)CD27(+)CD45RO(+), perforin(low)), and they acquired a late differentiation phenotype (CD28(-)CD27(-)CD45RA(+), perforin(high)) during the course of the infection. The differentiated cells showed potent perforin-dependent cytolytic activity and produced antiviral cytokines. The finding of a mature and functional CD8(+) T cell response to HCMV suggests that the machinery required to prime such responses is in place during fetal life and could be used to immunize newborns against viral pathogens.

Kaul R, Thottingal P, Kimani J, Kiama P, Waigwa CW, Bwayo JJ, Plummer FA, Rowland-Jones SL. 2003. Quantitative ex vivo analysis of functional virus-specific CD8 T lymphocytes in the blood and genital tract of HIV-infected women. AIDS, 17 (8), pp. 1139-1144. | Show Abstract | Read more

BACKGROUND: CD8 T lymphocytes are important in HIV-1 control and mediate virus-specific immunity in the blood and genital tract. The induction and monitoring of mucosal CD8 cell responses will be an important component of HIV-1 vaccine trials, but information regarding the frequency, phenotype and function of genital tract CD8 cell responses is lacking. METHODS: Simultaneous blood and cervical cytobrush samples were obtained from 16 HIV-1-infected Kenyan sex workers. Epitope-specific CD8 T lymphocyte frequencies in the blood and genital tract were analysed after short-term peptide incubation and intracellular cytokine staining for interferon-gamma (IFN gamma). RESULTS: Cervical sampling resulted in adequate cell numbers for analysis in 10/16 women. Background IFN gamma production was higher in CD3+/CD8+ lymphocytes from the genital tract than from blood (0.48% versus 0.1%; P < 0.01). Responses to staphylococcal enterotoxin B were detected in cervical CD8 lymphocytes from 10/10 women, at a similar frequency to blood (16.7% in cervix and 13.3% in blood; P = 0.4). HIV-1-specific responses were detected the cervix of 8/10 women, with a trend to higher response frequencies in the genital tract than blood (2.1% versus 0.8%; P = 0.09). Co-expression of integrin CD103 (alpha E beta 7), a mucosal marker, was used to confirm the mucosal origin of cervical responses. CONCLUSIONS: Cytobrush sampling and intracellular cytokine staining is well suited to the analysis of cervical CD8 cell responses. The frequency of functional virus-specific CD3+/CD8+ T cells is similar in the genital tract and blood of HIV-1-infected women. The role of genital tract CD8 cell responses in HIV-1 control warrants further investigation.

Rowland-Jones SL. 2003. Timeline: AIDS pathogenesis: what have two decades of HIV research taught us? Nat Rev Immunol, 3 (4), pp. 343-348. | Show Abstract | Read more

22 years ago, the first cases of an acquired immunodeficiency syndrome afflicting young, homosexual American men were reported, heralding what we now know to be the beginning of the HIV epidemic. Since then, billions of US dollars have been invested in HIV research in the hope of gaining a better understanding of this infection and how to prevent and treat it. What are the landmarks in HIV research over the past two decades, and what questions still remain to be answered? What has the intense study of HIV infection taught us about other virus infections and how our immune system responds to them?

Chakraborty R, Rees G, Bourboulia D, Cross AM, Dixon JR, D'Agostino A, Musoke R, Boshoff C, Rowland-Jones SL, Klenerman P. 2003. Viral coinfections among African children infected with human immunodeficiency virus type 1. Clin Infect Dis, 36 (7), pp. 922-924. | Show Abstract | Read more

City-dwelling children from Kenya who were infected with human immunodeficiency virus type 1 (HIV-1) were tested for coinfection with cytomegalovirus (CMV), human T cell lymphotropic viruses 1 and 2, Kaposi sarcoma-associated herpesvirus (KSHV), or hepatitis B, C, and G viruses. All children were found to be coinfected with CMV, whereas 5% had hepatitis G virus coinfection and 15% had KSHV coinfection. A protective role for hepatitis G virus cannot be excluded but likely affects only a minority of HIV-1-infected African children.

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Nelson PN, Carnegie PR, Martin J, Ejtehadi HD, Hooley P, Roden D, Rowland-Jones S, Warren P, Astley J, Murray PG. 2003. Demystified ... Human endogenous retroviruses JOURNAL OF CLINICAL PATHOLOGY-MOLECULAR PATHOLOGY, 56 (1), pp. 11-18. | Read more

Papagno L, Appay V, Sutton J, Rostron T, Gillespie GM, Ogg GS, King A, Makadzanhge AT, Waters A, Balotta C et al. 2002. Comparison between HIV- and CMV-specific T cell responses in long-term HIV infected donors. Clin Exp Immunol, 130 (3), pp. 509-517. | Show Abstract | Read more

The mechanisms underlying non-progression in HIV-1 infection are not well understood; however, this state has been associated previously with strong HIV-1-specific CD8+ T cell responses and the preservation of proliferative CD4+ T cell responses to HIV-1 antigens. Using a combination of interferon-gamma (IFN-gamma) ELISpot assays and tetramer staining, the HIV-1-specific CD8+ T cell populations were quantified and characterized in untreated long-term HIV-1-infected non-progressors and individuals with slowly progressive disease, both in relation to CD4+ T cell responses, and in comparison with responses to cytomegalovirus (CMV) antigens. High levels of CD8+ T cell responses specific for HIV-1 or CMV were observed, but neither their frequency nor their phenotype seemed to differ between the two patient groups. Moreover, while CMV-specific CD4+ T cell responses were preserved in these donors, IFN-gamma release by HIV-1-specific CD4+ T cells was generally low. These data raise questions with regard to the role played by CD8+ T cells in the establishment and maintenance of long-term non-progression.

Appay V, Rowland-Jones SL. 2002. Premature ageing of the immune system: the cause of AIDS? Trends Immunol, 23 (12), pp. 580-585. | Show Abstract | Read more

The reasons for the failure of the immune system to control HIV-1 infection, and the resulting immunodeficiency, remain unclear. HIV-1 persists in its host despite vigorous immune responses, including a strong, and probably functional, HIV-specific cytotoxic T-lymphocyte response. Interestingly the immunological features of HIV-1-infected individuals show many similarities to those seen in elderly people without HIV infection. We propose that, through a process of continuous immune activation, HIV-1 infection leads to an acceleration of the adaptive immune system ageing process, resulting in premature exhaustion of immune resources, which participates in the onset of immunodeficiency. This hypothesis might shed new light on HIV-1 pathogenesis and could suggest the need to reconsider current immunotherapeutic strategies to fight the virus.

McMichael AJ, Rowland-Jones SL. 2002. HIV: Bad news for stop--start therapy? Nature, 420 (6914), pp. 371-373. | Show Abstract | Read more

An HIV-infected patient who was being treated with anti-retroviral drugs in a 'stop-start' protocol has become infected with a second HIV strain, raising questions about both the treatment strategy and vaccine development.

Ozdemir E, St John LS, Gillespie G, Rowland-Jones S, Champlin RE, Molldrem JJ, Komanduri KV. 2002. Cytomegalovirus reactivation following allogeneic stem cell transplantation is associated with the presence of dysfunctional antigen-specific CD8+ T cells. Blood, 100 (10), pp. 3690-3697. | Show Abstract | Read more

Cytomegalovirus (CMV) infection causes significant morbidity and mortality in the setting of immunodeficiency, including the immune reconstitution phase following allogeneic stem cell transplantation (SCT). We assessed CMV-specific CD4(+) and CD8(+) T-cell responses in 87 HLA-A*0201-positive (A2+) and/or B*0702-positive (B7+) allogeneic stem cell transplant recipients using HLA-peptide tetramer staining and cytokine flow cytometry (CFC) to examine the association of CMV-specific immune reconstitution and CMV antigenemia following SCT. Strong CMV-specific T-cell responses recovered in most subjects (77 of 87, 88%) after SCT. Frequencies of CMV-specific CD8(+) T cells were significantly higher in those subjects who experienced early antigenemia relative to those who did not (2.2% vs 0.33%, P =.0002), as were frequencies of CMV-specific CD4(+) T cells (1.71% vs 0.75%, P =.002). Frequencies of CMV-specific CD8(+) T cells were also higher in subjects experiencing late antigenemia (2.4% vs 0.57%). When we combined tetramer staining and an assessment of cytokine production in a single assay, we found that individuals who experienced CMV antigenemia had lower tumor necrosis factor-alpha (TNF-alpha)-producing fractions of tetramer-staining CMV-specific CD8(+) T cells than subjects who did not (25% vs 65%, P =.015). Furthermore, individuals at high risk for CMV reactivation, including patients with acute graft-versus-host disease and those receiving steroids, had low fractions of cytokine-producing CMV-specific CD8(+) T cells (25% and 27%, respectively). These data suggest that the inability to control CMV reactivation following allogeneic SCT is due to the impaired function of antigen-specific CD8(+) T cells rather than an inability to recover sufficient numbers of CMV-specific T cells.

Oxenius A, Sewell AK, Dawson SJ, Günthard HF, Fischer M, Gillespie GM, Rowland-Jones SL, Fagard C, Hirschel B, Phillips RE et al. 2002. Functional discrepancies in HIV-specific CD8+ T-lymphocyte populations are related to plasma virus load. J Clin Immunol, 22 (6), pp. 363-374. | Show Abstract | Read more

The potent ability of current antiretroviral drug regimens to control human immunodeficiency Virus-1 (HIV-1) replication, in conjunction with the clinical practice of structured therapeutic interruptions, provides a system in which virus levels are manipulated during a persistent infection in humans. Here, we exploit this system to examine the impact of variable plasma virus load (pVL) on the functionality of HIV-specific CD8+ T-lymphocyte populations. Using both ELISpot methodology and intracellular cytokine staining for interferon (IFN)-gamma to assess functional status, together with fluorochrome-labeled peptide-major histocompatibility complex (pMHC) class I tetramer analysis to detect the physical presence of CD8+ T lymphocytes expressing cognate T-cell receptors (TCRs), we observed that the proportion of HIV-specific CD8+ T lymphocytes capable of mounting an effector response to antigen challenge directly ex vivo is related to the kinetics of virus exposure. Specifically, (a) after prolonged suppression of pVL with antiretroviral therapy (ART), physical and functional measures of HIV-specific CD8+ T-lymphocyte frequencies approximated; and (b) the percentage of functionally responsive cells in the HIV-specific CD8+ T lymphocyte populations declined substantially when therapy was discontinued and pVL recrudesced in the same patients. These results corroborate and extend observations in animal models that describe nonresponsive CD8+ T lymphocytes in the presence of high levels of antigen load and have implications for the interpretation of quantitative data generated by methods that rely on functional readouts.

Chakraborty R, Gillespie GM, Reinis M, Rostron T, Dong T, Philpott S, Burger H, Weiser B, Peto T, Rowland-Jones SL. 2002. HIV-1-specific CD8 T cell responses in a pediatric slow progressor infected as a premature neonate. AIDS, 16 (15), pp. 2085-2087. | Show Abstract | Read more

We describe the long-term survival of an individual infected with HIV-1 during extrauterine life as a premature newborn. In the absence of viral attenuation in the Nef/LTR structure or significant co-receptor polymorphisms, slow progression was associated with the strong HIV-1-specific broadly cross-reactive CD8 T cell responses. HIV-1 infection as early as 25 weeks' gestation may thus results in the development of immune responses that control viral replication and lead to prolonged survival.

Rowland-Jones SL, Lohman B. 2002. Interactions between malaria and HIV infection-an emerging public health problem? Microbes Infect, 4 (12), pp. 1265-1270. | Show Abstract | Read more

Recent evidence demonstrates interactions between malaria and HIV infection. HIV-infected people are more likely to experience clinical malaria, and acute malaria can up-regulate HIV replication, leading to higher plasma viral loads. This is most serious in pregnant women, where HIV infection increases the risk of placental malaria, leading to increased infant morbidity and mortality.

Appay V, Rowland-Jones SL. 2002. The assessment of antigen-specific CD8+ T cells through the combination of MHC class I tetramer and intracellular staining. J Immunol Methods, 268 (1), pp. 9-19. | Show Abstract | Read more

Peptide-bound histocompatibility leukocyte antigen (HLA) class I tetramers enable a precise identification of antigen-specific CD8+ T cells using flow cytometry. The combination of this technology with intracellular staining techniques opens up significantly better ways of studying these cells than previously possible, allowing immunologists to look at their life cycle (activation and proliferation), manner of death (aging and apoptosis) and effector function (cytotoxic potential and cytokine production). In this review, we hope to provide an overview of these possibilities, as well as making specific suggestions about the use of intracellular staining techniques in the study of antigen-specific T cells. Understanding how antigen-specific cells develop and function in different circumstances and pathologies will be the key to unravelling the secrets of our cellular immune system.

Bird TG, Kaul R, Rostron T, Kimani J, Embree J, Dunn PP, Bwayo JJ, Plummer FA, Rowland-Jones SL, Dong T, Oxford-Nairobi HLA Collaborative Group. 2002. HLA typing in a Kenyan cohort identifies novel class I alleles that restrict cytotoxic T-cell responses to local HIV-1 clades. AIDS, 16 (14), pp. 1899-1904. | Show Abstract | Read more

OBJECTIVES: To investigate HLA class I allele frequencies in a Kenyan commercial sex worker (CSW) cohort, and to examine HIV-1 specific cytotoxic T lymphocyte (CTL) responses directed against epitopes derived from locally prevalent clade A virus. METHODS: PCR-single strand polymorphism HLA class I typing. Sequencing of novel alleles and examination of their distribution in the CSW cohort, and a low risk HIV uninfected cohort. The peptide-binding motif of a novel class I allele was predicted, and a panel of candidate CTL epitopes was synthesized whose functional significance was examined using ELISpot and Cr release assays. RESULTS: Class I HLA-A and B frequencies within the cohort are presented. Two novel class I alleles were found, HLA-B*4415 and HLA-Cw*0407. These two class I alleles were relatively common, both in the CSW cohort (2.1% and 3.3% respectively) and in a cohort of lower risk women (1.9% and 3.8% respectively). Allele HLA-B*4415 restricted CTL responses against a novel epitope (EEKAFSPEV) derived from p24 of clade A HIV-1, and HLA-Cw0407 restricted CTL against a predefined HLA-Cw*0401 gp120 epitope. CONCLUSIONS: Multi-epitope vaccine design requires knowledge of HLA class I distribution and HIV CTL epitope characterization in potential target populations. The description of two novel HLA class I alleles at high frequency in this high risk Kenyan CSW cohort suggests that HLA mapping of vaccine cohorts and subsequent characterization of local CTL epitopes will be warranted prior to vaccine trials.

Appay V, Zaunders JJ, Papagno L, Sutton J, Jaramillo A, Waters A, Easterbrook P, Grey P, Smith D, McMichael AJ et al. 2002. Characterization of CD4(+) CTLs ex vivo. J Immunol, 168 (11), pp. 5954-5958. | Show Abstract

The cytotoxic potential of CD8(+) T cells and NK cells plays a crucial role in the immune response to pathogens. Although in vitro studies have reported that CD4(+) T cells are also able to mediate perforin-mediated killing, the in vivo existence and relevance of cytotoxic CD4(+) T cells have been the subject of debate. Here we show that a population of CD4(+) perforin(+) T cells is present in the circulation at low numbers in healthy donors and is markedly expanded in donors with chronic viral infections, in particular HIV infection, at all stages of the disease, including early primary infection. Ex vivo analysis shows that these cells have cytotoxic potential mediated through the release of perforin. In comparison with more classical CD4(+) T cells, this subset displays a distinct surface phenotype and functional profile most consistent with end-stage differentiated T cells and include Ag experienced CD4(+) T cells. The existence of CD4(+) cytotoxic T cells in vivo at relatively high levels in chronic viral infection suggests a role in the immune response.

Kaul R, Rowland-Jones SL, Gillespie G, Kimani J, Dong T, Kiama P, Simonsen JN, Bwayo JJ, McMichael AJ, Plummer FA. 2002. Gonococcal cervicitis is associated with reduced systemic CD8+ T cell responses in human immunodeficiency virus type 1-infected and exposed, uninfected sex workers. J Infect Dis, 185 (10), pp. 1525-1529. | Show Abstract | Read more

Neisseria gonorrhoeae cervicitis and human immunodeficiency virus (HIV) type 1 frequently coinfect core transmitter populations, such as female sex workers. Gonococcal cervicitis is associated with increased viral shedding and plasma viremia in HIV-1-infected women and increased HIV-1 susceptibility in uninfected women. We studied the influence of gonococcal cervicitis on CD8(+) interferon (IFN)-gamma responses to HIV-1 and cytomegalovirus (CMV) epitopes in HIV-1-infected and in highly-exposed, persistently seronegative (HEPS) female sex workers. In HIV-1-infected women, gonococcal cervicitis was associated with reduced IFN-gamma responses in bulk CD8(+) lymphocyte populations, and intracellular cytokine staining, combined with class I major histocompatibility complex (MHC)-peptide tetramer studies, demonstrated reduced IFN-gamma production by HIV-1 epitope-specific CD8(+) lymphocytes. In HEPS sex workers, cervicitis was associated with the transient loss of systemic HIV-1-specific CD8(+) responses and with reduced function of CMV-specific CD8(+) lymphocytes. Impaired function of virus-specific CD8(+) lymphocytes may partly explain the deleterious effects of gonococcal cervicitis on HIV-1 immune control and susceptibility.

Gillespie GM, Kaul R, Dong T, Yang HB, Rostron T, Bwayo JJ, Kiama P, Peto T, Plummer FA, McMichael AJ, Rowland-Jones SL. 2002. Cross-reactive cytotoxic T lymphocytes against a HIV-1 p24 epitope in slow progressors with B*57. AIDS, 16 (7), pp. 961-972. | Show Abstract | Read more

OBJECTIVES: To determine whether CD8 T lymphocytes from HIV-1-infected patients expressing B*5701 and B*5703 show broad cross-reactivity against different variants of a conserved p24 epitope, which might account for the good prognosis of HIV-1-infected individuals with HLA-B*57. DESIGN: B*5701+ and B*5703+ were recruited from Nairobi, Kenya and from Oxford, UK. All patients had been HIV positive for at least 8 years and could be categorized as slow progressors. METHODS: CD8 cytotoxic T cell clones were generated from B*5701+ and B*5703+ donors and tested for their ability to recognize clade variants of an index p24 epitope in standard cytolytic assays. Cross-reactive responses in freshly isolated peripheral blood mononuclear cells (PBMC) were assessed by interferon-gamma (IFNgamma) production and tetramer binding. RESULTS: Broad cross-clade reactivity for both cytolysis and tetramer binding was observed in CD8 T cell clones from patients harbouring the index epitope sequence. Patterns of cross-reactivity were similar in freshly isolated PBMC but varied between individuals in terms of strength and breath of responses generated. One common variant induced an unusual response with tetramer binding but often failed to induce IFNgamma production, and another was a weak stimulator of both IFNgamma and cytolytic activity. CONCLUSION: B*5701+ and B5703+ donors demonstrate broad functional cross-reactivity to both common and rare variants of a dominant p24 epitope, which could be relevant to the association of B*57 alleles with slow progression to AIDS.

Beattie T, Rowland-Jones S, Kaul R. 2002. HIV-1 and AIDS: what are protective immune responses? J HIV Ther, 7 (2), pp. 35-39. | Show Abstract

HIV-1 is the leading cause of death in sub-Saharan Africa, responsible for one in five deaths in the region. Although potent antiretroviral therapy has had a huge impact on HIV-associated morbidity and mortality in economically advantaged countries, it is beyond the reach of most infected people in the world. The development of an effective HIV vaccine would be a huge step towards stopping the pandemic, but an important precondition for such a vaccine is that it must induce a host immune response that can protect the host from HIV acquisition or disease progression. This article reviews the evidence that protective host immune responses do exist, either in highly exposed, persistently seronegative (HEPS) subjects or in HIV-1-infected long-term non-progressors (LTNPs), as well as efforts to reproduce putative protective immunity in animal vaccine models. HIV-1-specific cellular responses are a key to viral control in infected subjects, but generally fail in the long term. This suggests that the goal of a preventive HIV-1 vaccine should be sterile immunity, rather than improved virus control after infection. Achieving this goal will at least require the induction of HIV-1-specific cellular immune responses at the site of initial viral contact (generally the genital tract), perhaps in combination with HIV-1-specific neutralising antibody.

Appay V, Papagno L, Spina CA, Hansasuta P, King A, Jones L, Ogg GS, Little S, McMichael AJ, Richman DD, Rowland-Jones SL. 2002. Dynamics of T cell responses in HIV infection. J Immunol, 168 (7), pp. 3660-3666. | Show Abstract

Cytotoxic CD8(+) T cells play a major role in the immune response against viruses. However, the dynamics of CD8(+) T cell responses during the course of a human infection are not well understood. Using tetrameric complexes in combination with a range of intracellular and extracellular markers, we present a detailed analysis of the changes in activation and differentiation undergone by Ag-specific CD8(+) T cells, in relation to Ag-specific CD4(+) T cell responses, in the context of a human infection: HIV-1. During primary HIV-1 infection, the initial population of HIV-specific CD8(+) T cells is highly activated and prone to apoptosis. The Ag-specific cells differentiate rapidly from naive to cells at a perforin low intermediate stage of differentiation, later forming a stable pool of resting cells as viral load decreases during chronic infection. These observations have significant implications for our understanding of T cell responses in human viral infections in general and indicate that the definition of effector and memory subsets in humans may need revision.

Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L, Ogg GS, King A, Lechner F, Spina CA et al. 2002. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med, 8 (4), pp. 379-385. | Show Abstract | Read more

The viruses HIV-1, Epstein-Barr virus (EBV), cytomegalovirus (CMV) and hepatitis C virus (HCV) are characterized by the establishment of lifelong infection in the human host, where their replication is thought to be tightly controlled by virus-specific CD8+ T cells. Here we present detailed studies of the differentiation phenotype of these cells, which can be separated into three distinct subsets based on expression of the costimulatory receptors CD28 and CD27. Whereas CD8+ T cells specific for HIV, EBV and HCV exhibit similar characteristics during primary infection, there are significant enrichments at different stages of cellular differentiation in the chronic phase of persistent infection according to the viral specificity, which suggests that distinct memory T-cell populations are established in different virus infections. These findings challenge the current definitions of memory and effector subsets in humans, and suggest that ascribing effector and memory functions to subsets with different differentiation phenotypes is no longer appropriate.

Appay V, Hansasuta P, Sutton J, Schrier RD, Wong JK, Furtado M, Havlir DV, Wolinsky SM, McMichael AJ, Richman DD et al. 2002. Persistent HIV-1-specific cellular responses despite prolonged therapeutic viral suppression. AIDS, 16 (2), pp. 161-170. | Show Abstract | Read more

DESIGN: Antiretroviral therapy (ART) currently represents the best way to avert the lethal consequences of chronic persistent HIV-1 infection. It leads to significant reductions of plasma viremia, often to undetectable levels, but it can also be linked with the reduction and disappearance of detectable HIV-specific CD8 T-cell responses. RESULTS: Here we describe a group of patients in whom ongoing replication of HIV, particularly transcription of Nef mRNA species, was detected despite prolonged and clinically successful antiretroviral treatment. Modest, but significant, numbers of HIV-specific CD8 T cells and CD4 T-cell responses were found in these subjects, with the strongest responses directed towards Nef epitopes. Detailed phenotypic analysis of the HIV-specific CD8 cells demonstrated low perforin levels and persistent expression of CD27, a phenotype associated with incomplete differentiation of cytotoxic T lymphocytes (CTL). CONCLUSION: This immature CTL phenotype has been described previously in association with chronic HIV disease, but its continued persistence is surprising in the setting of prolonged viral suppression on therapy and the presence of HIV-specific CD4 cell activity.

Gillespie GMA, Appay V, Rowland-Jones SL, McMichael AJ. 2002. The use of tetramers in the quantitative analysis of T-cell responses IMMUNOLOGY OF INFECTION, SECOND EDITION, 32 pp. 125-156.

MacDonald KS, Matukas L, Embree JE, Fowke K, Kimani J, Nagelkerke NJ, Oyugi J, Kiama P, Kaul R, Luscher MA et al. 2001. Human leucocyte antigen supertypes and immune susceptibility to HIV-1, implications for vaccine design. Immunol Lett, 79 (1-2), pp. 151-157. | Show Abstract | Read more

T cell responses against HIV-1 have been identified in a number of exposed uninfected populations. We hypothesized that the ability to mount an effective T cell response is partly determined by the human leucocyte antigens (HLA) phenotype of the individual. We examined whether certain HLA supertypes were associated with differential HIV-1 susceptibility in sexually exposed adults and in the setting of mother to child HIV-1 transmission. By multivariate analysis, decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related class I HLA alleles (A2/6802 supertype) in sexually exposed adults (Hazard ratio=0.42, 95% confidence intervals (CI): 0.22-0.81, P=0.009) and perinatally exposed infants (Odds ratio=0.12, 95% CI: 0.03-0.54, P=0.006). The alleles in this HLA supertype are known in some cases, to present the same peptide epitopes (termed 'supertopes'), for T cell recognition. The identification of HIV-1 supertopes, which are associated with protection from HIV-1 infection, has important implications for the application of epitope-based HIV-l vaccines in a variety of racial groups.

Fang G, Burger H, Chappey C, Rowland-Jones S, Visosky A, Chen CH, Moran T, Townsend L, Murray M, Weiser B. 2001. Analysis of transition from long-term nonprogressive to progressive infection identifies sequences that may attenuate HIV type 1. AIDS Res Hum Retroviruses, 17 (15), pp. 1395-1404. | Show Abstract | Read more

Long-term nonprogressive human immunodeficiency virus type 1 (HIV-1) infection and its transition to progressive infection presents an opportunity to identify the molecular determinants of HIV-1 attenuation and pathogenesis. We studied an individual who underwent a transition from long-term nonprogressive to rapidly progressive infection. Because HIV-1 RNA genomes in plasma represent replicating virus, we developed a technique to clone full-length HIV-1 RNA genomes from plasma and used this technique to obtain clones from this individual before and during the transition. Most clones assayed were infectious, demonstrating that the RNA genomes encoded viable virus. Analysis of 20 complete HIV-1 RNA genomic sequences revealed one major difference between sequences found during the two phases of infection. During the nonprogressive phase, the predominant sequences had a large deletion in an Sp1-binding site and adjacent promoter in the U3 part of the long terminal repeat (LTR); when the infection became progressive, all viruses had intact Sp1 and promoter sequences and were derived from a minor species present earlier. Analysis of 184 clones of the LTR region obtained at five time points spanning a 7-year period confirmed this switch. In an in vitro assay, the deletion downregulated LTR-driven transcription of a reporter gene. In addition, analysis of cytotoxic T lymphocyte (CTL) epitopes predicted from the complete viral RNA genomes revealed multiple potential escape mutants that accumulated by the time of progression. These studies suggest that during the nonprogressive phase, the Sp1 enhancer-promoter deletion is likely to have played a role in decreasing replication, thereby attenuating HIV-1. The accumulation of CTL escape mutants suggests that a breakdown in immunologic surveillance may have allowed proliferation of intact virus, thus leading to rapid disease progression. These data reveal the viral and immune interactions characterizing a transition from long-term nonprogressive to rapidly progressive infection.

Vyakarnam A, Eyeson J, Teo I, Zuckerman M, Babaahmady K, Schuitemaker H, Shaunak S, Rostron T, Rowland-Jones S, Simmons G, Clapham P. 2001. Evidence for a post-entry barrier to R5 HIV-1 infection of CD4 memory T cells. AIDS, 15 (13), pp. 1613-1626. | Show Abstract | Read more

BACKGROUND: HIV-1 strains R5 and X4 can infect CD4 memory T cells in vivo. Anti-CD3/28 stimulation induces beta-chemokines and CCR5 down-regulation and renders these cells resistant to R5 HIV-1 infection. Here we describe an additional cellular mechanism that blocks productive R5 HIV-1 infection of CD4 memory T cells. METHODS: Blood-derived CD4 memory T cells and CD4 T-cell clones were infected with primary R5 and X4 HIV-1 strains. Virus replication was correlated with CCR5 expression and beta-chemokine production. Virus entry and infectivity were measured by PCR for early and late products of HIV reverse transcription respectively. RESULTS: R5 strains were up to 1000-fold less infectious than X4 viruses for CD4 memory T cells. This resistance was independent of CCR5 levels and of the Delta-32 mutation and the CCR2-V64I/CCR5-59653T linked mutations. Blocking endogenous beta-chemokines relieved minimally this restriction. At the single cell level, CD4 memory cells were either permissive or non-permissive for R5 HIV-1 infection. R5 HIV titre was up to 10-fold lower than X4 virus titre even in a permissive clone. However, R5 viruses replicated as efficiently as X4 viruses in the permissive clone when neutralizing anti-beta chemokine antibodies were added. Non-permissive cells blocked a post-entry step of the virus life-cycle and expressed early but not late HIV transcripts. Neutralizing anti-beta chemokine antibodies promoted R5 virus replication marginally in the non-permissive clone. CONCLUSION: Some blood memory CD4 T cells retard R5 HIV-1 replication via endogenous beta-chemokines whereas others block productive R5 HIV-1 infection by an additional mechanism that interferes with a post-entry step of the virus life cycle. These natural barriers might contribute to lower pathogenicity of R5 HIV-1 strains for CD4 memory T cells than X4 viruses that emerge late in disease.

John GC, Bird T, Overbaugh J, Nduati R, Mbori-Ngacha D, Rostron T, Dong T, Kostrikis L, Richardson B, Rowland-Jones SL. 2001. CCR5 promoter polymorphisms in a Kenyan perinatal human immunodeficiency virus type 1 cohort: association with increased 2-year maternal mortality. J Infect Dis, 184 (1), pp. 89-92. | Show Abstract | Read more

The CCR5 chemokine receptor acts as a coreceptor with CD4 to permit infection by primary macrophage-tropic human immunodeficiency virus type 1 (HIV-1) strains. The CCR5Delta32 mutation, which is associated with resistance to infection in homozygous individuals and delayed disease progression in heterozygous individuals, is rare in Africa, where the HIV-1 epidemic is growing rapidly. Several polymorphisms in the promoter region of CCR5 have been identified, the clinical and functional relevance of which remain poorly defined. We evaluated the effect of 4 CCR5 promoter mutations on systemic and mucosal HIV-1 replication, disease progression, and perinatal transmission in a cohort of 276 HIV-1-seropositive women in Nairobi, Kenya. Mutations at positions 59353, 59402, and 59029 were not associated with effects on mortality, virus load, genital shedding, or transmission in this cohort. However, women with the 59356 C/T genotype had a 3.1-fold increased risk of death during the 2-year follow-up period (95% confidence interval [CI], 1.0-9.5) and a significant increase in vaginal shedding of HIV-1-infected cells (odds ratio, 2.1; 95% CI, 1.0-4.3), compared with women with the 59356 C/C genotype.

Dorrell L, Willcox BE, Jones EY, Gillespie G, Njai H, Sabally S, Jaye A, DeGleria K, Rostron T, Lepin E et al. 2001. Cytotoxic T lymphocytes recognize structurally diverse, clade-specific and cross-reactive peptides in human immunodeficiency virus type-1 gag through HLA-B53. Eur J Immunol, 31 (6), pp. 1747-1756. | Show Abstract | Read more

Human immunodeficiency virus type-1 (HIV-1) cytotoxic T lymphocyte (CTL) epitopes have largely been defined in Caucasian populations infected with clade B virus. Identification of potentially protective CTL epitopes in non-B clade-infected African subjects is important for vaccine development. In a study of CTL responses in clade A-infected Gambians, using cytotoxicity, interferon-gamma (IFN-gamma) enzyme-linked immunospot (ELISpot) and HLA-B53-peptide tetramer assays, we identified three HLA-B53-restricted epitopes in HIV-1 gag p24. CTL specific for an epitope in a highly immunogenic region of the p24 protein showed no cross-reactivity to other HIV-1 clades. Two of the epitopes would not have been predicted from the peptide-binding motif due to the absence of a proline anchor at position 2. Structural analysis of HLA-B53 and its relative, HLA B35, enabled us to re-define the peptide-binding motif to include other P2 anchors. These results demonstrate the value of combined immunological and structural analyses in defining novel CTL epitopes and have implications for HIV-1 vaccine design.

Kaul R, Dong T, Plummer FA, Kimani J, Rostron T, Kiama P, Njagi E, Irungu E, Farah B, Oyugi J et al. 2001. CD8(+) lymphocytes respond to different HIV epitopes in seronegative and infected subjects. J Clin Invest, 107 (10), pp. 1303-1310. | Show Abstract | Read more

HIV-1-specific cytotoxic T-lymphocyte (CTL) responses have been detected at a low frequency in many HIV-1-exposed, persistently seronegative (HEPS) subjects. However, it is unclear how CTLs could protect against HIV acquisition in HEPS subjects, when high levels of circulating CTL fail to prevent disease progression in most seropositive subjects. To address this issue we studied CD8(+) lymphocyte responses to a panel of HIV-1 CTL epitopes in 91 HEPS and 87 HIV-1-infected Nairobi sex workers. HIV-specific responses in seropositive women focused strongly on epitopes rarely or never recognized in HEPS subjects, who targeted epitopes that were subdominant or unrecognized in infected women. These differences in epitope specificity were restricted by only those HLA class I alleles that are associated with a reduced risk of HIV-1 infection in this cohort. Late seroconversion in HEPS donors was associated with a switch in epitope specificity and/or immunodominance to those epitopes preferentially recognized by HIV-1-infected women. The likelihood of detecting HIV-1-specific responses in HEPS women increased with the duration of viral exposure, suggesting that HIV-1-specific CD8(+) responses are acquired over time. The association between differential recognition of distinct CTL epitopes and protection from HIV-1 infection may have significant implications for vaccine design.

McMichael AJ, Rowland-Jones SL. 2001. Cellular immune responses to HIV. Nature, 410 (6831), pp. 980-987. | Show Abstract | Read more

The cellular immune response to the human immunodeficiency virus, mediated by T lymphocytes, seems strong but fails to control the infection completely. In most virus infections, T cells either eliminate the virus or suppress it indefinitely as a harmless, persisting infection. But the human immunodeficiency virus undermines this control by infecting key immune cells, thereby impairing the response of both the infected CD4+ T cells and the uninfected CD8+ T cells. The failure of the latter to function efficiently facilitates the escape of virus from immune control and the collapse of the whole immune system.

Rowland-Jones S. 2001. HIV: vaccines out of Africa. Biologist (London), 48 (2), pp. 64-66. | Show Abstract

When HIV was first identified as the cause of AIDS in 1983, it was widely expected that a vaccine would be relatively straightforward to make. Why, eighteen years later, are we still waiting?

Champagne P, Ogg GS, King AS, Knabenhans C, Ellefsen K, Nobile M, Appay V, Rizzardi GP, Fleury S, Lipp M et al. 2001. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature, 410 (6824), pp. 106-111. | Show Abstract | Read more

Understanding the lineage differentiation of memory T cells is a central question in immunology. We investigated this issue by analysing the expression of the chemokine receptor CCR7, which defines distinct subsets of naive and memory T lymphocytes with different homing and effector capacities and antiviral immune responses to HIV and cytomegalovirus. Ex vivo analysis of the expression of CD45RA and CCR7 antigens, together with in vitro analysis of the cell-division capacity of different memory CD8+ T-cell populations, identified four subsets of HIV- and CMV-specific CD8+ T lymphocytes, and indicated the following lineage differentiation pattern: CD45RA+ CCR7+ --> CD45RA- CCR7+ --> CD45RA- CCR7- --> CD45RA+ CCR7-. Here we demonstrate through analysis of cell division (predominantly restricted to the CCR7+ CD8+ T-cell subsets) that the differentiation of antigen-specific CD8+ T cells is a two-step process characterized initially by a phase of proliferation largely restricted to the CCR7+ CD8+ cell subsets, followed by a phase of functional maturation encompassing the CCR7- CD8+ cell subsets. The distribution of these populations in HIV- and CMV-specific CD8+ T cells showed that the HIV-specific cell pool was predominantly (70%) composed of pre-terminally differentiated CD45RA- CCR7- cells, whereas the CMV-specific cell pool consisted mainly (50%) of the terminally differentiated CD45RA+ CCR7- cells. These results demonstrate a skewed maturation of HIV-specific memory CD8+ T cells during HIV infection.

Rowland-Jones S, Pinheiro S, Kaul R. 2001. New insights into host factors in HIV-1 pathogenesis. Cell, 104 (4), pp. 473-476. | Read more

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Kelleher AD, Long C, Holmes EC, Allen RL, Wilson J, Conlon C, Workman C, Shaunak S, Olson K, Goulder P et al. 2001. Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses JOURNAL OF EXPERIMENTAL MEDICINE, 193 (3), pp. 375-385. | Show Abstract | Read more

The immune response to HIV-1 in patients who carry human histocompatibility leukocyte antigen (HLA)-B27 is characterized by an immunodominant response to an epitope in p24 gag (amino acids 263-272, KR WIILGLNK). Substitution of lysine (K) or glycine (G) for arginine (R) at HIV-1 gag residue 264 (R264K and R264G) results in epitopes that bind to HLA-B27 poorly. We have detected a R264K mutation in four patients carrying HLA-B27. In three of these patients the mutation occurred late, coinciding with disease progression. In another it occurred within 1 yr of infection and was associated with a virus of syncytium-inducing phenotype. In each case, R264K was tightly associated with a leucine to methionine change at residue 268. After the loss of the cytotoxic T lymphocyte (CTL) response to this epitope and in the presence of high viral load, reversion to wild-type sequence was observed. In a fifth patient, a R264G mutation was detected when HIV-1 disease progressed. Its occurrence was associated with a glutamic acid to aspartic acid mutation at residue 260. Phylogenetic analyses indicated that these substitutions emerged under natural selection rather than by genetic drift or linkage. Outgrowth of CTL escape viruses required high viral loads and additional, possibly compensatory, mutations in the gag protein.

Kaul R, Rowland-Jones SL, Kimani J, Dong T, Yang HB, Kiama P, Rostron T, Njagi E, Bwayo JJ, MacDonald KS et al. 2001. Late seroconversion in HIV-resistant Nairobi prostitutes despite pre-existing HIV-specific CD8+ responses. J Clin Invest, 107 (3), pp. 341-349. | Show Abstract | Read more

Resistance to HIV infection in a small group of Kenyan sex workers is associated with CD8+-lymphocyte responses to HIV cytotoxic T-lymphocyte (CTL) epitopes. Eleven prostitutes meeting criteria for HIV resistance seroconverted between 1996 and 1999. The occurrence and specificity of preexisting HIV-1 epitope-specific responses were examined using the IFN-gamma enzyme-linked immunospot assay, and any epitopes recognized were cloned and sequenced from the infecting viral isolate. Immunologic and behavioral variables were compared between late seroconverters and persistently uninfected sex worker controls. HIV-1 CTL epitope responses were present in four of six cases, 5-18 months before seroconversion, and their presence was confirmed by bulk CTL culture. A possible viral escape mutation was found in one of six epitopes. The key epidemiologic correlate of late seroconversion was a reduction in sex work over the preceding year. In persistently uninfected controls, a break from sex work was associated with a loss of HIV-specific CD8+ responses. Late seroconversion may occur in HIV-1-resistant sex workers despite preceding HIV-specific CD8+ responses. Seroconversion generally occurs in the absence of detectable CTL escape mutations and may relate to the waning of HIV-specific CD8+ responses due to reduced antigenic exposure.

Appay V, Rowland-Jones SL. 2001. RANTES: a versatile and controversial chemokine. Trends Immunol, 22 (2), pp. 83-87. | Show Abstract | Read more

The activity of the chemokine RANTES is not restricted merely to chemotaxis. It is a powerful leukocyte activator, a feature potentially relevant in a range of inflammatory disorders. RANTES has attracted attention because it can potently suppress and, in some circumstances, enhance HIV replication. These characteristics are critically dependent on its ability to self-aggregate and bind to glycosaminoglycans.

Hansasuta P, Rowland-Jones SL. 2001. HIV-1 transmission and acute HIV-1 infection. Br Med Bull, 58 (1), pp. 109-127. | Show Abstract | Read more

An understanding of the central events in the transmission of HIV-1 infection is critical to the development of effective strategies to prevent infection. Although the main routes of transmission have been known for some time, surprisingly little is known about the factors that influence the likelihood of transmitting or acquiring HIV-1 infection. Once infection has taken place, the series of virological and immunopathological events that constitute primary HIV-1 infection are thought to be closely linked with the subsequent clinical course of the infected person. Recent studies have provided some support for the notion that intervention with aggressive anti-retroviral drug therapy at this stage has the potential to prevent some of the damage to the immune system that will otherwise develop in the vast majority of infected people.

Kaul R, Makadzange T, Rowland-Jones S. 2000. AIDS in Africa: a disaster no longer waiting to happen. Nat Immunol, 1 (4), pp. 267-270. | Show Abstract | Read more

The HIV-AIDS epidemic in Africa is now of epic proportions. This has precipitated a crisis in public health that needs to be resolved in a uniquely African way. Local and Western research efforts must be blended with strong political and social will to get the preventative message and appropriate therapies to the people whom need them most.

Dela Cruz CS, Tan R, Rowland-Jones SL, Barber BH. 2000. Creating HIV-1 reverse transcriptase cytotoxic T lymphocyte target structures by HLA-A2 heavy chain modifications. Int Immunol, 12 (9), pp. 1293-1302. | Show Abstract | Read more

Vigorous HIV-1-specific CD8(+) cytotoxic T lymphocyte (CTL) responses play an important role in the control of HIV-1 replication and the induction of a strong, broadly cross-reactive CTL response remains an important goal of HIV vaccine development. It is known that the display of high levels of class I MHC-viral peptide complexes at the cell surface of target cells is necessary to elicit a strong CTL response. We now report two strategies to enhance the presentation of defined HIV-1 epitope-specific CTL target structures, by incorporating subdominant HIV-1 reverse transcriptase (RT) CTL epitope sequences into the human class I MHC molecule HLA-A2. We show that either incorporation of HIV-1 CTL epitopes into the signal sequence of HLA or tethering of epitopes to the HLA-A2 heavy chain provide simple ways to create effective CTL target structures that can be recognized and lysed by human HLA-A2-restricted RT-specific CD8(+) CTL. Moreover, cells expressing these epitope-containing HLA-A2 constructs stimulated the generation of primary epitope-specific CTL in vitro. These strategies offer new options in the design of plasmid DNA-based vaccines or immunotherapeutics for the induction of CTL responses against subdominant HIV-1 epitopes.

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Gillespie GMA, Wills MR, Appay V, O'Callaghan C, Murphy M, Smith N, Sissons P, Rowland-Jones S, Bell JI, Moss PAH. 2000. Functional heterogeneity and high frequencies of cytomegalovirus-specific CD8(+) T lymphocytes in healthy seropositive donors JOURNAL OF VIROLOGY, 74 (17), pp. 8140-8150. | Show Abstract | Read more

Human cytomegalovirus (HCMV) infection is largely asymptomatic in the immunocompetent host, but remains a major cause of morbidity in immunosuppressed individuals. Using the recently described technique of staining antigen-specific CD8+ T cells with peptide-HLA tetrameric complexes, we have demonstrated high levels of antigen-specific cells specific for HCMV peptides and show that this may exceed 4% of CD8+ T cells in immunocompetent donors. Moreover, by staining with tetramers in combination with antibodies to cell surface markers and intracellular cytokines, we demonstrate functional heterogeneity of HCMV-specific populations. A substantial proportion of these are effector cytotoxic T lymphocytes, as demonstrated by their ability to lyse peptide-pulsed targets in 'fresh' killing assays. These data suggest that the immune response to HCMV is periodically boosted by a low level of HCMV replication and that sustained immunological surveillance contributes to the maintenance of host-pathogen homeostasis. These observations should improve our understanding of the immunobiology of persistent viral infection.

McMichael AJ, Callan M, Appay V, Hanke T, Ogg G, Rowland-Jones S. 2000. The dynamics of the cellular immune response to HIV infection: implications for vaccination. Philos Trans R Soc Lond B Biol Sci, 355 (1400), pp. 1007-1011. | Show Abstract | Read more

Recent advances in measuring T-cell responses to viruses have led to new insights into how these T cells respond. In the acute infection there are massive CD8+ T-cell responses to both Epstein-Barr virus (EBV) and to human immunodeficiency virus (HIV). Many of these T cells are effector cells and only a minority appear to be capable of maintaining immunological memory. In persistent virus infections, high levels of antigen-specific effector cells persist. If virus does not persist, the effectors fade in number but memory is maintained and is primed to react rapidly to a new challenge. A vaccine that stimulates only T-cell responses may protect when these memory cells respond rapidly enough to generate high numbers of effectors before the infecting virus becomes established.

Kelleher AD, Rowland-Jones SL. 2000. Functions of tetramer-stained HIV-specific CD4(+) and CD8(+) T cells. Curr Opin Immunol, 12 (4), pp. 370-374. | Show Abstract | Read more

Significant insight has been gained into constraints on the sensitivity and specificity of staining with class I tetramers. The function of the populations that are defined varies with the clinical situation. Insight has also been gained into the determinants of the CD8(+) T cell response during primary and chronic HIV infection. Human class II tetramers have been synthesised but their role in defining CD4(+) T cell function in HIV infection remains to be determined.

Appay V, Dunbar PR, Cerundolo V, McMichael A, Czaplewski L, Rowland-Jones S. 2000. RANTES activates antigen-specific cytotoxic T lymphocytes in a mitogen-like manner through cell surface aggregation. Int Immunol, 12 (8), pp. 1173-1182. | Show Abstract | Read more

RANTES (regulated upon activation, normal T cell expressed and secreted) is released by cytotoxic T lymphocytes (CTL), and is a potent chemoattractant factor for monocytes and T cells, also known for its ability to suppress HIV infection. At micromolar concentration, RANTES is able to activate leukocytes, and, paradoxically, to enhance HIV infection in vitro. These latter properties are dependent on its ability to self-aggregate. In order to understand further the mechanism of RANTES-induced activation, the effects of both aggregated and disaggregated RANTES on antigen-specific CD8(+) clones were studied in comparison with the effects of specific antigens and in the presence of specific inhibitors of RANTES-mediated activation. We observed large amounts of RANTES aggregated on the cell surface, which led to cell activation, including up-regulation of cell surface markers, and secretion of IFN-gamma and macrophage inflammatory protein (MIP)-1beta. Specific inhibitors of RANTES-induced activation, such as soluble glycosaminoglycans, MIP-1alpha and MIP-1beta, acted by preventing the binding of RANTES on the cell surface. These studies suggest that RANTES acted more like a mitogen than an antigen-independent activator.

Appay V, Nixon DF, Donahoe SM, Gillespie GM, Dong T, King A, Ogg GS, Spiegel HM, Conlon C, Spina CA et al. 2000. HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med, 192 (1), pp. 63-75. | Show Abstract | Read more

The use of peptide-human histocompatibility leukocyte antigen (HLA) class I tetrameric complexes to identify antigen-specific CD8(+) T cells has provided a major development in our understanding of their role in controlling viral infections. However, questions remain about the exact function of these cells, particularly in HIV infection. Virus-specific cytotoxic T lymphocytes exert much of their activity by secreting soluble factors such as cytokines and chemokines. We describe here a method that combines the use of tetramers and intracellular staining to examine the functional heterogeneity of antigen-specific CD8(+) T cells ex vivo. After stimulation by specific peptide antigen, secretion of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, macrophage inflammatory protein (MIP)-1beta, and perforin is analyzed by FACS((R)) within the tetramer-positive population in peripheral blood. Using this method, we have assessed the functional phenotype of HIV-specific CD8(+) T cells compared with cytomegalovirus (CMV)-specific CD8(+) T cells in HIV chronic infection. We show that the majority of circulating CD8(+) T cells specific for CMV and HIV antigens are functionally active with regards to the secretion of antiviral cytokines in response to antigen, although a subset of tetramer-staining cells was identified that secretes IFN-gamma and MIP-1beta but not TNF-alpha. However, a striking finding is that HIV-specific CD8(+) T cells express significantly lower levels of perforin than CMV-specific CD8(+) T cells. This lack of perforin is linked with persistent CD27 expression on HIV-specific cells, suggesting impaired maturation, and specific lysis ex vivo is lower for HIV-specific compared with CMV-specific cells from the same donor. Thus, HIV-specific CD8(+) T cells are impaired in cytolytic activity.

Dorrell L, Hessell AJ, Wang M, Whittle H, Sabally S, Rowland-Jones S, Burton DR, Parren PW. 2000. Absence of specific mucosal antibody responses in HIV-exposed uninfected sex workers from the Gambia. AIDS, 14 (9), pp. 1117-1122. | Show Abstract | Read more

OBJECTIVES: Specific antibodies to HIV envelope that inactivate virus at the mucosal surfaces involved in sexual contact are of interest for the design of a vaccine against HIV-1. It has been suggested that, in frequently HIV-exposed but uninfected individuals, HIV-specific mucosal antibody responses may exist and play a role in resistance against HIV. This study investigated HIV-1 envelope specific mucosal antibody responses in HIV-resistant sex workers in west Africa. METHODS: A group of 26 exposed uninfected female commercial sex workers from the Gambia, who have had repeated exposures to HIV-1 and HIV-2 were studied. We assessed the presence of vaginal IgA and IgG in vaginal swabs against a range of HIV-1 and HIV-2 envelope presentations and performed HIV-1 neutralization assays. RESULTS: No significant vaginal IgA or IgG responses against HIV-1 or HIV-2 were detected, and none of the vaginal secretions tested displayed any HIV-1 neutralizing activity. CONCLUSION: Vaginal antibody responses against HIV were not found in Gambian sex workers who resist HIV infection. Resistance against HIV infection can therefore occur in the absence of specific antibodies against HIV at the genital mucosa. A protective role for HIV-envelope specific IgA in resistance against HIV-1 infection in exposed uninfected individuals as reported in the literature is uncertain.

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John GC, Rousseau C, Dong T, Rowland-Jones S, Nduati R, Mbori-Ngacha D, Rostron T, Kreiss JK, Richardson BA, Overbaugh J. 2000. Maternal SDF1 3 ' A polymorphism is associated with increased perinatal human immunodeficiency virus type 1 transmission JOURNAL OF VIROLOGY, 74 (12), pp. 5736-5739. | Show Abstract | Read more

Genetic polymorphisms in chemokine and chemokine receptor genes influence susceptibility to human immunodeficiency virus type 1 (HIV-1) infection and disease progression, but little is known regarding the association between these allelic variations and the ability of the host to transmit virus. In this study, we show that the maternal heterozygous SDF1 genotype (SDF1 3'A/wt) is associated with perinatal transmission of HIV-1 (risk ratio [RR], 1.8; 95% confidence interval [CI], 1.0 to 3.3) and particularly postnatal breastmilk transmission (RR, 3.1; 95% CI, 1.1 to 8.6). In contrast, the infant SDF1 genotype had no effect on mother-to-infant transmission. These data suggest that SDF1, which is a ligand for the T- tropic HIV-1 coreceptor CXCR4, may affect the ability of a mother to transmit the virus to her infant. This suggests that a genetic polymorphism in a gene encoding a chemokine receptor ligand may be associated with increased infectivity of the index case and highlights the importance of considering transmission as well as clinical outcome in designing chemokine-based therapies for HIV-1.

MacDonald KS, Fowke KR, Kimani J, Dunand VA, Nagelkerke NJ, Ball TB, Oyugi J, Njagi E, Gaur LK, Brunham RC et al. 2000. Influence of HLA supertypes on susceptibility and resistance to human immunodeficiency virus type 1 infection. J Infect Dis, 181 (5), pp. 1581-1589. | Show Abstract | Read more

Certain human leukocyte antigens, by presenting conserved immunogenic epitopes for T cell recognition, may, in part, account for the observed differences in human immunodeficiency virus type 1 (HIV-1) susceptibility. To determine whether HLA polymorphism influences HIV-1 susceptibility, a longitudinal cohort of highly HIV-1-exposed female sex workers based in Nairobi, Kenya, was prospectively analyzed. Decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related HLA alleles (A2/6802 supertype; incidence rate ratio [IRR], 0.45; 95% confidence interval [CI], 0.27-0.72; P=.0003). The alleles in this supertype are known in some cases to present the same peptide epitopes for T cell recognition. In addition, resistance to HIV-1 infection was independently associated with HLA DRB1*01 (IRR, 0.22; 95% CI, 0.06-0.60; P=.0003), which suggests that anti-HIV-1 class II restricted CD4 effector mechanisms may play an important role in protecting against viral challenge. These data provide further evidence that resistance to HIV-1 infection in this cohort of sex workers is immunologically mediated.

Wilson JD, Ogg GS, Allen RL, Davis C, Shaunak S, Downie J, Dyer W, Workman C, Sullivan S, McMichael AJ, Rowland-Jones SL. 2000. Direct visualization of HIV-1-specific cytotoxic T lymphocytes during primary infection. AIDS, 14 (3), pp. 225-233. | Show Abstract | Read more

OBJECTIVE: HIV-specific cytotoxic T lymphocytes (CTL) are believed to play an important role in containing viral replication throughout HIV-1 infection. Previous studies have attempted to quantify the HIV-1-specific CTL precursor frequency during primary HIV infection by using limiting dilution analysis, which almost certainly underestimates the true CTL frequency. Here we use a relatively new technique to quantify HIV-specific CD8 T cells in primary HIV infection. METHODS: We have used soluble tetrameric complexes of HLA class I molecules complexed with HIV epitope peptides to study the dynamics and frequency of HIV-specific CD8 T cells in relation to plasma viral load in early HIV infection, in three patients with a highly focused HIV-specific CTL response. RESULTS: We show that the frequencies of HIV-1-specific CD8 T cells in acute infection are significantly higher than previously documented and can be demonstrated well before full seroconversion. These studies also confirm the immunodominance of the B27-restricted response in HIV infection and demonstrate a close temporal relationship between the numbers of circulating HIV-specific CD8 T cells and viral load. CONCLUSIONS: These findings strongly suggest that HIV-1-specific CD8 T cells are responding directly to the level of viral replication in early HIV infection and are a major factor in its control. In addition, the data indicate that immunodominance for CD8 T-cell responses is established in the acute phase of HIV infection.

Kaul R, Plummer FA, Kimani J, Dong T, Kiama P, Rostron T, Njagi E, MacDonald KS, Bwayo JJ, McMichael AJ, Rowland-Jones SL. 2000. HIV-1-specific mucosal CD8+ lymphocyte responses in the cervix of HIV-1-resistant prostitutes in Nairobi. J Immunol, 164 (3), pp. 1602-1611. | Show Abstract

Understanding how individuals with a high degree of HIV exposure avoid persistent infection is paramount to HIV vaccine design. Evidence suggests that mucosal immunity, particularly virus-specific CTL, could be critically important in protection against sexually acquired HIV infection. Therefore, we have looked for the presence of HIV-specific CD8+ T cells in cervical mononuclear cells from a subgroup of highly HIV-exposed but persistently seronegative female sex workers in Nairobi. An enzyme-linked immunospot assay was used to measure IFN-gamma release in response to known class I HLA-restricted CTL epitope peptides using effector cells from the blood and cervix of HIV-1-resistant and -infected sex workers and from lower-risk uninfected controls. Eleven of 16 resistant sex workers had HIV-specific CD8+ T cells in the cervix, and a similar number had detectable responses in blood. Where both blood and cervical responses were detected in the same individual, the specificity of the responses was similar. Neither cervical nor blood responses were detected in lower-risk control donors. HIV-specific CD8+ T cell frequencies in the cervix of HIV-resistant sex workers were slightly higher than in blood, while in HIV-infected donor cervical response frequencies were markedly lower than blood, so that there was relative enrichment of cervical responses in HIV-resistant compared with HIV-infected donors. HIV-specific CD8+ T cell responses in the absence of detectable HIV infection in the genital mucosa of HIV-1-resistant sex workers may be playing an important part in protective immunity against heterosexual HIV-1 transmission.

Mear JP, Schreiber KL, Münz C, Zhu X, Stevanović S, Rammensee HG, Rowland-Jones SL, Colbert RA. 1999. Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J Immunol, 163 (12), pp. 6665-6670. | Show Abstract

The MHC class I protein HLA-B27 is strongly associated with susceptibility to spondyloarthropathies and can cause arthritis when expressed in rats and mice, implying a direct role in disease pathogenesis. A prominent hypothesis to explain this role suggests that the unique peptide binding specificity of HLA-B27 confers an ability to present arthritogenic peptides. The B pocket, a region of the peptide binding groove that is an important determinant of allele-specific peptide binding, is thought to be critical for arthritogenicity. However, this hypothesis remains unproven. We show that in addition to its role in peptide selection, the B pocket causes a portion of the pool of assembling HLA-B27 heavy chains in the endoplasmic reticulum to misfold, resulting in their degradation in the cytosol. The misfolding phenotype is corrected by replacing the HLA-B27 B pocket with one from HLA-A2. Our results suggest an alternative to the arthritogenic peptide hypothesis. Misfolding and its consequences, rather than allele-specific peptide presentation, may underlie the strong link between the HLA-B27 B pocket and susceptibility to spondyloarthropathies.

Hemsley C, Abraham S, Rowland-Jones S. 1999. Corynebacterium pseudodiphtheriticum--a skin pathogen. Clin Infect Dis, 29 (4), pp. 938-939. | Read more

Rowland-Jones S. 1999. HIV infection: where have all the T cells gone? Lancet, 354 (9172), pp. 5-7. | Read more

Rowland-Jones S. 1999. The role of chemokine receptors in HIV infection. Sex Transm Infect, 75 (3), pp. 148-151. | Read more

Rice PS, Cybulska B, Parry JV, Rowland-Jones S, Daniels RS. 1999. Reappearance of HIV antibody in an infected, seronegative individual after treatment with highly active antiretroviral therapy. AIDS, 13 (6), pp. 729-731. | Read more

Rowland-Jones SL. 1999. HIV: The deadly passenger in dendritic cells. Curr Biol, 9 (7), pp. R248-R250. | Show Abstract | Read more

A picture is emerging of how HIV subverts a normal immunological surveillance mechanism to establish primary infection. This involves the infection of dendritic cells at mucosal surfaces: as these cells then mature, they transport the virus to lymphoid tissue, where viral replication begins and infection of CD4(+) T cells occurs.

Rowland-Jones S. 1999. Long-term non-progression in HIV infection: clinico pathological issues. J Infect, 38 (2), pp. 67-70. | Read more

Tan R, Xu X, Ogg GS, Hansasuta P, Dong T, Rostron T, Luzzi G, Conlon CP, Screaton GR, McMichael AJ, Rowland-Jones S. 1999. Rapid death of adoptively transferred T cells in acquired immunodeficiency syndrome. Blood, 93 (5), pp. 1506-1510. | Show Abstract

Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) probably play the major role in controlling HIV replication. However, the value of adoptive transfer of HIV-specific CTL expanded in vitro to HIV+ patients has been limited: this contrasts with the success of CTL therapy in treating or preventing Epstein-Barr virus and cytomegalovirus disease after bone marrow transplantation (BMT). We investigated the fate of expanded HIV-specific CTL clones in vivo following adoptive transfer to a patient with acquired immunodeficiency syndrome (AIDS). Two autologous CTL clones specific for HIV Gag and Pol were expanded to large numbers (>10(9)) in vitro and infused into an HIV-infected patient whose viral load was rising despite antiretroviral therapy. The fate of one clone was monitored by staining peripheral blood mononuclear cells (PBMCs) with T-cell receptor-specific tetrameric major histocompatibility complex (MHC)-peptide complexes. Although the CTL transfer was well tolerated, there were no significant changes in CD4 and CD8 lymphocyte counts and virus load. By tracking an infused clone using soluble MHC-peptide complexes, we show that cells bearing the Gag-specific T-cell receptors were rapidly eliminated within hours of infusion through apoptosis. Thus, the failure of adoptively transferred HIV-specific CTL to reduce virus load in AIDS may be due to rapid apoptosis of the infused cells, triggered by a number of potential mechanisms. Further trials of adoptive transfer of CTL should take into account the susceptibility of infused cells to in vivo apoptosis.

Tan LC, Gudgeon N, Annels NE, Hansasuta P, O'Callaghan CA, Rowland-Jones S, McMichael AJ, Rickinson AB, Callan MF. 1999. A re-evaluation of the frequency of CD8+ T cells specific for EBV in healthy virus carriers. J Immunol, 162 (3), pp. 1827-1835. | Show Abstract

EBV is a gammaherpesvirus that can establish both nonproductive (latent) and productive (lytic) infections within the cells of its host. Although T cell responses to EBV latent proteins have been well characterized, little is known about the importance of responses to lytic proteins in long term virus carriers. Here we have compared the frequencies of CD8+ T cells specific for EBV latent and lytic Ags in healthy virus carriers, using three techniques: limiting dilution analysis, enzyme-linked immunospot assay, and FACS staining with tetrameric MHC-peptide complexes. T cells specific for EBV lytic protein epitopes were readily detectable in all donors and were usually more abundant than those specific for latent epitopes. We infer that direct T cell control of viral replicative lesions is maintained in long term carriers of EBV and is an important component of the immune response to this virus. Estimates of CD8+ T cell frequencies varied considerably according to methodology; values obtained from MHC-peptide tetramer staining were, on the average, 4.4-fold higher than those obtained from enzyme-linked immunospot assays, which were, in turn, on the average, 5.3-fold higher than those obtained from limiting dilution analysis. Tetramer staining showed that as many as 5.5% circulating CD8+ T cells in a virus carrier were specific for a single EBV lytic protein epitope. Such values are much greater than previously imagined and illustrate how antigenic challenge from a persistent herpesvirus can influence the composition of the host's CD8+ T cell pool.

Dorrell L, Dong T, Ogg GS, Lister S, McAdam S, Rostron T, Conlon C, McMichael AJ, Rowland-Jones SL. 1999. Distinct recognition of non-clade B human immunodeficiency virus type 1 epitopes by cytotoxic T lymphocytes generated from donors infected in Africa. J Virol, 73 (2), pp. 1708-1714. | Show Abstract

We present detailed studies of human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) responses to clade A or C HIV type 1 in three donors infected in East Africa. We define several novel non-clade B CTL epitopes, including some restricted by HLA alleles common in Africans. Although cross-clade CTL recognition of these epitopes does occur, recognition can also be highly clade specific.

Goulder PJ, Rowland-Jones SL, McMichael AJ, Walker BD. 1999. Anti-HIV cellular immunity: recent advances towards vaccine design. AIDS, 13 Suppl A pp. S121-S136.

Ogg GS, Jin X, Bonhoeffer S, Moss P, Nowak MA, Monard S, Segal JP, Cao Y, Rowland-Jones SL, Hurley A et al. 1999. Decay kinetics of human immunodeficiency virus-specific effector cytotoxic T lymphocytes after combination antiretroviral therapy. J Virol, 73 (1), pp. 797-800. | Show Abstract

Little is known of the changes in human immunodeficiency virus type 1 (HIV-1)-specific effector cytotoxic T lymphocytes (CTL) after potent antiretroviral therapy. Using HLA/peptide tetrameric complexes, we show that after starting treatment, there are early rapid fluctuations in the HIV-1-specific CTL response which last 1 to 2 weeks. These fluctuations are followed by an exponential decay (median half-life, 45 days) of HIV-1-specific CTL which continues while viremia remains undetectable. These data have implications for the immunological control of drug-resistant virus.

Dyer WB, Ogg GS, Demoitie MA, Jin X, Geczy AF, Rowland-Jones SL, McMichael AJ, Nixon DF, Sullivan JS. 1999. Strong human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte activity in Sydney Blood Bank Cohort patients infected with nef-defective HIV type 1. J Virol, 73 (1), pp. 436-443. | Show Abstract

Proposals for the use of live attenuated human immunodeficiency virus (HIV) type 1 (HIV-1) as a vaccine candidate in humans have been based on the protection afforded by attenuated simian immunodeficiency virus in the macaque model. Although it is not yet known if this strategy could succeed in humans, a study of the Sydney Blood Bank Cohort (SBBC), infected with an attenuated HIV-1 quasispecies with natural nef and nef/long terminal repeat deletions for up to 17 years, could provide insights into the long-term immunological consequences of living with an attenuated HIV-1 infection. In this study, HIV-specific cytoxic T-lymphocyte (CTL) responses in an SBBC donor and six recipients were examined over a 3-year period with enzyme-linked immunospot, tetrameric complex binding, direct CTL lysis, and CTL precursor level techniques. Strong HIV-specific CTL responses were detected in four of seven patients, including one patient with an undetectable viral load. Two of seven patients had weak CTL responses, and in one recipient, no HIV-specific CTLs were detected. High levels of circulating effector and memory HIV-specific CTLs can be maintained for prolonged periods in these patients despite very low viral loads.

Tan R, Wilson JD, Rostron T, Peto T, McMichael AJ, Rowland-Jones SL. 1998. Prolonged CD8+ T-cell expansions after adoptive transfer of syngeneic lymphocytes between HIV-discordant identical twins. AIDS, 12 (16), pp. 2240-2241.

Rowland-Jones SL, Dong T, Fowke KR, Kimani J, Krausa P, Newell H, Blanchard T, Ariyoshi K, Oyugi J, Ngugi E et al. 1998. Cytotoxic T cell responses to multiple conserved HIV epitopes in HIV-resistant prostitutes in Nairobi. J Clin Invest, 102 (9), pp. 1758-1765. | Show Abstract | Read more

Many people who remain persistently seronegative despite frequent HIV exposure have HIV-specific immune responses. The study of these may provide information about mechanisms of natural protective immunity to HIV-1. We describe the specificity of cytotoxic T lymphocyte responses to HIV in seronegative prostitutes in Nairobi who are apparently resistant to HIV infection. These women have had frequent exposure to a range of African HIV-1 variants, primarily clades A, C, and D, for up to 12 yr without becoming infected. Nearly half of them have CTL directed towards epitopes previously defined for B clade virus, which are largely conserved in the A and D clade sequences. Stronger responses are frequently elicited using the A or D clade version of an epitope to stimulate CTL, suggesting that they were originally primed by exposure to these virus strains. CTL responses have been defined to novel epitopes presented by HLA class I molecules associated with resistance to infection in the cohort, HLA-A*6802 and HLA-B18. Estimates using a modified interferon-gamma Elispot assay indicate a circulating frequency of CTL to individual epitopes of between 1:3,200 and 1:50,000. Thus, HIV-specific immune responses-particularly cross-clade CTL activity- may be responsible for protection against persistent HIV infection in these African women.

Rowland-Jones SL. 1998. Survival with HIV infection: good luck or good breeding? Trends Genet, 14 (9), pp. 343-345. | Read more

Ogg GS, Dong T, Hansasuta P, Dorrell L, Clarke J, Coker R, Luzzi G, Conlon C, McMichael AP, Rowland-Jones S. 1998. Four novel cytotoxic T-lymphocyte epitopes in the highly conserved major homology region of HIV-1 Gag, restricted through B*4402, B*1801, A*2601, B*70 (B*1509) AIDS, 12 (12), pp. 1561-1563. | Read more

Wilson JD, Ogg GS, Allen RL, Goulder PJ, Kelleher A, Sewell AK, O'Callaghan CA, Rowland-Jones SL, Callan MF, McMichael AJ. 1998. Oligoclonal expansions of CD8(+) T cells in chronic HIV infection are antigen specific. J Exp Med, 188 (4), pp. 785-790. | Show Abstract | Read more

Acute HIV infection is associated with a vigorous immune response characterized by the proliferation of selected T cell receptor V beta (BV)-expressing CD8(+) T cells. These 'expansions', which are commonly detected in the peripheral blood, can persist during chronic HIV infection and may result in the dominance of particular clones. Such clonal populations are most consistent with antigen-driven expansions of CD8(+) T cells. However, due to the difficulties in studying antigen-specific T cells in vivo, it has been hard to prove that oligoclonal BV expansions are actually HIV specific. The use of tetrameric major histocompatibility complex-peptide complexes has recently enabled direct visualization of antigen-specific T cells ex vivo but has not provided information on their clonal composition. We have now made use of these tetrameric complexes in conjunction with anti-BV chain-specific monoclonal antibodies and analysis of cytotoxic T lymphocyte lines/clones to show that chronically clonally expanded CD8(+) T cells are HIV specific in vivo.

Whittle HC, Ariyoshi K, Rowland-Jones S. 1998. HIV-2 and T cell recognition. Curr Opin Immunol, 10 (4), pp. 382-387. | Show Abstract | Read more

HIV-2 is less pathogenic and less transmissible than HIV-1. Recent research in relation to deletions in the HIV nef gene and to immune cross-reactions between infections by HIV-2, HIV-1 and simian immunodeficiency virus suggests that T cell recognition and the control of viral replication may be more efficient in HIV-2 infection than in HIV-1 infection. These insights may be crucial to the design of effective vaccines.

Rowland-Jones S, Colbert RA, Dong T, McAdam S, Brown M, Ariyoshi K, Sabally A, Whittle H, McMichael A. 1998. Distinct recognition of closely-related HIV-1 and HIV-2 cytotoxic T-cell epitopes presented by HLA-B*2703 and B*2705 AIDS, 12 (11), pp. 1391-1393. | Read more

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Anzala AO, Ball TB, Rostron T, O'Brien SJ, Plummer FA, Rowland-Jones SL, Res UNCHIV. 1998. CCR2-64I allele and genotype association with delayed AIDS progression in African women LANCET, 351 (9116), pp. 1632-1633. | Read more

Ogg GS, Jin X, Bonhoeffer S, Dunbar PR, Nowak MA, Monard S, Segal JP, Cao Y, Rowland-Jones SL, Cerundolo V et al. 1998. Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science, 279 (5359), pp. 2103-2106. | Show Abstract | Read more

Although cytotoxic T lymphocytes (CTLs) are thought to be involved in the control of human immunodeficiency virus-type 1 (HIV-1) infection, it has not been possible to demonstrate a direct relation between CTL activity and plasma RNA viral load. Human leukocyte antigen-peptide tetrameric complexes offer a specific means to directly quantitate circulating CTLs ex vivo. With the use of the tetrameric complexes, a significant inverse correlation was observed between HIV-specific CTL frequency and plasma RNA viral load. In contrast, no significant association was detected between the clearance rate of productively infected cells and frequency of HIV-specific CTLs. These data are consistent with a significant role for HIV-specific CTLs in the control of HIV infection and suggest a considerable cytopathic effect of the virus in vivo.

Price DA, Sewell AK, Dong T, Tan R, Goulder PJ, Rowland-Jones SL, Phillips RE. 1998. Antigen-specific release of beta-chemokines by anti-HIV-1 cytotoxic T lymphocytes. Curr Biol, 8 (6), pp. 355-358. | Show Abstract | Read more

A major advance in understanding human immunodeficiency virus (HIV) biology was the discovery that the beta-chemokines MIP-1 alpha (macrophage inflammatory protein-1 alpha), MIP-1 beta (macrophage inflammatory protein-1 beta) and RANTES (regulated on activation, normal T-cell expressed and secreted) inhibit entry of HIV-1 into CD4+ cells by blocking the critical interaction between the CCR5 coreceptor and the V3 domain of the viral envelope glycoprotein gp120 [1,2]. CD8+ lymphocytes are a major source of beta-chemokines [3], but the stimulus for chemokine release has not been well defined. Here, we have shown that engagement of CD8+ cytotoxic T lymphocytes (CTLs) with HIV-1-encoded human leukocyte antigen (HLA) class I-restricted peptide antigens caused rapid and specific release of these beta-chemokines. This release paralleled cytolytic activity and could be attenuated by naturally occurring amino acid variation within the HLA class I-restricted peptide sequence. Epitope variants that bound to appropriate HLA class I molecules but failed to stimulate cytolytic activity in CTLs also failed to stimulate chemokine release. We conclude that signalling through the T-cell receptor (TCR) following binding of antigen results in beta-chemokine release from CTLs in addition to cytolytic activity, and that both responses can be abolished by epitope mutation. These results suggest that antigenic variation within HIV-1 might not only allow the host cell to escape lysis, but might also contribute to the propagation of infection by failing to activate beta-chemokine-mediated inhibition of HIV-1 entry.

Bertoletti A, Cham F, McAdam S, Rostron T, Rowland-Jones S, Sabally S, Corrah T, Ariyoshi K, Whittle H. 1998. Cytotoxic T cells from human immunodeficiency virus type 2-infected patients frequently cross-react with different human immunodeficiency virus type 1 clades. J Virol, 72 (3), pp. 2439-2448. | Show Abstract

Knowledge of immune mechanisms responsible for the cross-protection between highly divergent viruses such as human immunodeficiency virus type 1 (HIV-1) and HIV-2 may contribute to an understanding of whether virus variability may be overcome in the design of vaccine candidates which are broadly protective across the HIV subtypes. We demonstrate that despite the significant difference in virus amino acid sequence, the majority of HIV-2-infected individuals with different HLA molecules possess a dominant cytotoxic T-cell response which is able to recognize HIV-1 Gag protein. Furthermore, HLA-B5801-positive subjects show broad cross-recognition of HIV-1 subtypes since they mounted a T-cell response that tolerated extensive amino acid substitutions within HLA-B5801-restricted HIV-1 and HIV-2 epitopes. These results suggests that HLA-B5801-positive HIV-2-infected individuals have an enhanced ability to react with HIV-1 that could play a role in cross-protection.

Rowland-Jones S, Dong T, Krausa P, Sutton J, Newell H, Ariyoshi K, Gotch F, Sabally S, Corrah T, Kimani J et al. 1998. The role of cytotoxic T-cells in HIV infection. Dev Biol Stand, 92 pp. 209-214. | Show Abstract

HIV-specific cytotoxic T lymphocytes (CTL) are believed to play a major role in controlling virus levels through the asymptomatic period of HIV infection. For the rational design of an HIV vaccine, we need to know whether protective immunity can ever develop following HIV exposure in people who remain uninfected. We have detected HIV-specific CTL in 5/6 repeatedly exposed, persistently seronegative female sex-workers in The Gambia. Their CTL, repeatedly detected over two years, recognise epitopes presented by HLA-B35 which are cross-reactive between HIV-1 & HIV-2, suggesting they could have been primed first by HIV-2 exposure and subsequently boosted by exposure to HIV-1. Using previously identified clade B HIV-1 epitope peptides, we have now detected HIV-specific CTL in 6/15 highly exposed and apparently HIV-resistant Kenyan prostitutes, predominantly towards epitopes highly conserved between B and the Kenyan A & D clades of HIV-1. This CTL activity towards conserved virus epitopes may represent protective immunity to HIV generated in response to repeated exposure, and prophylactic HIV vaccines should aim to generate similar CTL responses.

Lalvani A, Dong T, Ogg G, Patham AA, Newell H, Hill AV, McMichael AJ, Rowland-Jones S. 1997. Optimization of a peptide-based protocol employing IL-7 for in vitro restimulation of human cytotoxic T lymphocyte precursors. J Immunol Methods, 210 (1), pp. 65-77. | Show Abstract | Read more

A variety of different methods for the in vitro restimulation of human cytotoxic T lymphocyte (CTL) precursors (CTLp) are in use. Our aim was to enhance the detection of circulating human CTLp in peripheral blood. We have developed a standardized and highly efficient method for restimulating CTLp. Synthetic peptides were used to restimulate cognate CTLp from peripheral blood mononuclear cells (PBMC), and effector CTL capable of lysing peptide-pulsed and virus infected targets were generated. The effects of several parameters on CTL specific for influenza A, EBV and HIV-1 were evaluated, and the optimum peptide concentration for CTL generation was established. Supplementation of initial cultures with IL-7 greatly enhanced peptide-specific lytic activity for all peptides tested and the dose-response relationship for IL-7 was delineated. A novel technique using peptide-MHC class I molecule tetramers to stain T cells bearing cognate T cell receptors permitted enumeration of antigen-specific CD8 + CTL during in vitro restimulation; IL-7 supplementation selectively expanded the population of peptide-specific CD8 + CTL. Importantly, this protocol, whilst enhancing the restimulation and lytic activity of secondary CTL, does not induce primary CTL in vitro. The improved efficiency with which CTL are generated in this system substantially enhances the sensitivity of CTL culture and the 51Cr release assay to detect low levels of CTL activity.

Griffin TA, Yuan J, Friede T, Stevanovic S, Ariyoshi K, Rowland-Jones SL, Rammensee HG, Colbert RA. 1997. Naturally occurring A pocket polymorphism in HLA-B*2703 increases the dependence on an accessory anchor residue at P1 for optimal binding of nonamer peptides. J Immunol, 159 (10), pp. 4887-4897. | Show Abstract

Previous studies have shown the B*2703 subtype of HLA-B27, which differs from B*2705 and other MHC class I molecules by having a His substituted for Tyr at position 59 in the A pocket, inefficiently presents certain B*2705-restricted peptides. The current work investigates the influence of the first peptidic amino acid (P1) on peptide binding to B*2705 and B*2703. Results show P1 has a marked effect for both subtypes, with relative affinities (EC50) of P1-substituted peptides spanning four orders of magnitude. All peptides tested bind better to B*2705 than to B*2703. However, Lys, Arg, Phe, or Trp at P1 result in a < or = 2-fold difference between subtypes, while other amino acids produce greater differences (maximum approximately 50-fold for Leu). Self peptides eluted from B*2703, as well as two viral epitopes, have a motif similar to B*2705 peptides, except for a stronger preference for Lys or Arg at P1, consistent with peptide binding data. Computer modeling of B*2703 reveals movement of a water molecule and the alpha1 alpha-helix to allow His at position 59 to maintain important hydrogen bonds with the peptide N terminus in the A pocket. However, these bonds are weaker, and the water molecule movement results in the loss of a hydrogen bond with Glu-45 in the B pocket. We conclude that B*2703, as a consequence of its unique A pocket polymorphism, appears to have a greater dependency on an accessory anchor residue at P1 to maintain tight binding of peptides.

Rowland-Jones S. 1997. Dimers are a girl's best friend. Nat Med, 3 (11), pp. 1199-1200. | Read more

Goulder P, Price D, Nowak M, Rowland-Jones S, Phillips R, McMichael A. 1997. Co-evolution of human immunodeficiency virus and cytotoxic T-lymphocyte responses. Immunol Rev, 159 (1), pp. 17-29. | Show Abstract | Read more

After more than a decade of intensive research, the precise role of human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) in determining the course of the infection remains open to argument. It is established that HIV-specific CTL appear early in the infection and are temporally associated with the clearance of culturable virus from the blood; that CTL are generally detectable at very high levels throughout the asymptomatic phase and decline at the time of progression to AIDS; and that CTL-mediated killing is sufficiently fast to prevent production of new virions by HIV-infected cells. However, viral turnover is high throughout the course of the infection, and infected individuals progress inexorably to disease in spite of the CTL response. In order to address the question of whether CTL play an active part in influencing the course of HIV infection, one approach has been to seek evidence for CTL-mediated selection pressure on the virus. Several clear examples of CTL epitope-specific mutations selected to fixation are described. We argue that CTL escape is a common event which occurs at all stages of the infection. Detailed longitudinal studies are required to detect CTL escape and to understand the complexities contributed by factors such as a polyvalent CTL response and the presence of epitope variants which antagonise the CTL response. In conclusion, there is strong evidence of a dynamic process in which CTL impose important selection constraints upon HIV from which the virus attempts to escape; ultimately, at the time of disease progression, the tenuous control of CTL over the virus is lost.

Rowland-Jones S, Tan R. 1997. Control of HIV co-receptor expression: implications for pathogenesis and treatment. Trends Microbiol, 5 (8), pp. 300-302. | Read more

Goulder PJ, Phillips RE, Colbert RA, McAdam S, Ogg G, Nowak MA, Giangrande P, Luzzi G, Morgan B, Edwards A et al. 1997. Late escape from an immunodominant cytotoxic T-lymphocyte response associated with progression to AIDS. Nat Med, 3 (2), pp. 212-217. | Show Abstract | Read more

The precise role played by HIV-specific cytotoxic T lymphocytes (CTL) in HIV infection remains controversial. Despite strong CTL responses being generated during the asymptomatic phase, the virus persists and AIDS ultimately develops. It has been argued that the virus is so variable, and the virus turnover so great that escape from CTL recognition would occur continually, but so far there is limited evidence for CTL escape. The opposing argument is that evidence for CTL escape is present but hard to find because multiple anti-HIV immune responses are acting simultaneously during the asymptomatic phase of infection. We describe six donors who make a strong CTL response to an immunodominant HLA-B27-restricted epitope. In the two donors who progressed to AIDS, CTL escape to fixation by the same mutation was observed, but only after 9-12 years of epitope stability. CTL escape may play an important role in the pathogenesis of HIV infection.

Rowland-Jones S, Tan R, McMichael A. 1997. Role of cellular immunity in protection against HIV infection. Adv Immunol, 65 pp. 277-346. | Read more

Blanchard T, Rowland-Jones S, Gotch F, McMichael A, Smith GL. 1996. Future vaccines for HIV. Lancet, 348 (9043), pp. 1741. | Read more

Dong T, Boyd D, Rosenberg W, Alp N, Takiguchi M, McMichael A, Rowland-Jones S. 1996. An HLA-B35-restricted epitope modified at an anchor residue results in an antagonist peptide. Eur J Immunol, 26 (2), pp. 335-339. | Show Abstract | Read more

Peptides associated with HLA-B35 commonly have a proline or occasionally a serine residue in the P2 anchor position of the peptide, with a tyrosine at the C terminus. Based on this motif, we identified an octamer epitope from influenza A matrix protein which is presented by HLA-B35. The requirements for MHC binding and T cell receptor contact have been analyzed using analogs of this peptide with substitutions at positions 1, 2, 4, 7 and 8. The natural epitope contains a serine residue at P2 of the peptide. Substitution of this residue with proline (the favored amino acid in this position in B35-associated peptides) considerably enhances binding to HLA-B35 in the T2-B35 cell line, but the peptide is not recognized by the majority of CTL clones and can antagonize recognition of the index peptide. This suggests that a conservative substitution at the P2 anchor position results in a conformational change in the peptide-MHC surface exposed to the T cell receptor.

Barouch D, Friede T, Stevanović S, Tussey L, Smith K, Rowland-Jones S, Braud V, McMichael A, Rammensee HG. 1995. HLA-A2 subtypes are functionally distinct in peptide binding and presentation. J Exp Med, 182 (6), pp. 1847-1856. | Show Abstract | Read more

Nearly half of HLA-A2-positive individuals in African populations have a subtype of HLA-A2 other than the A*0201 allele. We have isolated the common African HLA-A2 subtype genes from Epstein-Barr virus-transformed B cell lines and have established stable class I reduced transfectants expressing these alleles. We have studied the peptide binding and presentation properties of A*0201, A*0202, A*0205, A*0214, and A*6901 by a combination of approaches: assaying direct binding of labeled synthetic peptides, studying the ability of antigen-specific cytotoxic T lymphocytes to recognize peptide-pulsed cells, and sequencing peptide pools and individual ligands eluted from cells. We find that A*0201-restricted peptides can also bind to A*0202 but do not bind strongly to the other alleles in this study. We show that some cytotoxic T lymphocytes can recognize all subtypes capable of binding an antigenic peptide, whereas others are subtype specific. Sequencing of eluted peptides reveals that A*0202 has a similar peptide motif to A*0201, but that A*0205, A*0214, and A*6901 have different motifs. These data strongly support a model in which residue 9 (Phe or Tyr) of the A2/A68/A69 molecules is a critical factor in determining the specificity of the B pocket of the major histocompatibility complex and the position 2 anchor residue of associated peptides. We conclude that a single-amino acid difference in the major histocompatibility complex can be sufficient to cause a dramatic change in the nature of bound peptides, implying that individuals with closely related HLA subtypes may present very different repertoires of antigenic peptides to T cells in an immune response. It is likely to be a general phenomenon that very similar class I subtypes will behave as functionally distinct HLA allotypes.

McAdam S, Klenerman P, Tussey L, Rowland-Jones S, Lalloo D, Phillips R, Edwards A, Giangrande P, Brown AL, Gotch F. 1995. Immunogenic HIV variant peptides that bind to HLA-B8 can fail to stimulate cytotoxic T lymphocyte responses. J Immunol, 155 (5), pp. 2729-2736. | Show Abstract

Cytotoxic T lymphocyte responses in HIV infection can be impaired through variation in the epitope regions of viral proteins such as a gag. We report here an analysis of variant epitope peptides in three gag epitopes presented by HLA B8. Fifteen variant peptides were examined for their binding to HLA-B8; all but one bound at concentrations comparable to known epitopes. All except two of those that bound could be recognized by CTL from an HLA-B8 positive HIV-1-infected patient and were therefore immunogenic. However, in a hemophiliac patient studied in detail, there was a failure to respond to two immunogenic peptide epitopes representing virus present as provirus in the patient's peripheral blood. In one case, the patient's CTL had previously responded to the peptide; in the other case, there was a good response to a peptide of closely related sequence. Thus there was a selective failure of the CTL response to some proviral epitopes. This impaired reaction to new variants could contribute to the loss of immune control of the infection.

Rowland-Jones SL, McMichael A. 1995. Immune responses in HIV-exposed seronegatives: have they repelled the virus? Curr Opin Immunol, 7 (4), pp. 448-455. | Show Abstract | Read more

Over the past two years, a number of reports have described specific cellular immune responses to HIV in some individuals who, despite exposure to the virus, remain uninfected. A recent description of virus disappearance in a child born to an infected mother should be seen against the background of several previous studies that have hinted at the possibility of clearance of HIV. These findings suggest that immune-mediated clearance of virus may occur in a few fortunate individuals.

Tussey LG, Rowland-Jones S, Zheng TS, Androlewicz MJ, Cresswell P, Frelinger JA, McMichael AJ. 1995. Different MHC class I alleles compete for presentation of overlapping viral epitopes. Immunity, 3 (1), pp. 65-77. | Show Abstract | Read more

We previously identified an HLA-B8+ donor, NW, whose lymphoblastoid cells failed to present a B8-restricted epitope from the influenza A nucleoprotein following viral infection, although added peptide could still be presented. The failure to present through HLA-B8 following viral infection appears to be specific for the NP epitope. Here, we report that donor NW makes an HLA-B2702-restricted influenza-specific CTL response to an epitope in the nucleoprotein that overlaps the B8-restricted epitope by 8 aa. Two mechanisms for the failure of this cell line to present the B8-restricted epitope following viral infection are investigated. One is that there is an antigen processing polymorphism specific to the NW cell line, so that there is either preferential generation or preferential transport of the B2702 epitope. The other is that B8 and B2702 compete for a common peptide fragment in the ER and this leads to suboptimal loading of HLA-B8.

Moss PA, Rowland-Jones SL, Frodsham PM, McAdam S, Giangrande P, McMichael AJ, Bell JI. 1995. Persistent high frequency of human immunodeficiency virus-specific cytotoxic T cells in peripheral blood of infected donors. Proc Natl Acad Sci U S A, 92 (13), pp. 5773-5777. | Show Abstract | Read more

Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTLs) are thought to play a major role in the immune response to HIV infection. The HIV-specific CTL response is much stronger than previously documented in an infectious disease, yet estimates of CTL frequency derived from limiting-dilution analysis (LDA) are relatively low and comparable to other viral infections. Here we show that individual CTL clones specific for peptides from HIV gag and pol gene products are present at high levels in the peripheral blood of three infected patients and that individual CTL clones may represent between 0.2% and 1% of T cells. Previous LDA in one donor had shown a frequency of CTL precursors of 1/8000, suggesting that LDA may underestimate CTL effector frequency. In some donors individual CTL clones persisted in vivo for at least 5 years. In contrast, in one patient there was a switch in CTL usage suggesting that different populations of CTLs can be recruited during infection. These data imply strong stimulation of CTLs, potentially leading some clones to exhaustion.

Nowak MA, May RM, Phillips RE, Rowland-Jones S, Lalloo DG, McAdam S, Klenerman P, Köppe B, Sigmund K, Bangham CR. 1995. Antigenic oscillations and shifting immunodominance in HIV-1 infections. Nature, 375 (6532), pp. 606-611. | Show Abstract | Read more

A typical protein antigen contains several epitopes that can be recognized by cytotoxic T lymphocytes (CTL), but in a characteristic antiviral immune response in vivo, CTL recognize only a small number of these potential epitopes, sometimes only one, this phenomenon is known as immunodominance. Antigenic variation within CTL epitopes has been demonstrated for the human immunodeficiency virus HIV-1 (ref. 11) and other viruses and such 'antigenic escape' may be responsible for viral persistence. Here we develop a new mathematical model that deals with the interaction between CTL and multiple epitopes of a genetically variable pathogen, and show that the nonlinear competition among CTL responses against different epitopes can explain immunodominance. This model suggests that an antigenically homogeneous pathogen population tends to induce a dominant response against a single epitope, whereas a heterogeneous pathogen population can stimulate complicated fluctuating responses against multiple epitopes. Antigenic variation in the immunodominant epitope can shift responses to weaker epitopes and thereby reduce immunological control of the pathogen population. These ideas are consistent with detailed longitudinal studies of CTL responses in HIV-1 infected patients. For vaccine design, the model suggests that the major response should be directed against conserved epitopes even if they are subdominant.

Callan MF, Reyburn HT, Bowness P, Rowland-Jones S, Bell JI, McMichael AJ. 1995. Selection of T cell receptor variable gene-encoded amino acids on the third binding site loop: a factor influencing variable chain selection in a T cell response. Eur J Immunol, 25 (6), pp. 1529-1534. | Show Abstract | Read more

The 3' end of the T cell receptor V beta 7.1 gene contains the five nucleotides CAAGA between the broadly conserved consensus sequence of nucleotides TGC/T GCC AGC AGC (which encode cysteine, alanine, serine and serine at positions 92-95 of the beta chain) and the heptamer that signals rearrangement. These nucleotides are frequently preserved during gene rearrangement, resulting in the common presence of glutamine at position 96 and of aspartate or glutamate at position 97 of the V beta 7.1 chain CDR3 loop in peripheral blood lymphocytes. There is selection of V beta 7.1 and of the V beta 7.1 gene-encoded glutamate at position 97 of the beta chain CDR3 loop in the cytotoxic T lymphocyte response to the HLA B2705-restricted influenza A nucleoprotein epitope SRYWAIRTR. Our results indicate that selection of V beta 7.1 gene-encoded amino acid residues on CDR3 loops may be one factor driving selection of V beta 7.1 in this response.

Hill A, Worth A, Elliott T, Rowland-Jones S, Brooks J, Rickinson A, McMichael A. 1995. Characterization of two Epstein-Barr virus epitopes restricted by HLA-B7. Eur J Immunol, 25 (1), pp. 18-24. | Show Abstract | Read more

We have identified two epitopes for Epstein-Barr virus specific cytotoxic T lymphocytes (CTL) restricted by the common allele HLA-B7. They are EBNA 3C 881-9 (QPRAPIRPI) and EBNA 3A 379-387 (RPPIFIRRL). The epitopes conform well to the recently described motif for HLA-B7-binding peptides (Huckzo et al., J. Immunol. 1993. 151:2572). Titration of the peptides in CTL assays and detergent lysate binding assays revealed that extending the peptides at either the N or C terminus did not reduce their affinity for HLA-B7. This behavior contrasted with HLA-B51, which binds peptides with a similar motif to B7, and has identical amino acid residues at sites expected to form the "F" pocket of the peptide-binding groove. HLA-B51 also bound the peptide EBNA 3C 881-9, but was unable to bind peptides extended at the C terminus.

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Rowland-Jones S, Sutton J, Ariyoshi K, Dong T, Gotch F, McAdam S, Whitby D, Sabally S, Gallimore A, Corrah T et al. 1995. HIV-specific cytotoxic T-cells in HIV-exposed but uninfected Gambian women Nature Medicine, 1 (1), pp. 59-64. | Show Abstract | Read more

A crucial requirement in the rational design of a prophylactic vaccine against the hu-uman immunodeficiency virus (HIV) is to establish whether or not protective immunity can occur following natural infection. The immune response to HIV infection is characterized by very vigorous HIV-specific cytotoxic T-lymphocyte (CTL) activity. We have identified four HIV-1 and HIV-2 cross-reactive peptide epitopes, presented to CTL from HIV-infected Gambians by HLA-B35 (the most common Gambian class I HLA molecule). These peptides were used to elicit HIV-specific CTLs from three out of six repeatedly exposed but HIV-seronegative female prostitutes with HLA-B35. These women remain seronegative with no evidence of HIV infection by polymerase chain reaction or viral culture. Their CTL activity may represent protective immunity against HIV infection. © 1995 Nature Publishing Group.

Klenerman P, Rowland-Jones S, McAdam S, Edwards J, Daenke S, Lalloo D, Köppe B, Rosenberg W, Boyd D, Edwards A. 1994. Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants. Nature, 369 (6479), pp. 403-407. | Show Abstract | Read more

Most asymptomatic individuals infected with HIV-1 have a cytotoxic T lymphocyte (CTL) response to the virus Gag proteins which can be demonstrated in vitro. Epitopes have been mapped in p17 Gag and p24 Gag restricted by HLA-B8 (p17-3 and p24-13) and -B27 (p24-14). Viruses isolated from patients who make CTL responses to these peptides vary within the genetic sequences encoding these epitopes and some mutations lead to reduction in killing activity in vitro. This was attributed to either failure of the variant epitope to bind major histocompatibility complex class I or failure of T-cell receptors to bind the presented peptide. But peptide variants of class I-restricted epitopes cause 'antagonism', that is, the presence of a variant epitope (in the form of peptide) inhibits normal lysis of targets presenting the original epitope. This mirrors similar findings in class II-restricted systems. Here we report that naturally occurring variant forms of p17-3, p24-13 and p24-14 may cause antagonism of CTL lines derived from the same individuals. The effect is present if the epitopes are derived from synthetic peptides and when they are processed from full-length proteins expressed by either recombinant vaccinia constructs or replicating HIV.

Colbert RA, Rowland-Jones SL, McMichael AJ, Frelinger JA. 1994. Differences in peptide presentation between B27 subtypes: the importance of the P1 side chain in maintaining high affinity peptide binding to B*2703. Immunity, 1 (2), pp. 121-130. | Show Abstract | Read more

Susceptibility to spondyloarthropathies is strongly associated with the MHC class I molecule HLA-B27, and is hypothesized to result from the presentation of arthritogenic peptides. Subtypes of B27 that differ structurally but are disease-associated ought to be capable of presenting such peptides, while nondisease-associated subtypes would not. We demonstrate that B*2703, the predominant West African B27 subtype that may not predispose to disease, is not recognized by most B*2705-alloreactive CTL, and does not efficiently present a known B*2705-restricted influenza A nucleoprotein (NP) peptide. We show inefficient presentation is due to a reduced binding affinity of B*2703 for the NP peptide. Furthermore, substituting Arg for the naturally occurring Ser at P1 of the NP peptide, restores high affinity binding and efficient presentation by B*2703. Our results suggest that B*2703 will bind and present efficiently only a subset of the peptides that bind to B*2705, in particular those with Arg or Lys at P1. The apparent lack of disease in individuals with B*2703 may be due to an inability to bind and present putative arthritogenic peptides.

Warburton RJ, Matsui M, Rowland-Jones SL, Gammon MC, Katzenstein GE, Wei T, Edidin M, Zweerink HJ, McMichael AJ, Frelinger JA. 1994. Mutation of the alpha 2 domain disulfide bridge of the class I molecule HLA-A*0201. Effect on maturation and peptide presentation. Hum Immunol, 39 (4), pp. 261-271. | Show Abstract | Read more

A combination of saturation and site-directed mutagenesis was utilized to disrupt the alpha 2 domain disulfide bridge of HLA-A*0201. Mutation of cysteine 101 to a serine (C101S) or of cysteine 164 to alanine (C164A) decreased the rate of maturation of the heavy chain, the total amount of mature heavy chain within the cell, and the level of surface expression. Cells expressing these genes and loaded with a synthetic peptide derived from the influenza A matrix protein (58-66) were recognized poorly by HLA-A*0201-restricted, peptide-specific CTLs. Cells expressing mutant HLA-A*0201 loaded with a synthetic peptide derived from the HIV-1 pol protein (476-484) were not recognized by pol IV-9-specific CTLs. Mutant C164A cells infected with influenza virus were partially recognized by influenza matrix peptide-specific CTLs, while C101S cells were not lysed. Surprisingly, endogenous peptide loading of cells expressing mutant HLA-A*0201 using a minigene coding for either the influenza A matrix peptide 58-66, or HIV-1 pol peptide 476-484, resulted in efficient CTL recognition. This suggests different structural constraints for peptide binding in the endoplasmic reticulum during biosynthesis and for binding to exported molecules on the cells surface.

Tussey LG, Matsui M, Rowland-Jones S, Warburton R, Frelinger JA, McMichael A. 1994. Analysis of mutant HLA-A2 molecules. Differential effects on peptide binding and CTL recognition. J Immunol, 152 (3), pp. 1213-1221. | Show Abstract

Previous studies have identified several residues lining the groove of the HLA-A2.1 molecule that are critical for Ag presentation. However, it is not clear whether these residues are critical for binding of the peptide epitope per se or for determining the appropriate conformation of bound peptide. To distinguish between these possibilities, mutations at eight of these residues have been tested for their effects on the ability of the molecule to bind and present two known peptide epitopes--one derived from the influenza A matrix protein, the other from HIV pol. With only one exception, the mutations were found to affect the binding of the two peptides similarly. Most of the mutations resulted in intermediate deleterious effects on binding, with the B pocket mutant F9Y having the most dramatic negative effect on binding for both peptides. Two of the mutations significantly enhanced binding of both peptides and a peptide-specific effect on binding was seen with the substitution, Y99H, which enhanced binding of the matrix peptide yet diminished binding of the pol peptide. In contrast to the effects on binding, the effects of the mutations on presentation differed considerably for the two peptides. The most striking difference was seen with two alpha 2 alpha helix mutants that are fully recognized by pol peptide-specific CTL but not recognized by matrix peptide-specific CTL even though levels of binding were comparably diminished for the two peptides. These results suggest that some interactions, although not critical for binding per se, are critical for functional binding and the importance of these interactions differs among peptide epitopes.

Rowland-Jones SL, Powis SH, Sutton J, Mockridge I, Gotch FM, Murray N, Hill AB, Rosenberg WM, Trowsdale J, McMichael AJ. 1993. An antigen processing polymorphism revealed by HLA-B8-restricted cytotoxic T lymphocytes which does not correlate with TAP gene polymorphism. Eur J Immunol, 23 (8), pp. 1999-2004. | Show Abstract | Read more

In previous studies of antigen presentation through HLA-B27, we identified a healthy person whose lymphoblastoid cells do not present three B27-restricted viral epitopes to specific cytotoxic T lymphocytes (CTL), despite adequate cell surface expression of HLA-B2702 of normal sequence. Similar findings were observed in all members of his family sharing the HLA-A3-B2702 haplotype. The original donor, NW, carries HLA-B8 on his other class I haplotype, which his daughter, HW, has inherited. We now report a failure to present an HLA-B8-restricted epitope from influenza nucleoprotein following viral infection of NW cells, although exogenous added peptide is still presented normally. However, cells from HW, which do not carry the A3-B2702 haplotype, present the expected epitope after viral infection. Another B8-restricted epitope, from human immunodeficiency virus-gag, is presented equally well by both cell lines when infected with gag-vaccinia. This antigen processing phenotype does not correlate with any of the known human TAP-1 and TAP-2 polymorphisms.

Colbert RA, Rowland-Jones SL, McMichael AJ, Frelinger JA. 1993. Allele-specific B pocket transplant in class I major histocompatibility complex protein changes requirement for anchor residue at P2 of peptide. Proc Natl Acad Sci U S A, 90 (14), pp. 6879-6883. | Show Abstract | Read more

To investigate the role of an anchoring pocket in allele-specific peptide presentation by a major histocompatibility complex class I molecule, we "transplanted" a B pocket from HLA-A*0201 into HLA-B*2705 by site-directed mutagenesis. The resulting protein, designated B27.A2B, binds a different set of endogenous peptides than B*2705 as evidenced by complete loss of allorecognition as well as restored expression in the antigen processing-defective mutant cell line T2. B27.A2B also fails to present an HLA-B27-restricted influenza virus peptide [nucleoprotein (383-391)] to cytotoxic T lymphocytes (CTLs). However, substitution of leucine, the predominant P2 anchor residue in A*0201-restricted peptides, for arginine, the P2 anchor in nucleoprotein-(383-391) and other B*2705-restricted peptides, restores recognition of B27.A2B by the same B*2705-restricted peptide-specific CTLs. These results demonstrate that a dominant polymorphic pocket in a class I molecule, through interaction with the anchor residue of an antigenic peptide, can distinguish among peptides differing by only a single amino acid and thus determine the allelic specificity of peptide presentation.

Bowness P, Moss PA, Rowland-Jones S, Bell JI, McMichael AJ. 1993. Conservation of T cell receptor usage by HLA B27-restricted influenza-specific cytotoxic T lymphocytes suggests a general pattern for antigen-specific major histocompatibility complex class I-restricted responses. Eur J Immunol, 23 (7), pp. 1417-1421. | Show Abstract | Read more

Eight HLA B27-restricted influenza A virus nucleoprotein 383-391-specific cytotoxic T lymphocyte (CTL) clones were obtained from three unrelated donors following natural infection. T cell receptor (TcR) usage was studied using the "anchored" polymerase chain reaction. TcR alpha-chain usage was restricted with three predominant V alpha (V alpha 12.1, 14.1, 22) and two predominant J alpha segments. beta-chain variable-region usage was also conserved, with V beta 7 being used by five clones despite contributing less than 2% of peripheral blood lymphocyte V beta sequences of one individual studied. The TcR beta-chain junctional region was highly conserved even between CTL clones from unrelated individuals, with a negatively charged amino acid, contributed to by N-region addition, encoded at position 97 in all but two clones. This study shows that peptide-specific HLA B27-restricted CTL following influenza virus infection use very similar TcR and, when considered with previous studies, suggests a pattern of TcR conservation for major histocompatibility complex class I-restricted responses. No difference in TcR usage was detected between one healthy donor and two with HLA B27-associated arthritis.

Rowland-Jones SL, Nixon DF, Aldhous MC, Gotch F, Ariyoshi K, Hallam N, Kroll JS, Froebel K, McMichael A. 1993. HIV-specific cytotoxic T-cell activity in an HIV-exposed but uninfected infant. Lancet, 341 (8849), pp. 860-861. | Show Abstract | Read more

The factors necessary for protective immunity against HIV-1 are unknown. Important information about these factors should come from study of people at high risk of HIV infection who have not apparently become infected. Among these are the estimated 60-85% of children who may be exposed in utero or perinatally to HIV-1 but do not become infected. We observed the transient appearance of HIV-specific cytotoxic T-lymphocyte (CTL) activity in a baby born to HIV-1-infected parents, in whom all standard markers of infection remained negative. These findings suggest that HIV-specific CTLs may be a marker for recently exposed, but uninfected, individuals.

Sutton J, Rowland-Jones S, Rosenberg W, Nixon D, Gotch F, Gao XM, Murray N, Spoonas A, Driscoll P, Smith M. 1993. A sequence pattern for peptides presented to cytotoxic T lymphocytes by HLA B8 revealed by analysis of epitopes and eluted peptides. Eur J Immunol, 23 (2), pp. 447-453. | Show Abstract | Read more

HLA B8-restricted cytotoxic T lymphocytes (CTL) specific for influenza A virus were generated and shown to recognize the nucleoprotein (NP). The dominant epitope was mapped using recombinant vaccinia viruses that expressed fragments of the NP and then synthetic peptides based on the NP amino acid sequence. The peptide 380-393 was first identified and further refined; it was shown that the glutamic acid at position 380 was essential for recognition by CTL and that the nonamer 380-388 was the optimum peptide. Six HLA B8-positive influenza immune donors that we have tested respond to this peptide as part of their influenza-specific CTL response. The amino acid sequence of the peptide epitope was compared to six other known virus peptides known to be restricted by HLA B8 and a sequence homology was identified, which predicted nonamer and octamer epitope sequences. Probable anchor residues were identified at peptide residues 3 (lysine/arginine), 5 (lysine/arginine) and 9 (leucine/isoleucine). Support for this pattern came from sequencing peptides eluted from purified HLA B8 molecules, where lysines were predominant at positions 3 and 5. One of the predicted epitope peptides was made and shown to be recognized by specific CTL. These and the two others were shown to compete with NP 380-388 for binding to HLA B8. A model was made of the HLA B8 molecule and negatively charged pockets predicted, which could accommodate the positively charged side chains of the peptide anchor residues.

Rowland-Jones S, McMichael A. 1993. Cytotoxic T lymphocytes in HIV infection Seminars in Virology, 4 (2), pp. 83-94. | Show Abstract | Read more

Infection with human immunodeficiency virus (HIV) induces potent cytotoxic T lymphocyte (CTL) response. Their level of activity is often extraordinary high, which in the presence of normal precursor levels suggests that effector CTL may be overstimulated and terminally differentiated. Late in HIV infection the CTL response declines. Possible mechanisms for this are discussed, including clonal exhaustion, lack of T cell help and virus escape by mutations involving epitope sequences. Evidence for the last is presented. Such escape potential implies that CTL are important in controlling the virus infection and that HLA type could have an effect on outcome. Escape mutation also has implications for vaccine design. © 1993 Academic Press. All rights reserved.

Gao XM, Tite JP, Lipscombe M, Rowland-Jones S, Ferguson DJ, McMichael AJ. 1992. Recombinant Salmonella typhimurium strains that invade nonphagocytic cells are resistant to recognition by antigen-specific cytotoxic T lymphocytes. Infect Immun, 60 (9), pp. 3780-3789. | Show Abstract

To address the question of whether Salmonella-infected nonphagocytic cells could serve as target cells for recognition by antigen-specific, major histocompatibility complex class I-restricted cytotoxic T lymphocytes (CTL), four recombinant Salmonella typhimurium constructs that expressed full-length, or fragments of, influenza A virus nucleoprotein (NP) were made. The bacteria were shown to infect Chinese hamster ovary (CHO) cells. Appropriate major histocompatibility complex restriction molecules, HLA-B27 and H-2 Db, were transfected into CHO cells, which were then infected with recombinant S. typhimurium and used as targets for NP-specific CTL. The cells in which NP was expressed by intracellularly replicating bacteria were not lysed by NP-specific CTL, although they were killed when appropriate influenza A virus or peptides were used. Thus, S.typhimurium bacteria within nonphagocytic cells were resistant to CTL recognition. In contrast to these results, mice infected with recombinant S.typhimurium that expressed fragments of NP in the periplasm were primed for NP-specific CTL responses. The results indicate that CTL responses specific to Salmonella antigens can be generated, but the bacteria may be safe from the CTL attack once they have entered the nonphagocytic cells.

Pazmany L, Rowland-Jones S, Huet S, Hill A, Sutton J, Murray R, Brooks J, McMichael A. 1992. Genetic modulation of antigen presentation by HLA-B27 molecules. J Exp Med, 175 (2), pp. 361-369. | Show Abstract | Read more

In studies of antigenic peptide presentation, we have found a healthy volunteer whose lymphoblastoid cells were unable to present three different virus-derived epitopes to cytotoxic T lymphocytes (CTL) despite expressing the correct restricting HLA-B27 molecules on the cell surface. B cell lines were established from other members of the donor's family, including individuals suffering from ankylosing spondylitis and related diseases, and were tested for their ability to function as target cells in the same assay. None of the eight B cell lines that expressed HLA-B27 presented a known peptide epitope to CTL. However, cells from a family member that expressed HLA-B8 could present an epitope peptide restricted by that molecule. The B27 molecule in this family proved to be the B2702 subtype on isoelectric focusing gels, appearing in exactly the same position as B2702 from other cell lines that did present the peptide. To exclude mutations resulting in noncharged amino acid substitutions, cDNA coding for B2702 was cloned from the proband's cell line and sequenced. No coding changes were found. The cloned cDNA was transfected into HLA-A- and B-negative HMy/C1R cells, and the B2702 molecules generated in this environment rendered these cells, after incubation with peptide, susceptible to lysis by peptide-specific CTL. These data are compatible with the presence of a factor(s), possibly HLA linked, interfering with antigen presentation by otherwise normal B2702 molecules in this family.

Phillips RE, Rowland-Jones S, Nixon DF, Gotch FM, Edwards JP, Ogunlesi AO, Elvin JG, Rothbard JA, Bangham CR, Rizza CR. 1991. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature, 354 (6353), pp. 453-459. | Show Abstract | Read more

In a longitudinal study of HIV seropositive patients, there were fluctuations in the specificity of cytotoxic T cells for the virus. This was matched by variability in proviral gag DNA epitope sequences in the lymphocytes of these patients. Some of these viral variants are not recognized by autologous T cells. Accumulation of such mutations in T-cell antigenic targets would provide a mechanism for immune escape.

Moss PA, Moots RJ, Rosenberg WM, Rowland-Jones SJ, Bodmer HC, McMichael AJ, Bell JI. 1991. Extensive conservation of alpha and beta chains of the human T-cell antigen receptor recognizing HLA-A2 and influenza A matrix peptide. Proc Natl Acad Sci U S A, 88 (20), pp. 8987-8990. | Show Abstract | Read more

The major histocompatibility complex class I molecule HLA-A2.1 presents the influenza A virus matrix peptide 57-68 to cytotoxic T lymphocytes in all individuals with this common HLA type and is among the most thoroughly studied immune responses in humans. We have studied the T-cell receptor (TCR) heterogeneity of T cells specific for HLA-A2 and influenza A matrix peptide using the polymerase chain reaction. The usage of V alpha and V beta sequences seen on these T cells is remarkably conserved as are certain junctional sequences associated with alpha and beta chains. Furthermore, two unrelated HLA-A2 individuals have a similar pattern of TCR usage, implying that this is a predominant response in HLA-A2 populations. Analysis in one individual showed that the conserved TCR V alpha and V beta genes are minor members of the peripheral blood TCR repertoire. The sequences provide important information on the TCR necessary for the final structural analysis of this ternary complex.

Thomas MG, Rowland-Jones S, Smyth E. 1989. Klebsiella pneumoniae endocarditis. J R Soc Med, 82 (2), pp. 114-115. | Read more

Jallow S, Leligdowicz A, Kramer HB, Onyango C, Cotten M, Wright C, Whittle HC, McMichael A, Dong T, Kessler BM, Rowland-Jones SL. 2015. The presence of prolines in the flanking region of an immunodominant HIV-2 gag epitope influences the quality and quantity of the epitope generated. Eur J Immunol, 45 (8), pp. 2232-2242. | Show Abstract | Read more

Both the recognition of HIV-infected cells and the immunogenicity of candidate CTL vaccines depend on the presentation of a peptide epitope at the cell surface, which in turn depends on intracellular antigen processing. Differential antigen processing maybe responsible for the differences in both the quality and the quantity of epitopes produced, influencing the immunodominance hierarchy of viral epitopes. Previously, we showed that the magnitude of the HIV-2 gag-specific T-cell response is inversely correlated with plasma viral load, particularly when responses are directed against an epitope, 165 DRFYKSLRA173 , within the highly conserved Major Homology Region of gag-p26. We also showed that the presence of three proline residues, at positions 119, 159 and 178 of gag-p26, was significantly correlated with low viral load. Since this proline motif was also associated with stronger gag-specific CTL responses, we investigated the impact of these prolines on proteasomal processing of the protective 165 DRFYKSLRA173 epitope. Our data demonstrate that the 165 DRFYKSLRA173 epitope is most efficiently processed from precursors that contain two flanking proline residues, found naturally in low viral-load patients. Superior antigen processing and enhanced presentation may account for the link between infection with HIV-2 encoding the "PPP-gag" sequence and both strong gag-specific CTL responses as well as lower viral load.

Jayasooriya S, de Silva TI, Njie-jobe J, Sanyang C, Leese AM, Bell AI, McAulay KA, Yanchun P, Long HM, Dong T et al. 2015. Early virological and immunological events in asymptomatic Epstein-Barr virus infection in African children. PLoS Pathog, 11 (3), pp. e1004746. | Show Abstract | Read more

Epstein-Barr virus (EBV) infection often occurs in early childhood and is asymptomatic. However, if delayed until adolescence, primary infection may manifest as acute infectious mononucleosis (AIM), a febrile illness characterised by global CD8+ T-cell lymphocytosis, much of it reflecting a huge expansion of activated EBV-specific CD8+ T-cells. While the events of AIM have been intensely studied, little is known about how these relate to asymptomatic primary infection. Here Gambian children (14-18 months old, an age at which many acquire the virus) were followed for the ensuing six months, monitoring circulating EBV loads, antibody status against virus capsid antigen (VCA) and both total and virus-specific CD8+ T-cell numbers. Many children were IgG anti-VCA-positive and, though no longer IgM-positive, still retained high virus loads comparable to AIM patients and had detectable EBV-specific T-cells, some still expressing activation markers. Virus loads and the frequency/activation status of specific T-cells decreased over time, consistent with resolution of a relatively recent primary infection. Six children with similarly high EBV loads were IgM anti-VCA-positive, indicating very recent infection. In three of these donors with HLA types allowing MHC-tetramer analysis, highly activated EBV-specific T-cells were detectable in the blood with one individual epitope response reaching 15% of all CD8+ T-cells. That response was culled and the cells lost activation markers over time, just as seen in AIM. However, unlike AIM, these events occurred without marked expansion of total CD8+ numbers. Thus asymptomatic EBV infection in children elicits a virus-specific CD8+ T-cell response that can control the infection without over-expansion; conversely, in AIM it appears the CD8 over-expansion, rather than virus load per se, is the cause of disease symptoms.

Shepherd BL, Ferrand R, Munyati S, Folkard S, Boyd K, Bandason T, Jallow S, Rowland-Jones SL, Yindom LM. 2015. HLA Correlates of Long-Term Survival in Vertically Infected HIV-1-Positive Adolescents in Harare, Zimbabwe. AIDS Res Hum Retroviruses, 31 (5), pp. 504-507. | Show Abstract | Read more

African infants with vertically acquired HIV infection progress rapidly, with only 50% surviving beyond 2 years in the absence of treatment. Despite this high initial mortality, recent reports describe a substantial burden of older children living with untreated vertically acquired HIV infection in Southern Africa. The immunological and genetic factors associated with long-term survival following vertical infection are poorly understood. We performed medium-to-high resolution HLA typing on DNA samples obtained from a cohort of presumed vertically HIV-1-infected children and age-matched uninfected controls in Harare, Zimbabwe. Overall, 93 HLA class I alleles were detected in the study population with a significant enrichment of HLA-C*08:02 and -C*08:04 in the HIV-1-infected long-term survivor group. Conversely, HLA-A*02:01, A*34:02, and -B*58:02 were overrepresented in the uninfected control group. Our data indicate that HLA alleles may have differential effects against HIV acquisition and disease progression in vertical HIV-1 infection.

Afran L, Garcia Knight M, Nduati E, Urban BC, Heyderman RS, Rowland-Jones SL. 2014. HIV-exposed uninfected children: a growing population with a vulnerable immune system? Clin Exp Immunol, 176 (1), pp. 11-22. | Show Abstract | Read more

Through the successful implementation of policies to prevent mother-to-child-transmission (PMTCT) of HIV-1 infection, children born to HIV-1-infected mothers are now much less likely to acquire HIV-1 infection than previously. Nevertheless, HIV-1-exposed uninfected (HEU) children have substantially increased morbidity and mortality compared with children born to uninfected mothers (unexposed uninfected, UU), predominantly from infectious causes. Moreover, a range of phenotypical and functional immunological differences between HEU and UU children has been reported. As the number of HEU children continues to increase worldwide, two questions with clear public health importance need to be addressed: first, does exposure to HIV-1 and/or ART in utero or during infancy have direct immunological consequences, or are these poor outcomes simply attributable to the obvious disadvantages of being born into an HIV-affected household? Secondly, can we expect improved maternal care and ART regimens during and after pregnancy, together with optimized infant immunization schedules, to reduce the excess morbidity and mortality of HEU children?

de Silva TI, Peng Y, Leligdowicz A, Zaidi I, Li L, Griffin H, Blais ME, Vincent T, Saraiva M, Yindom LM et al. 2013. Correlates of T-cell-mediated viral control and phenotype of CD8(+) T cells in HIV-2, a naturally contained human retroviral infection. Blood, 121 (21), pp. 4330-4339. | Show Abstract | Read more

While a significant proportion of HIV-2-infected individuals are asymptomatic and maintain undetectable viral loads (controllers), 15% to 20% progress to AIDS and are predicted by detectable viremia. Identifying immune correlates that distinguish these 2 groups should provide insights into how a potentially pathogenic retrovirus can be naturally controlled. We performed a detailed study of HIV-2-specific cellular responses in a unique community cohort in Guinea-Bissau followed for over 2 decades. T-cell responses were compared between controllers (n = 33) and viremic subjects (n = 27) using overlapping peptides, major histocompatibility complex class I tetramers, and multiparameter flow cytometry. HIV-2 viral control was significantly associated with a high-magnitude, polyfunctional Gag-specific CD8(+) T-cell response but not with greater perforin upregulation. This potentially protective HIV-2-specific response is surprisingly narrow. HIV-2 Gag-specific CD8(+) T cells are at an earlier stage of differentiation than cytomegalovirus-specific CD8(+) T-cells, do not contain high levels of cytolytic markers, and exhibit low levels of activation and proliferation, representing distinct properties from CD8(+) T cells associated with HIV-1 control. These data reveal the potential T-cell correlates of HIV-2 control and the detailed phenotype of virus-specific CD8(+) T cells in a naturally contained retroviral infection.

Blais ME, Zhang Y, Rostron T, Griffin H, Taylor S, Xu K, Yan H, Wu H, James I, John M et al. 2012. High frequency of HIV mutations associated with HLA-C suggests enhanced HLA-C-restricted CTL selective pressure associated with an AIDS-protective polymorphism. J Immunol, 188 (9), pp. 4663-4670. | Show Abstract | Read more

Delayed HIV-1 disease progression is associated with a single nucleotide polymorphism upstream of the HLA-C gene that correlates with differential expression of the HLA-C Ag. This polymorphism was recently shown to be a marker for a protective variant in the 3'UTR of HLA-C that disrupts a microRNA binding site, resulting in enhanced HLA-C expression at the cell surface. Whether individuals with "high" HLA-C expression show a stronger HLA-C-restricted immune response exerting better viral control than that of their counterparts has not been established. We hypothesized that the magnitude of the HLA-C-restricted immune pressure on HIV would be greater in subjects with highly expressed HLA-C alleles. Using a cohort derived from a unique narrow source epidemic in China, we identified mutations in HIV proviral DNA exclusively associated with HLA-C, which were used as markers for the intensity of the immune pressure exerted on the virus. We found an increased frequency of mutations in individuals with highly expressed HLA-C alleles, which also correlated with IFN-γ production by HLA-C-restricted CD8(+) T cells. These findings show that immune pressure on HIV is stronger in subjects with the protective genotype and highlight the potential role of HLA-C-restricted responses in HIV control. This is, to our knowledge, the first in vivo evidence supporting the protective role of HLA-C-restricted responses in nonwhites during HIV infection.

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Dong T, Zhang Y, Xu KY, Yan H, James I, Peng Y, Blais M-E, Gaudieri S, Chen X, Lun W et al. 2011. Extensive HLA-driven viral diversity following a narrow-source HIV-1 outbreak in rural China BLOOD, 118 (1), pp. 98-106. | Show Abstract | Read more

Obstacles to developing an HIV-1 vaccine include extensive viral diversity and lack of correlates of protective immunity. High mutation rates allow HIV-1 to adapt rapidly to selective forces such as antiretroviral therapy and immune pressure, including HIV-1-specific CTLs that select viral variants which escape T-cell recognition. Multiple factors contribute to HIV-1 diversity, making it difficult to disen-tangle the contribution of CTL selection without using complex analytical approaches. We describe an HIV-1 outbreak in 231 former plasma donors in China, where a narrow-source virus that had contaminated the donation system was apparently transmitted to many persons contemporaneously. The genetic divergence now evident in these subjects should uniquely reveal how much viral diversity at the population level is solely attributable to host factors. We found significant correlations between pair-wise divergence of viral sequences and HLA class I genotypes across epitope-length windows in HIV-1 Gag, reverse transcriptase, integrase, and Nef, corresponding to sites of 140 HLA class I allele-associated viral polymorphisms. Of all polymorphic sites across these 4 proteins, 24%-56% were sites of HLA-associated selection. These data confirm that CTL pressure has a major effect on inter-host HIV-1 viral diversity and probably represents a key element of viral control. © 2011 by The American Society of Hematology.

Slyker JA, John-Stewart GC, Dong T, Lohman-Payne B, Reilly M, Atzberger A, Taylor S, Maleche-Obimbo E, Mbori-Ngacha D, Rowland-Jones SL. 2011. Phenotypic characterization of HIV-specific CD8+ T cells during early and chronic infant HIV-1 infection. PLoS One, 6 (5), pp. e20375. | Show Abstract | Read more

Although CD8(+) T cells play an important role in the containment of adult HIV-1 replication, their role in infant HIV-1 infection is not as well understood. Impaired HIV-specific CD8(+) T cell responses may underlie the persistently high viral loads observed in infants. We examined the frequency and phenotype of infant HIV-specific CD8(+) T cells in 7 HIV-infected antiretroviral therapy-naïve infants during the first 2 years of life, using class I HLA tetramers and IFN-γ-ELISPOT. The frequency (0.088-3.9% of CD3(+)CD8(+) cells) and phenotype (CD27(+)CD28(-), CD45RA(+/-), CD57(+/-), HLA-DR(+), CD95(+)) of infant HIV-specific CD8(+) T cells were similar to reports in adults undergoing early infection. Unlike adults, at 23-24 months post-infection a high frequency of HIV-specific CD8(+) T cells expressed HLA-DR (mean 80%, range 68-85%) and CD95 (mean 88%, range 79-96%), suggesting sustained activation and vulnerability to apoptosis. Despite comparable expansion of HIV-specific CD8(+) T cells of a similar phenotype to adults during early infection, infant T cells failed to contain HIV-1 replication, and remained persistently activated and vulnerable to apoptosis during chronic infection.

Leligdowicz A, Onyango C, Yindom LM, Peng Y, Cotten M, Jaye A, McMichael A, Whittle H, Dong T, Rowland-Jones S. 2010. Highly avid, oligoclonal, early-differentiated antigen-specific CD8+ T cells in chronic HIV-2 infection. Eur J Immunol, 40 (7), pp. 1963-1972. | Show Abstract | Read more

HIV-1-specific CD8(+) T cells are present in most HIV-1-infected people and play an important role in controlling viral replication, but the characteristics of an effective HIV-specific T-cell response are largely unknown. The majority of HIV-2-infected people behave as long-term non-progressors while those who progress to AIDS do so in a manner indistinguishable from HIV-1. A detailed study of HIV-2 infection may identify protective immune responses. Robust gag p26-specific T-cell responses are elicited during HIV-2 infection and correlate with control of viremia. In this study, we analyzed features of an HLA-B 3501-restricted T-cell response to HIV-2 p26 that may contribute to virus control. In contrast to HIV-1, HIV-2-specific T cells are at an early stage of differentiation (CD27(+)CD28(+)), a finding that relates directly to CD4(+) T-cell levels and inversely to immune activation. The cells demonstrate IFN-gamma secretion, oligoclonal T-cell receptor Vbeta gene segment usage, exceptional avidity and secretion of pro-inflammatory cytokines. Despite the potentially strong selection pressure imposed on the virus by these cells, there was no evidence of HIV-2 sequence evolution. We propose that in chronic HIV-2 infection, the maintenance of early-differentiated, highly avid CD8(+) T cells could account for the non-progressive course of disease. Such responses may be desirable from an HIV vaccine.

Flanagan KL, Halliday A, Burl S, Landgraf K, Jagne YJ, Noho-Konteh F, Townend J, Miles DJ, van der Sande M, Whittle H, Rowland-Jones S. 2010. The effect of placental malaria infection on cord blood and maternal immunoregulatory responses at birth. Eur J Immunol, 40 (4), pp. 1062-1072. | Show Abstract | Read more

Placental malaria (PM), a frequent infection of pregnancy, provides an ideal opportunity to investigate the impact on immune development of exposure of the foetal immune system to foreign Ag. We investigated the effect of PM on the regulatory phenotype and function of cord blood cells from healthy Gambian newborns and peripheral blood cells from their mothers, and analyzed for effects on the balance between regulatory and effector responses. Using the gold standard for classifying PM we further distinguished between resolved infection and acute or chronic PM active at the time of delivery. We show that exposure to malarial Ag in utero results in the expansion of malaria-specific FOXP3(+) Treg and more generalized FOXP3(+) CD4(+) Treg in chronic and resolved PM, alongside increased Th1 pro-inflammatory responses (IFN-gamma, TNF-alpha, IFN-gamma:IL-10) in resolved PM infection only. These observations demonstrate a clear effect of exposure to malarial Ag in foetal life on the immune environment at birth, with a regulatory response dominating in the newborns with ongoing chronic PM, while those with resolved infection produce both regulatory and inflammatory responses. The findings might explain some of the adverse effects on the health of babies born to women with PM.

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Leligdowicz A, Feldmann J, Jaye A, Cotten M, Dong T, McMichael A, Whittle H, Rowland-Jones S. 2010. Direct relationship between virus load and systemic immune activation in HIV-2 infection Journal of Infectious Diseases, 201 (1), pp. 114-122. | Show Abstract | Read more

Immune activation is a hallmark of disease progression in human immunodeficiency virus (HIV) type 1 (HIV1) and HIV type 2 (HIV-2) infection. However, the relationship between viremia and systemic immune activation is unclear. We assessed the relationship between HIV-2 plasma virus load and immune system activation in a cross-sectional study in a community cohort of HIV-1-positive, HIV-2-positive, and HIV-negative patients, in which many HIV-2-positive patients had nonprogressing infection. HLA-DR and CD38 expression on CD4+ and CD8+ T cells was measured, as were plasma β2-microglobulin levels. These markers were related to clinical (virus load and CD4+ cell count) and immunological (HIV-2-specific interferon γ secretion) correlates of delayed disease progression. A consistent positive correlation was identified between the level of HIV-2 viremia and immune activation. We propose that increasing virus load may contribute to systemic immune activation in HIV-2 infection. © 2009 by the Infectious Diseases Society of America. All rights reserved.

Feldmann J, Leligdowicz A, Jaye A, Dong T, Whittle H, Rowland-Jones SL. 2009. Downregulation of the T-cell receptor by human immunodeficiency virus type 2 Nef does not protect against disease progression. J Virol, 83 (24), pp. 12968-12972. | Show Abstract | Read more

Chronic immune activation is thought to play a major role in human immunodeficiency virus (HIV) pathogenesis, but the relative contributions of multiple factors to immune activation are not known. One proposed mechanism to protect against immune activation is the ability of Nef proteins from some HIV and simian immunodeficiency virus strains to downregulate the T-cell receptor (TCR)-CD3 complex of the infected cell, thereby reducing the potential for deleterious activation. HIV type 1 (HIV-1) Nef has lost this property. In contrast to HIV-1, HIV-2 infection is characterized by a marked disparity in the disease course, with most individuals maintaining a normal life span. In this study, we examined the relationship between the ability of HIV-2 Nef proteins to downregulate the TCR and immune activation, comparing progressors and nonprogressors. Representative Nef variants were isolated from 28 HIV-2-infected individuals. We assessed their abilities to downregulate the TCR from the surfaces of CD4 T cells. In the same individuals, the activation of peripheral lymphocytes was evaluated by measurement of the expression levels of HLA-DR and CD38. We observed a striking correlation of the TCR downregulation efficiency of HIV-2 Nef variants with immune activation in individuals with a low viral load. This strongly suggests that Nef expression can influence the activation state of the immune systems of infected individuals. However, the efficiency of TCR downregulation by Nef was not reduced in progressing individuals, showing that TCR downregulation does not protect against progression in HIV-2 infection.

HIV-2 infection: what determines T-cell control?

Supervisor:      Prof. Sarah Rowland-Jones (sarah.rowland-jones@ndm.ox.ac.uk), Nuffield Dept of Medicine, OxfordCo-supervisor: Professor Tao Dong, Radcliffe department of Medicine, Oxford (tao.dong@rdm.ox.ac.uk)The second AIDS virus, HIV-2, was isolated in 1986 and is thought to have arisen from a retrovirus infecting sooty mangabey monkeys that entered humans in West Africa on multiple occasions. Despite a very similar size and gene organisation, as well as approximately 30-60% amino acid ...

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Immunologic and genetic correlates of protection associated with delayed HIV disease progression in children with vertically-acquired HIV-1, Harare, Zimbabwe

The natural history of perinatal HIV infection in the pre-anti-retroviral treatment (ART) era was associated with rapid disease progression[1, 2], leading to the assumption that survival of vertically-infected children to older childhood would be exceptional. However, recent studies from southern Africa now demonstrates that as the HIV epidemic matures, a substantial number of older children are presenting late to health services with undiagnosed/untreated vertical HIV-infection[3-6]. Although ...

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The pathogenesis of previously undiagnosed vertical HIV-1 infection in HIV-infected adolescents in Zimbabwe

Mother to child transmission (MTCT) remains an important cause of HIV-1 infection worldwide, despite increased implementation of prevention strategies. Infants who acquire perinatal infection, particularly in sub-Saharan Africa (SSA), experience unusually rapid disease progression compared to adults, with mortality rates in the absence of anti-retroviral therapy (ART) as high as 20-52% in the first two years of life1,2. Infants have very high peak viral loads (VL) in the first 1-2 months after ...

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