register interest

Professor Lucy Dorrell

Research Area: Immunology
Technology Exchange: Cell sorting, Cellular immunology, Flow cytometry, Microscopy (Confocal) and Vaccine production and evaluation
Scientific Themes: Immunology & Infectious Disease
Keywords: hiv, t cell, vaccine, clinical trial, viral vector and antiretroviral
Web Links:
Laser scanning confocal microscopy image of human primary CD8+ T cells (magenta) forming a conjugate with an HIV-infected primary CD4+ T cell (p24 antigen – green) leading to cell death through upregulation of caspase-3 (red) in the infected cell. 
Image credit: Zoe Wallace, Nuffield Department of Medicine.

Laser scanning confocal microscopy image of human primary CD8+ T cells (magenta) forming a ...

The goal of our research is to understand the mechanisms that determine successful containment of HIV and how these can be exploited in the development of vaccines and T cell-based therapies. Our work encompasses studies at the single cell level, patient cohorts and clinical trials.

We are currently focusing on the following areas of investigation:

New approaches to reducing HIV reservoirs

Natural immune responses keep HIV under control to some degree in most people but are unable to prevent disease progression. ART stops viral replication but is not able to eliminate cells that harbour dormant (the latent reservoir) HIV. New approaches are needed to eliminate this viral reservoir. We are testing ART in combination with vaccines and other agents in clinical trials. The vaccines comprise a conserved region immunogen, HIVconsv, delivered by replication-defective chimpanzee adenovirus and MVA vectors. These trials are among the first to evaluate latent HIV reservoirs before and after vaccination. In addition, in collaboration with Immunocore Ltd, Oxon, we are investigating the potency of novel engineered immune-mobilising T cell receptors-based drugs (‘ImmTAVs’) that are designed to clear HIV-infected cells.

Immunological correlates of HIV control

We demonstrated that ex vivo CD8+ T cell viral inhibitory activity measured in HIV-positive patients is correlated with viral load set-point and is predictive of the rate of HIV disease progression. A critical next step in the development of preventive and therapeutic vaccines is to define the components of an HIV immunogen that could induce CD8+ T cells with broad and potent inhibitory capacity. Through collaboration with the NIAID-funded HIV Vaccine Trials Network and Duke University NC, we have shown that targeting of selected vulnerable regions within the HIV proteome by CD8+ T cells is strongly associated with their capacity to inhibit HIV replication in vitro.

This work has paved the way for new imaging studies of HIV-immune cell interactions using the first ever containment level 3 high-resolution microscopy facility at the Weatherall Institute of Molecular Medicine.

Prevention of co-infections

As HIV-positive people are living longer, prevention of comorbidities has become a priority. PEACHI is an EU FP7-funded project to develop vaccines for prevention of hepatitis C and HIV co-infections. The PEACHI consortium brings together expertise in the HIV and HCV fields, with European partners from academia (Oxford, St. James Hospital Dublin, Kantosspital St Gallen) and industry (GSK and Okairos) (www.peachi.eu). We are planning a series of vaccine trials to evaluate vaccinations with HIV and/or HCV immunogens, each delivered by replication-defective chimpanzee adenovirus and MVA vectors, in healthy volunteers and in HIV-positive HCV-uninfected patients on ART. We will also test next-generation viral vectored vaccines employing an HCV immunogen fused to HLA class II invariant chain. These clinical studies will be complemented by comprehensive immunomonitoring with the goal of identifying possible immune correlates that could be tested in future efficacy trials.

New projects

We are starting a new project to develop new multi-genotype vaccines for therapy of human papilloma virus (HPV) infections that are responsible for cervical cancer (0.5 million cases per year worldwide) and other anogenital cancers. We exploit the same potent viral vectors for delivery of a novel HPV immunogen that have proven safe and immunogenic for HIV and HCV.

Name Department Institution Country
Professor Tomas Hanke Jenner Institute University of Oxford United Kingdom
Professor Brian J Angus FRCP Tropical Medicine University of Oxford United Kingdom
Dr Cameron Holloway University of Oxford United Kingdom
Prof Stefan Neubauer FMedSci FRCP (RDM) Cardiovascular Medicine University of Oxford United Kingdom
Dr Christian Brander Fundacio irsiCaixa Spain
Professor Benedikt M Kessler Target Discovery Institute University of Oxford United Kingdom
Professor Johnson Mak Deakin University Australia
Professor Arturo Reyes-Sandoval Jenner Institute University of Oxford United Kingdom
Professor Ellie (Eleanor) Barnes Experimental Medicine Division University of Oxford United Kingdom
Dr Nicola Ternette Jenner Institute University of Oxford United Kingdom
Yang H, Buisson S, Bossi G, Wallace Z, Hancock G, So C, Ashfield R, Vuidepot A et al. 2016. Elimination of Latently HIV-infected Cells from Antiretroviral Therapy-suppressed Subjects by Engineered Immune-mobilizing T-cell Receptors. Mol Ther, | Show Abstract | Read more

Persistence of human immunodeficiency virus (HIV) in a latent state in long-lived CD4+ T-cells is a major barrier to eradication. Latency-reversing agents that induce direct or immune-mediated cell death upon reactivation of HIV are a possible solution. However, clearance of reactivated cells may require immunotherapeutic agents that are fine-tuned to detect viral antigens when expressed at low levels. We tested the antiviral efficacy of immune-mobilizing monoclonal T-cell receptors against viruses (ImmTAVs), bispecific molecules that redirect CD8+ T-cells to kill HIV-infected CD4+ T-cells. T-cell receptors specific for an immunodominant Gag epitope, SL9, and its escape variants were engineered to achieve supraphysiological affinity and fused to a humanised CD3-specific single chain antibody fragment. Ex vivo polyclonal CD8+ T-cells were efficiently redirected by immune-mobilising monoclonal T-cell receptors against viruses to eliminate CD4+ T-cells from human histocompatibility leukocyte antigen (HLA)-A*0201-positive antiretroviral therapy-treated patients after reactivation of inducible HIV in vitro. The efficiency of infected cell elimination correlated with HIV Gag expression. Immune-mobilising monoclonal T-cell receptors against viruses have potential as a therapy to facilitate clearance of reactivated HIV reservoir cells.Molecular Therapy (2016); doi:10.1038/mt.2016.114.

Ewer KJ, Lambe T, Rollier CS, Spencer AJ, Hill AV, Dorrell L. 2016. Viral vectors as vaccine platforms: from immunogenicity to impact. Curr Opin Immunol, 41 pp. 47-54. | Show Abstract | Read more

Viral vectors are the vaccine platform of choice for many pathogens that have thwarted efforts towards control using conventional vaccine approaches. Although the STEP trial encumbered development of recombinant human adenovirus vectors only a few years ago, replication-deficient simian adenoviruses have since emerged as a crucial component of clinically effective prime-boost regimens. The vectors discussed here elicit functionally relevant cellular and humoral immune responses, at extremes of age and in diverse populations. The recent Ebola virus outbreak highlighted the utility of viral vectored vaccines in facilitating a rapid response to public health emergencies. Meanwhile, technological advances in manufacturing to support scale-up of viral vectored vaccines have helped to consolidate their position as a leading approach to tackling 'old' and emerging infections.

Lord E, Newnham T, Dorrell L, Jesuthasan G, Clarke L, Jeffery K, Sherrard J. 2016. Detecting asymptomatic Trichomonas vaginalis in females using the BD ProbeTec™ Trichomonas vaginalis Qx nucleic acid amplification test. Int J STD AIDS, | Show Abstract | Read more

Trichomonas vaginalis (TV) rates in women are increasing and many are asymptomatic. Nucleic acid amplification tests (NAATs) are becoming the 'gold standard' for diagnosis. We aimed to establish our asymptomatic TV rates by testing all women attending Oxfordshire's Sexual Health service, regardless of symptoms, using the BD ProbeTec™ TV Q(x) NAATs (BDQ(x)). During BDQ(x)'s verification process, the sensitivity and specificity were calculated using results of 220 endocervical samples from symptomatic women, compared with culture. BDQ(x) was subsequently implemented and prospectively evaluated over 6 months in female attendees. Wet mount microscopy was also performed in symptomatics. Demographic and clinical characteristics of those diagnosed were analysed. From 220 samples tested by BDQ(x) and culture: 5 were positive on both and one solely using BDQ(x), giving a sensitivity and specificity of 100% and 99.53%, respectively. In the prospective cohort, of 5775 BDQ(x) tests, 33 (0.57%) were positive. 11/33 (33%) patients were asymptomatic. All patients diagnosed had risk factors: age >25 years (85%), residence in a deprived area (79%) and black ethnicity (21%). Despite BDQ(x) being highly sensitive and specific, with our low TV prevalence universal screening may not be justified. Targeted screening using local demographic data merits further investigation.

Ntusi N, O'Dwyer E, Dorrell L, Wainwright E, Piechnik S, Clutton G, Hancock G, Ferreira V et al. 2016. HIV-1-Related Cardiovascular Disease Is Associated With Chronic Inflammation, Frequent Pericardial Effusions, and Probable Myocardial Edema. Circ Cardiovasc Imaging, 9 (3), pp. e004430. | Show Abstract | Read more

BACKGROUND: Patients with treated HIV infection have clear survival benefits although with increased cardiac morbidity and mortality. Mechanisms of heart disease may be partly related to untreated chronic inflammation. Cardiovascular magnetic resonance imaging allows a comprehensive assessment of myocardial structure, function, and tissue characterization. We investigated, using cardiovascular magnetic resonance, subclinical inflammation and myocardial disease in asymptomatic HIV-infected individuals. METHODS AND RESULTS: Myocardial structure and function were assessed using cardiovascular magnetic resonance at 1.5-T in treated HIV-infected individuals without known cardiovascular disease (n=103; mean age, 45±10 years) compared with healthy controls (n=92; mean age, 44±10 years). Assessments included left ventricular volumes, ejection fraction, strain, regional systolic, diastolic function, native T1 mapping, edema, and gadolinium enhancement. Compared with controls, subjects with HIV infection had 6% lower left ventricular ejection fraction (P<0.001), 7% higher myocardial mass (P=0.02), 29% lower peak diastolic strain rate (P<0.001), 4% higher short-tau inversion recovery values (P=0.02), and higher native T1 values (969 versus 956 ms in controls; P=0.01). Pericardial effusions and myocardial fibrosis were 3 and 4× more common, respectively, in subjects with HIV infection (both P<0.001). CONCLUSIONS: Treated HIV infection is associated with changes in myocardial structure and function in addition to higher rates of subclinical myocardial edema and fibrosis and frequent pericardial effusions. Chronic systemic inflammation in HIV, which involves the myocardium and pericardium, may explain the high rate of myocardial fibrosis and increased cardiac dysfunction in people living with HIV.

Ahmed T, Borthwick NJ, Gilmour J, Hayes P, Dorrell L, Hanke T. 2016. Control of HIV-1 replication in vitro by vaccine-induced human CD8(+) T cells through conserved subdominant Pol epitopes. Vaccine, 34 (9), pp. 1215-1224. | Show Abstract | Read more

OBJECTIVE: The specificity of CD8(+) T cells is critical for early control of founder/transmitted and reactivated HIV-1. To tackle HIV-1 variability and escape, we designed vaccine immunogen HIVconsv assembled from 14 highly conserved regions of mainly Gag and Pol proteins. When administered to HIV-1-negative human volunteers in trial HIV-CORE 002, HIVconsv vaccines elicited CD8(+) effector T cells which inhibited replication of up to 8 HIV-1 isolates in autologous CD4(+) cells. This inhibition correlated with interferon-γ production in response to Gag and Pol peptide pools, but direct evidence of the inhibitory specificity was missing. Here, we aimed to define through recognition of which epitopes these effectors inhibit HIV-1 replication. DESIGN: CD8(+) T-cells from the 3 broadest HIV-1 inhibitors out of 23 vaccine recipients were expanded in culture by Gag or Pol peptide restimulation and tested in viral inhibition assay (VIA) using HIV-1 clade B and A isolates. METHODS: Frozen PBMCs were expanded first using peptide pools from Gag or Pol conserved regions and tested on HIV-1-infected cells in VIA or by individual peptides for their effector functions. Single peptide specificities responsible for inhibition of HIV-1 replication were then confirmed by single-peptide expanded effectors tested on HIV-1-infected cells. RESULTS: We formally demonstrated that the vaccine-elicited inhibitory human CD8(+) T cells recognized conserved epitopes of both Pol and Gag proteins. We defined 7 minimum epitopes, of which 3 were novel, presumably naturally subdominant. The effectors were oligofunctional producing several cytokines and chemokines and killing peptide-pulsed target cells. CONCLUSIONS: These results implicate the use of functionally conserved regions of Pol in addition to the widely used Gag for T-cell vaccine design. Proportion of volunteers developing these effectors and their frequency in circulating PBMC are separate issues, which can be addressed, if needed, by more efficient vector and regimen delivery of conserved immunogens.

Kinloch-de Loes S, Dorrell L, Yang H, Hardy GA, Yerly S, Cellerai C, Vandekerckhove L, De Spielgelaere W, Malatinkova E, Wee Lee Koh W, Johnson MA. 2015. Aviremia 10 Years Postdiscontinuation of Antiretroviral Therapy Initiated During Primary Human Immunodeficiency Virus-1 Infection and Association With Gag-Specific T-Cell Responses. Open Forum Infect Dis, 2 (4), pp. ofv144. | Show Abstract | Read more

Combination antiretroviral therapy during primary human immunodeficiency virus-1 infection may enable long-term drug-free virological control in rare individuals. We describe a female who maintained aviremia and a normal CD4(+)/CD8(+) T cell ratio for 10 years after stopping therapy, despite a persistent viral reservoir. Cellular immune responses may have contributed to this outcome.

Ternette N, Yang H, Partridge T, Llano A, Cedeño S, Fischer R, Charles PD, Dudek NL et al. 2016. Defining the HLA class I-associated viral antigen repertoire from HIV-1-infected human cells. Eur J Immunol, 46 (1), pp. 60-69. | Show Abstract | Read more

Recognition and eradication of infected cells by cytotoxic T lymphocytes is a key defense mechanism against intracellular pathogens. High-throughput definition of HLA class I-associated immunopeptidomes by mass spectrometry is an increasingly important analytical tool to advance our understanding of the induction of T-cell responses against pathogens such as HIV-1. We utilized a liquid chromatography tandem mass spectrometry workflow including de novo-assisted database searching to define the HLA class I-associated immunopeptidome of HIV-1-infected human cells. We here report for the first time the identification of 75 HIV-1-derived peptides bound to HLA class I complexes that were purified directly from HIV-1-infected human primary CD4(+) T cells and the C8166 human T-cell line. Importantly, one-third of eluted HIV-1 peptides had not been previously known to be presented by HLA class I. Over 82% of the identified sequences originated from viral protein regions for which T-cell responses have previously been reported but for which the precise HLA class I-binding sequences have not yet been defined. These results validate and expand the current knowledge of virus-specific antigenic peptide presentation during HIV-1 infection and provide novel targets for T-cell vaccine development.

Kinloch S, Johnson M, Yang H, Dorrell L, Vandekerckhove L, Malatinkova E, De Spiegelaere W, Webster D. 2015. Aviremia 10-year post-ART discontinuation initiated at seroconversion HIV MEDICINE, 16 pp. 21-21.

Ternette N, Block PD, Sánchez-Bernabéu Á, Borthwick N, Pappalardo E, Abdul-Jawad S, Ondondo B, Charles PD, Dorrell L, Kessler BM, Hanke T. 2015. Early Kinetics of the HLA Class I-Associated Peptidome of MVA.HIVconsv-Infected Cells. J Virol, 89 (11), pp. 5760-5771. | Show Abstract | Read more

UNLABELLED: Cytotoxic T cells substantially contribute to the control of intracellular pathogens such as human immunodeficiency virus type 1 (HIV-1). Here, we evaluated the immunopeptidome of Jurkat cells infected with the vaccine candidate MVA.HIVconsv, which delivers HIV-1 conserved antigenic regions by using modified vaccinia virus Ankara (MVA). We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify 6,358 unique peptides associated with the class I human leukocyte antigen (HLA), of which 98 peptides were derived from the MVA vector and 7 were derived from the HIVconsv immunogen. Human vaccine recipients responded to the peptide sequences identified by LC-MS/MS. Peptides derived from the conserved HIV-1 regions were readily detected as early as 1.5 h after MVA.HIVconsv infection. Four of the seven conserved peptides were monitored between 0 and 3.5 h of infection by using quantitative mass spectrometry (Q-MS), and their abundance in HLA class I associations reflected levels of the whole HIVconsv protein in the cell. While immunopeptides delivered by the incoming MVA vector proteins could be detected, all early HIVconsv-derived immunopeptides were likely synthesized de novo. MVA.HIVconsv infection generally altered the composition of HLA class I-associated human (self) peptides, but these changes corresponded only partially to changes in the whole cell host protein abundance. IMPORTANCE: The vast changes in cellular antigen presentation after infection of cells with a vectored vaccine, as shown here for MVA.HIVconsv, highlight the complexity of factors that need to be considered for efficient antigen delivery and presentation. Identification and quantitation of HLA class I-associated peptides by Q-MS will not only find broad application in T-cell epitope discovery but also inform vaccine design and allow evaluation of efficient epitope presentation using different delivery strategies.

Clutton G, Bridgeman A, Reyes-Sandoval A, Hanke T, Dorrell L. 2015. Transient IL-10 receptor blockade can enhance CD8(+) T cell responses to a simian adenovirus-vectored HIV-1 conserved region immunogen. Hum Vaccin Immunother, 11 (4), pp. 1030-1035. | Show Abstract | Read more

Viral vector vaccines designed to elicit CD8(+) T cells in non-human primates exert potent control of immunodeficiency virus infections; however, similar approaches have been unsuccessful in humans. Adenoviral vectors elicit potent T cell responses but also induce production of immunosuppressive interleukin-10 (IL-10), which can limit the expansion of T cell responses. We investigated whether inhibiting IL-10 signaling prior to immunization with a candidate adenovirus vectored-HIV-1 vaccine, ChAdV63.HIVconsv, could modulate innate and adaptive immune responses in BALB/c mice. Transient IL-10 receptor blockade led to a modest but significant increase in the total magnitude CD8(+) T cell response to HIVconsv, but did not affect T cell responses to immunodominant epitopes. Anti-IL-10R-treated animals also exhibited greater expression of CD86 on CD11c(+) dendritic cells. Our data support further investigation and optimization of IL-10 blocking strategies to improve the immunogenicity of vaccines based on replication-defective adenoviruses.

Hancock G, Yang H, Yorke E, Wainwright E, Bourne V, Frisbee A, Payne TL, Berrong M et al. 2015. Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses. PLoS Pathog, 11 (2), pp. e1004658. | Show Abstract | Read more

Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control.

Mothe B, Hu X, Llano A, Rosati M, Olvera A, Kulkarni V, Valentin A, Alicea C et al. 2015. A human immune data-informed vaccine concept elicits strong and broad T-cell specificities associated with HIV-1 control in mice and macaques. J Transl Med, 13 (1), pp. 60. | Show Abstract | Read more

BACKGROUND: None of the HIV T-cell vaccine candidates that have reached advanced clinical testing have been able to induce protective T cell immunity. A major reason for these failures may have been suboptimal T cell immunogen designs. METHODS: To overcome this problem, we used a novel immunogen design approach that is based on functional T cell response data from more than 1,000 HIV-1 clade B and C infected individuals and which aims to direct the T cell response to the most vulnerable sites of HIV-1. RESULTS: Our approach identified 16 regions in Gag, Pol, Vif and Nef that were relatively conserved and predominantly targeted by individuals with reduced viral loads. These regions formed the basis of the HIVACAT T-cell Immunogen (HTI) sequence which is 529 amino acids in length, includes more than 50 optimally defined CD4(+) and CD8(+) T-cell epitopes restricted by a wide range of HLA class I and II molecules and covers viral sites where mutations led to a dramatic reduction in viral replicative fitness. In both, C57BL/6 mice and Indian rhesus macaques immunized with an HTI-expressing DNA plasmid (DNA.HTI) induced broad and balanced T-cell responses to several segments within Gag, Pol, and Vif. DNA.HTI induced robust CD4(+) and CD8(+) T cell responses that were increased by a booster vaccination using modified virus Ankara (MVA.HTI), expanding the DNA.HTI induced response to up to 3.2% IFN-γ T-cells in macaques. HTI-specific T cells showed a central and effector memory phenotype with a significant fraction of the IFN-γ(+) CD8(+) T cells being Granzyme B(+) and able to degranulate (CD107a(+)). CONCLUSIONS: These data demonstrate the immunogenicity of a novel HIV-1 T cell vaccine concept that induced broadly balanced responses to vulnerable sites of HIV-1 while avoiding the induction of responses to potential decoy targets that may divert effective T-cell responses towards variable and less protective viral determinants.

Yang H, Buisson S, Bossi G, Hancock G, Ashfield R, Vuidepot A, Mahon T, Molloy P et al. 2014. Engineered Gag-specific T-cell Receptors Redirect Polyclonal CD8(+) T-cells to Clear HIV-1-infected CD4(+) T-cells from ART-treated Patients. AIDS Res Hum Retroviruses, 30 Suppl 1 (S1), pp. A18. | Read more

Borthwick NJ, Ahmed T, Dorrell L, Van Hateren A, Elliot T, Hanke T. 2014. Phase I Clinical Trial HIV-CORE002 of a Universal T-cell Vaccine: Mapping of CD8+ T Cell Epitopes. AIDS Res Hum Retroviruses, 30 Suppl 1 (S1), pp. A187. | Read more

Rider OJ, Asaad M, Ntusi N, Wainwright E, Clutton G, Hancock G, Banerjee R, Pitcher A et al. 2014. HIV is an independent predictor of aortic stiffness. J Cardiovasc Magn Reson, 16 (1), pp. 57. | Show Abstract | Read more

BACKGROUND: Patients with treated Human Immunodeficiency Virus-1 (HIV) infection are at increased risk of cardiovascular events. Traditionally much of this risk has been attributed to metabolic and anthropometric abnormalities associated with HIV, which are similar to the metabolic syndrome (MS), an established risk factor for cardiovascular mortality. It remains unclear whether treated HIV infection is itself associated with increased risk, via increase vascular stiffness. METHODS: 226 subjects (90 with HIV) were divided into 4 groups based on HIV and MS status: 1) HIV-ve/MS-ve, 2) HIV-ve/MS + ve, 3) HIV + ve/MS-ve and 4)HIV + ve/MS + ve. CMR was used to determine aortic pulse wave velocity (PWV) and regional aortic distensibility (AD). RESULTS: PWV was 11% higher and regional AD up to 14% lower in the HIV + ve/MS-ve group when compared to HIV-ve/MS-ve (p < 0.01 all analyses). PWV and AD in the HIV + ve/MS-ve group was similar to that observed in the HIV-ve/MS + ve group (p > 0.99 all analyses). The HIV + ve/MS + ve group had 32% higher PWV and 30-34% lower AD than the HIV-ve/MS-ve group (all p < 0.001), and 19% higher PWV and up to 31% lower AD than HIV + ve/MS-ve subjects (all p < 0.05). On multivariable regression, age, systolic blood pressure and treated HIV infection were all independent predictors of both PWV and regional AD. CONCLUSION: Across multiple measures, treated HIV infection is associated with increased aortic stiffness and is also an independent predictor of both PWV and regional AD. The magnitude of the effect of treated HIV and MS are similar, with additive detrimental effects on central vascular elasticity.

Vince N, Bashirova AA, Lied A, Gao X, Dorrell L, McLaren PJ, Fellay J, Carrington M. 2014. HLA class I and KIR genes do not protect against HIV type 1 infection in highly exposed uninfected individuals with hemophilia A. J Infect Dis, 210 (7), pp. 1047-1051. | Show Abstract | Read more

A recent genome-wide association study (GWAS) involving patients with hemophilia A who were exposed to but uninfected with human immunodeficiency virus type 1 (HIV-1) did not reveal genetic variants associated with resistance to HIV-1 infection, beyond homozygosity for CCR5-Δ32. Since variation in HLA class I and KIR genes is not well interrogated by standard GWAS techniques, we tested whether these 2 loci were involved in protection from HIV-1 infection in the same hemophilia cohort, using controls from the general population. Our data indicate that HLA class I alleles, presence or absence of KIR genes, and functionally relevant combinations of the HLA/KIR genotypes are not involved in resistance to parenterally transmitted HIV-1 infection.

Dorrell L, Clutton G, Hancock G, Corrah T, Fox J. 2014. Evaluation of circulating gut-homing T cells as a marker of HIV-1 progression and immune reconstitution HIV MEDICINE, 15 pp. 4-4.

McMichael A, Dorrell L. 2014. Comment on clinical development of candidate HIV vaccines: different problems for different vaccines. AIDS Res Hum Retroviruses, 30 (4), pp. 331-332. | Read more

Cited:

53

Scopus

Borthwick N, Ahmed T, Ondondo B, Hayes P, Rose A, Ebrahimsa U, Hayton EJ, Black A et al. 2014. Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1 Molecular Therapy, 22 (2), pp. 464-475. | Show Abstract | Read more

Virus diversity and escape from immune responses are the biggest challenges to the development of an effective vaccine against HIV-1. We hypothesized that T-cell vaccines targeting the most conserved regions of the HIV-1 proteome, which are common to most variants and bear fitness costs when mutated, will generate effectors that efficiently recognize and kill virus-infected cells early enough after transmission to potentially impact on HIV-1 replication and will do so more efficiently than whole protein-based T-cell vaccines. Here, we describe the first-ever administration of conserved immunogen vaccines vectored using prime-boost regimens of DNA, simian adenovirus and modified vaccinia virus Ankara to uninfected UK volunteers. The vaccine induced high levels of effector T cells that recognized virus-infected autologous CD4 + cells and inhibited HIV-1 replication by up to 5.79 log 10. The virus inhibition was mediated by both Gag- and Pol- specific effector CD8 + T cells targeting epitopes that are typically subdominant in natural infection. These results provide proof of concept for using a vaccine to target T cells at conserved epitopes, showing that these T cells can control HIV-1 replication in vitro. © The American Society of Gene & Cell Therapy.

Hayton EJ, Rose A, Ibrahimsa U, Del Sorbo M, Capone S, Crook A, Black AP, Dorrell L, Hanke T. 2014. Safety and tolerability of conserved region vaccines vectored by plasmid DNA, simian adenovirus and modified vaccinia virus ankara administered to human immunodeficiency virus type 1-uninfected adults in a randomized, single-blind phase I trial. PLoS One, 9 (7), pp. e101591. | Show Abstract | Read more

TRIAL DESIGN: HIV-1 vaccine development has advanced slowly due to viral antigenic diversity, poor immunogenicity and recently, safety concerns associated with human adenovirus serotype-5 vectors. To tackle HIV-1 variation, we designed a unique T-cell immunogen HIVconsv from functionally conserved regions of the HIV-1 proteome, which were presented to the immune system using a heterologous prime-boost combination of plasmid DNA, a non-replicating simian (chimpanzee) adenovirus ChAdV-63 and a non-replicating poxvirus, modified vaccinia virus Ankara. A block-randomized, single-blind, placebo-controlled phase I trial HIV-CORE 002 administered for the first time candidate HIV-1- vaccines or placebo to 32 healthy HIV-1/2-uninfected adults in Oxford, UK and elicited high frequencies of HIV-1-specific T cells capable of inhibiting HIV-1 replication in vitro. Here, detail safety and tolerability of these vaccines are reported. METHODS: Local and systemic reactogenicity data were collected using structured interviews and study-specific diary cards. Data on all other adverse events were collected using open questions. Serum neutralizing antibody titres to ChAdV-63 were determined before and after vaccination. RESULTS: Two volunteers withdrew for vaccine-unrelated reasons. No vaccine-related serious adverse events or reactions occurred during 190 person-months of follow-up. Local and systemic events after vaccination occurred in 27/32 individuals and most were mild (severity grade 1) and predominantly transient (<48 hours). Myalgia and flu-like symptoms were more strongly associated with MVA than ChAdV63 or DNA vectors and more common in vaccine recipients than in placebo. There were no intercurrent HIV-1 infections during follow-up. 2/24 volunteers had low ChAdV-63-neutralizing titres at baseline and 7 increased their titres to over 200 with a median (range) of 633 (231-1533) post-vaccination, which is of no safety concern. CONCLUSIONS: These data demonstrate safety and good tolerability of the pSG2.HIVconsv DNA, ChAdV63.HIVconsv and MVA.HIVconsv vaccines and together with their high immunogenicity support their further development towards efficacy studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01151319.

Borthwick N, Ahmed T, Ondondo B, Hayes P, Rose A, Ebrahimsa U, Hayton EJ, Black A et al. 2014. Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1. Mol Ther, 22 (2), pp. 464-475. | Show Abstract | Read more

Virus diversity and escape from immune responses are the biggest challenges to the development of an effective vaccine against HIV-1. We hypothesized that T-cell vaccines targeting the most conserved regions of the HIV-1 proteome, which are common to most variants and bear fitness costs when mutated, will generate effectors that efficiently recognize and kill virus-infected cells early enough after transmission to potentially impact on HIV-1 replication and will do so more efficiently than whole protein-based T-cell vaccines. Here, we describe the first-ever administration of conserved immunogen vaccines vectored using prime-boost regimens of DNA, simian adenovirus and modified vaccinia virus Ankara to uninfected UK volunteers. The vaccine induced high levels of effector T cells that recognized virus-infected autologous CD4(+) cells and inhibited HIV-1 replication by up to 5.79 log10. The virus inhibition was mediated by both Gag- and Pol- specific effector CD8(+) T cells targeting epitopes that are typically subdominant in natural infection. These results provide proof of concept for using a vaccine to target T cells at conserved epitopes, showing that these T cells can control HIV-1 replication in vitro.

Cited:

25

Scopus

Holloway CJ, Ntusi N, Suttie J, Mahmod M, Wainwright E, Clutton G, Hancock G, Beak P et al. 2013. Comprehensive cardiac magnetic resonance imaging and spectroscopy reveal a high burden of myocardial disease in HIV patients Circulation, 128 (8), pp. 814-822. | Show Abstract | Read more

BACKGROUND - : HIV infection continues to be endemic worldwide. Although treatments are successful, it remains controversial whether patients receiving optimal therapy have structural, functional, or biochemical cardiac abnormalities that may underlie their increased cardiac morbidity and mortality. The purpose of this study was to characterize myocardial abnormalities in a contemporary group of HIV-infected individuals undergoing combination antiretroviral therapy. METHODS AND RESULTS - : Volunteers with HIV who were undergoing combination antiretroviral therapy and age-matched control subjects without a history of cardiovascular disease underwent cardiac magnetic resonance imaging and spectroscopy for the determination of cardiac function, myocardial fibrosis, and myocardial lipid content. A total of 129 participants were included in this analysis. Compared with age-matched control subjects (n=39; 30.23%), HIV-infected subjects undergoing combination antiretroviral therapy (n=90; 69.77%) had 47% higher median myocardial lipid levels (P <0.003) and 74% higher median plasma triglyceride levels (both P<0.001). Myocardial fibrosis, predominantly in the basal inferolateral wall of the left ventricle, was observed in 76% of HIV-infected subjects compared with 13% of control subjects (P<0.001). Peak myocardial systolic and diastolic longitudinal strain were also lower in HIV-infected individuals than in control subjects and remained statistically significant after adjustment for available confounders. CONCLUSIONS - : Comprehensive cardiac imaging revealed cardiac steatosis, alterations in cardiac function, and a high prevalence of myocardial fibrosis in a contemporary group of asymptomatic HIV-infected subjects undergoing combination antiretroviral therapy. Cardiac steatosis and fibrosis may underlie cardiac dysfunction and increased cardiovascular morbidity and mortality in subjects with HIV. © 2013 American Heart Association, Inc.

Clutton G, Yang H, Hancock G, Sande N, Holloway C, Angus B, von Delft A, Barnes E et al. 2013. Emergence of a distinct HIV-specific IL-10-producing CD8+ T-cell subset with immunomodulatory functions during chronic HIV-1 infection. Eur J Immunol, 43 (11), pp. 2875-2885. | Show Abstract | Read more

Interleukin-10 (IL-10) plays a key role in regulating proinflammatory immune responses to infection but can interfere with pathogen clearance. Although IL-10 is upregulated throughout HIV-1 infection in multiple cell subsets, whether this is a viral immune evasion strategy or an appropriate response to immune activation is unresolved. Analysis of IL-10 production at the single cell level in 51 chronically infected subjects (31 antiretroviral (ART) naïve and 20 ART treated) showed that a subset of CD8(+) T cells with a CD25(neg) FoxP3(neg) phenotype contributes substantially to IL-10 production in response to HIV-1 gag stimulation. The frequencies of gag-specific IL-10- and IFN-γ-producing T cells in ART-naïve subjects were strongly correlated and the majority of these IL-10(+) CD8(+) T cells co-produced IFN-γ; however, patients with a predominant IL-10(+) /IFN-γ(neg) profile showed better control of viraemia. Depletion of HIV-specific CD8(+) IL-10(+) cells from PBMCs led to upregulation of CD38 on CD14(+) monocytes together with increased IL-6 production, in response to gag stimulation. Increased CD38 expression was positively correlated with the frequency of the IL-10(+) population and was also induced by exposure of monocytes to HIV-1 in vitro. Production of IL-10 by HIV-specific CD8(+) T cells may represent an adaptive regulatory response to monocyte activation during chronic infection.

Schiffner T, Sattentau QJ, Dorrell L. 2013. Development of prophylactic vaccines against HIV-1. Retrovirology, 10 (1), pp. 72. | Show Abstract | Read more

The focus of most current HIV-1 vaccine development is on antibody-based approaches. This is because certain antibody responses correlated with protection from HIV-1 acquisition in the RV144 phase III trial, and because a series of potent and broad spectrum neutralizing antibodies have been isolated from infected individuals. Taken together, these two findings suggest ways forward to develop a neutralizing antibody-based vaccine. However, understanding of the correlates of protection from disease in HIV-1 and other infections strongly suggests that we should not ignore CTL-based research. Here we review recent progress in the field and highlight the challenges implicit in HIV-1 vaccine design and some potential solutions.

Wainwright EC, Rider OJ, Asaad M, Ntusi N, Hancock G, Pitcher A, Clarke K, Dorrell L, Neubauer S, Holloway C. 2013. HIV IS AN INDEPENDENT PREDICTOR OF AORTIC PULSE WAVE VELOCITY SEXUALLY TRANSMITTED INFECTIONS, 89 (Suppl 1), pp. A125-A125. | Read more

Wainwright E, Sherrard J, Duncan S, Shine B, Dorrell L. 2013. Hypophosphataemia with non-tenofovir-containing antiretroviral therapy. Int J STD AIDS, 24 (7), pp. 579-581. | Show Abstract | Read more

Hypophosphataemia with tenofovir (TDF) treatment has been well described. The role of HIV infection and of other antiretroviral (ART) agents in hypophosphataemia has received less attention. The aim of this study was to determine the prevalence of hypophosphataemia in HIV-positive adults. We measured the fasting plasma phosphate level and estimated glomerular filtration rate (eGFR) in 123 HIV-positive patients. A total of 26% had hypophosphataemia and 11% had hypophosphataemia of grades 2-4 (0.65 mmol/L or less). Hypophosphataemia of any grade was more frequent in those who were ART-treated than ART-naive (35% versus 10%; P = 0.0001). Multiple linear regression analysis showed no significant association between phosphate level and gender, TDF status, duration of ART, duration of HIV infection and eGFR. Increasing age was significantly associated with a very small rise in phosphate level. Isolated hypophosphataemia was significantly more frequent in HIV-positive subjects receiving ART than ART-naive individuals, irrespective of the drug regimen.

Holloway CJ, Ntusi N, Suttie J, Mahmod M, Wainwright E, Clutton G, Hancock G, Beak P et al. 2013. Comprehensive cardiac magnetic resonance imaging and spectroscopy reveal a high burden of myocardial disease in HIV patients. Circulation, 128 (8), pp. 814-822. | Show Abstract | Read more

BACKGROUND: HIV infection continues to be endemic worldwide. Although treatments are successful, it remains controversial whether patients receiving optimal therapy have structural, functional, or biochemical cardiac abnormalities that may underlie their increased cardiac morbidity and mortality. The purpose of this study was to characterize myocardial abnormalities in a contemporary group of HIV-infected individuals undergoing combination antiretroviral therapy. METHODS AND RESULTS: Volunteers with HIV who were undergoing combination antiretroviral therapy and age-matched control subjects without a history of cardiovascular disease underwent cardiac magnetic resonance imaging and spectroscopy for the determination of cardiac function, myocardial fibrosis, and myocardial lipid content. A total of 129 participants were included in this analysis. Compared with age-matched control subjects (n=39; 30.23%), HIV-infected subjects undergoing combination antiretroviral therapy (n=90; 69.77%) had 47% higher median myocardial lipid levels (P <0.003) and 74% higher median plasma triglyceride levels (both P<0.001). Myocardial fibrosis, predominantly in the basal inferolateral wall of the left ventricle, was observed in 76% of HIV-infected subjects compared with 13% of control subjects (P<0.001). Peak myocardial systolic and diastolic longitudinal strain were also lower in HIV-infected individuals than in control subjects and remained statistically significant after adjustment for available confounders. CONCLUSIONS: Comprehensive cardiac imaging revealed cardiac steatosis, alterations in cardiac function, and a high prevalence of myocardial fibrosis in a contemporary group of asymptomatic HIV-infected subjects undergoing combination antiretroviral therapy. Cardiac steatosis and fibrosis may underlie cardiac dysfunction and increased cardiovascular morbidity and mortality in subjects with HIV.

Yang H, Yorke E, Hancock G, Clutton G, Sande N, Angus B, Smyth R, Mak J, Dorrell L. 2013. Improved quantification of HIV-1-infected CD4+ T cells using an optimised method of intracellular HIV-1 gag p24 antigen detection Journal of Immunological Methods, 391 (1-2), pp. 174-178. | Show Abstract | Read more

The capacity of CD8+ T cells to inhibit HIV-1 replication in vitro strongly correlates with virus control in vivo. Post-hoc evaluations of HIV-1 vaccine candidates suggest that this immunological parameter is a promising benchmark of vaccine efficacy. Large-scale analysis of CD8+ T cell antiviral activity requires a rapid, robust and economical assay for accurate quantification of HIV-1 infection in primary CD4+ T cells. Detection of intracellular HIV-1 p24 antigen (p24 Ag) by flow cytometry is one such method but it is thought to be less sensitive and quantitative than p24 Ag ELISA. We report that fixation and permeabilisation of HIV-infected cells using paraformaldehyde/50% methanol/Nonidet P-40 instead of a conventional paraformaldehyde/saponin-based protocol improved their detection across multiplicities of infection (MOI) ranging from 10-2 to 8×10-5, and by nearly two-fold (p<0.001) at the optimal MOI tested (10-2). The frequency of infected cells was strongly correlated with p24 Ag release during culture, thus validating its use as a measure of productive infection. We were also able to quantify infection with a panel of HIV-1 isolates representing the major clades. The protocol described here is rapid and cost-effective compared with ELISA and thus could be a useful component of immune monitoring of HIV-1 vaccines and interventions to reduce viral reservoirs. © 2013 Elsevier B.V.

Yang H, Yorke E, Hancock G, Clutton G, Sande N, Angus B, Smyth R, Mak J, Dorrell L. 2013. Improved quantification of HIV-1-infected CD4+ T cells using an optimised method of intracellular HIV-1 gag p24 antigen detection. J Immunol Methods, 391 (1-2), pp. 174-178. | Show Abstract | Read more

The capacity of CD8+ T cells to inhibit HIV-1 replication in vitro strongly correlates with virus control in vivo. Post-hoc evaluations of HIV-1 vaccine candidates suggest that this immunological parameter is a promising benchmark of vaccine efficacy. Large-scale analysis of CD8+ T cell antiviral activity requires a rapid, robust and economical assay for accurate quantification of HIV-1 infection in primary CD4+ T cells. Detection of intracellular HIV-1 p24 antigen (p24 Ag) by flow cytometry is one such method but it is thought to be less sensitive and quantitative than p24 Ag ELISA. We report that fixation and permeabilisation of HIV-infected cells using paraformaldehyde/50% methanol/Nonidet P-40 instead of a conventional paraformaldehyde/saponin-based protocol improved their detection across multiplicities of infection (MOI) ranging from 10(-2) to 8×10(-5), and by nearly two-fold (p<0.001) at the optimal MOI tested (10(-2)). The frequency of infected cells was strongly correlated with p24 Ag release during culture, thus validating its use as a measure of productive infection. We were also able to quantify infection with a panel of HIV-1 isolates representing the major clades. The protocol described here is rapid and cost-effective compared with ELISA and thus could be a useful component of immune monitoring of HIV-1 vaccines and interventions to reduce viral reservoirs.

Huang LC, Pan X, Yang H, Wan LK, Stewart-Jones G, Dorrell L, Ogg G. 2013. Linking genotype to phenotype on beads: high throughput selection of peptides with biological function. Sci Rep, 3 pp. 3030. | Show Abstract | Read more

Although peptides are well recognised biological molecules in vivo, their selection from libraries is challenging because of relative low affinity whilst in linear conformation. We hypothesized that multiplexed peptides and DNA on the surface of beads would provide a platform for enhanced avidity and the selection of relevant peptides from a library (ORBIT bead display). Using human immunodeficiency virus (HIV-1) gp120 as a target, we identify peptides that inhibit HIV-1 replication in vitro through blocking of protein:protein interaction with the co-receptor CCR5. The bead display approach has many potential applications for probing biological systems and for drug lead development.

Lane J, McLaren PJ, Dorrell L, Shianna KV, Stemke A, Pelak K, Moore S, Oldenburg J et al. 2013. A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A. Hum Mol Genet, 22 (9), pp. 1903-1910. | Show Abstract | Read more

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.

Corrah T, Brackenridge S, Goonetilleke N, Yang H, Deeks S, Dorrell L, Cohen M, McMichael A. 2012. The HIV-1 protective-35SNP effect in Caucasians is CD8 T cell mediated RETROVIROLOGY, 9 (Suppl 2), pp. P281-P281. | Read more

Borthwick NJ, Ahmed T, Rose A, Ebrahimsa U, Black A, Hayton E, Yang H, Hancock G et al. 2012. Immunogenicity of a universal HIV-1 vaccine vectored by DNA, MVA and CHADV-63 in a Phase I/IIA clinical trial RETROVIROLOGY, 9 (Suppl 2), pp. P118-P118. | Read more

Ahmed T, Borthwick N, Yang H, Hancock G, Yorke L, Ebrahimsa U, Rose A, Black A et al. 2012. Recombinant DNA/MVA/ChAdV-63-elicited T cells specific for conserved regions of the HIV-1 proteome recognize HIV-1 infected cells and suppress HIV-1 RETROVIROLOGY, 9 (Suppl 2), pp. P259-P259. | Read more

Yang H, Wu H, Hancock G, Clutton G, Sande N, Xu X, Yan H, Huang X et al. 2012. Antiviral inhibitory capacity of CD8+ T cells predicts the rate of CD4+ T-cell decline in HIV-1 infection. J Infect Dis, 206 (4), pp. 552-561. | Show Abstract | Read more

BACKGROUND: Rare human immunodeficiency virus type 1 (HIV-1)-infected individuals who maintain control of viremia without therapy show potent CD8+ T-cell-mediated suppression of viral replication in vitro. Whether this is a determinant of the rate of disease progression in viremic individuals is unknown. METHODS: We measured CD8+ T-cell-mediated inhibition of a heterologous HIV-1 isolate in 50 HIV-1-seropositive adults with diverse progression rates. Linear mixed models were used to determine whether CD8+ T-cell function could explain variation in the rate of CD4+ T-cell decline. RESULTS: There was a significant interaction between CD8+ T-cell antiviral activity in vitro and the rate of CD4+ T-cell decline in chronically infected individuals (P < .0001). In a second prospective analysis of recently infected subjects followed for up to 3 years, CD8+ T-cell antiviral activity strongly predicted subsequent CD4+ T-cell decline (P < .0001) and explained up to 73% of the interindividual variation in the CD4+ T-cell slope. In addition, it was inversely associated with viral load set point (r = -0.68 and P = .002). CONCLUSIONS: The antiviral inhibitory capacity of CD8+ T cells is highly predictive of CD4+ T-cell loss in early HIV-1 infection. It has potential as a benchmark of effective immunity in vaccine evaluation.

Asaad M, Rider O, Beak P, Wainwright E, Pitcher A, Hancock G, Clutton G, Dorrell L, Holloway C. 2012. Cardiovascular magnetic resonance reveals human immunodeficiency virus is an independent risk factor for vascular stiffness HIV MEDICINE, 13 pp. 47-47.

Holloway C, Ntusi N, Suttie J, Mahmod M, Clutton G, Hancock G, Wainwright E, Angus B et al. 2012. Comprehensive Cardiac Magnetic Resonance Reveals HIV is Associated with High Burden of Myocardial Disease HIV MEDICINE, 13 pp. 3-3.

Guimaraes-Walker A, Mackie N, McCormack S, Hanke T, Schmidt C, Gilmour J, Barin B, McMichael A et al. 2011. Lessons from IAVI-006, a Phase I clinical trial to evaluate the safety and immunogenicity of the pTHr.HIVA DNA and MVA.HIVA vaccines in a prime-boost strategy to induce HIV-1 specific T-cell responses in healthy volunteers (vol 26, pg 6671, 2008) VACCINE, 29 (18), pp. 3511-3511. | Read more

Wainwright E, Dorrell L, Sherrard J, Shine B. 2011. Hypophosphataemia in HIV-positive patients taking non-tenofovir-containing antiretrovirals HIV MEDICINE, 12 pp. 54-54.

Klenerman P, Webb A, McPherson T, Brennan N, Petrou A, Prassas E, Sullivan P, Adams E et al. 2011. Proceedings of Research in Clinical Practice 2010: Research in Clinical Practice was held at the Academic Centre of the John Radcliffe Hospital, Oxford, on Wednesday, 10 November 2010. QJM, 104 (4), pp. 345-364. | Read more

Guimarães-Walker A, Mackie N, McCormack S, Hanke T, Schmidt C, Gilmour J, Barin B, McMichael A et al. 2011. Corrigendum to "Lessons from IAVI-006, a Phase I clinical trial to evaluate the safety and immunogenicity of the pTHr.HIVA DNA and MVA.HIVA vaccines in a prime-boost strategy to induce HIV-1 specific T-cell responses in healthy volunteers" [Vaccine 26 (2008) 6671-6677] (DOI:10.1016/j.vaccine.2008.09.016) Vaccine,

Howles S, Guimarães-Walker A, Yang H, Hancock G, di Gleria K, Tarragona-Fiol T, Hayes P, Gilmour J et al. 2010. Vaccination with a modified vaccinia virus Ankara (MVA)-vectored HIV-1 immunogen induces modest vector-specific T cell responses in human subjects. Vaccine, 28 (45), pp. 7306-7312. | Show Abstract | Read more

We investigated whether vaccination of healthy HIV-seronegative and HIV-1-seropositive antiretroviral therapy-treated subjects with recombinant modified vaccinia virus Ankara expressing an HIV-1 immunogen (MVA.HIVA) induced MVA-specific T cell responses. Using IFN-γ Elispot assays, we observed new or increased responses to MVA virus in 52% of HIV-seronegative subjects and 93% HIV-1 seropositive subjects; MVA-specific T cell frequencies were generally low and correlated poorly with T cell responses to the HIV-1 immunogen. In two vaccinees, responses were mapped to CD8+ T cell epitopes present in replication-competent vaccinia virus. These data support further evaluation of MVA as a viral vector for HIV-1 immunogens.

Dorrell L, Shianna KV, Fellay J, McMichael A, Goldstein DB, Tr CPH. 2010. The genetics of HIV resistance in exposed uninfected Haemophilia A patients: an update on the CHAVI 014 protocol HAEMOPHILIA, 16 (2), pp. 404-404.

Yang H, Guimarães-Walker A, Hibbs S, Dong T, Stacey A, Borrow P, Hanke T, Davenport MP, McMichael A, Dorrell L. 2009. Interleukin-10 responses to therapeutic vaccination during highly active antiretroviral therapy and after analytical therapy interruption. AIDS, 23 (16), pp. 2226-2230. | Show Abstract | Read more

We investigated whether therapeutic vaccination in highly active antiretroviral therapy (HAART)-treated patients with a modified vaccinia virus Ankara-vectored HIV-1 vaccine, with or without therapy interruption, induced the production of interleukin (IL)-10. Plasma IL-10 levels were not significantly increased postvaccination, but increased in parallel with viraemia in patients who interrupted therapy. Surprisingly, IL-10 blockade augmented HIV-specific T cell proliferative responses in HAART-suppressed patients but had no effect once virological control was lost. Modulation of IL-10 might enhance vaccine-induced immune responses.

Murphy RL, Autran B, Katlama C, Brucker G, Debre P, Calvez V, Clotet B, Clumeck N et al. 2009. A step ahead on the HIV collaboratory. Science, 324 (5932), pp. 1264-1265. | Read more

McMichael A, Dorrell L. 2009. The immune response to HIV Medicine, 37 (7), pp. 321-325. | Show Abstract | Read more

HIV-1 elicits vigorous humoral and cell-mediated responses: these fail to clear the infection but contain viral replication for several years, at the expense of ongoing immune activation and CD4+ T cell loss. Over the past 25 years, several mechanisms by which HIV-1 and other AIDS viruses evade host immune responses have been elucidated. Genetic variability, rapid establishment of a reservoir of latently-infected long-lived CD4+ T cells and resistance to neutralization by antibodies are formidable obstacles to the development of a preventive vaccine. This has been highlighted by the disappointing results of recent efficacy trials. However, this remains an urgent priority, as available prevention strategies have been insufficient to stop the global epidemic. Rare individuals who show no signs of progression after one or two decades of infection indicate that immune control of HIV-1 is possible and may inform vaccine design. © 2009 Elsevier Ltd. All rights reserved.

Guimarães-Walker A, Mackie N, McCormack S, Hanke T, Schmidt C, Gilmour J, Barin B, McMichael A et al. 2008. Lessons from IAVI-006, a phase I clinical trial to evaluate the safety and immunogenicity of the pTHr.HIVA DNA and MVA.HIVA vaccines in a prime-boost strategy to induce HIV-1 specific T-cell responses in healthy volunteers. Vaccine, 26 (51), pp. 6671-6677. | Show Abstract | Read more

IAVI-006 was the first large randomised, double-blinded, placebo-controlled Phase I clinical trial to systematically investigate the prime-boost strategy for induction of HIV-1 specific CD8+ cytotoxic T-lymphocytes (CTL) in a factorial trial design using (i) priming with 0.5 mg or 2 mg of pTHr.HIVA DNA vaccine, followed by (ii) two booster vaccinations with 5 x 10(7) MVA.HIVA at weeks 8 and 12 (early boost) or weeks 20 and 24 (late boost). This study set the basis for later clinical trials and demonstrated the safety of these candidate HIV vaccines. The safety and immunogenicity results are presented and the lessons derived from this clinical trial are discussed.

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.

Dorrell L. 2008. Twenty-five years of HIV research: what we have learned and what we still need to know HAEMOPHILIA, 14 pp. 38-38.

Yang H, Dong T, Turnbull E, Ranasinghe S, Ondondo B, Goonetilleke N, Winstone N, di Gleria K et al. 2007. Broad TCR usage in functional HIV-1-specific CD8+ T cell expansions driven by vaccination during highly active antiretroviral therapy. J Immunol, 179 (1), pp. 597-606. | Show Abstract

During chronic HIV-1 infection, continuing viral replication is associated with impaired proliferative capacity of virus-specific CD8+ T cells and with the expansion and persistence of oligoclonal T cell populations. TCR usage may significantly influence CD8+ T cell-mediated control of AIDS viruses; however, the potential to modulate the repertoire of functional virus-specific T cells by immunotherapy has not been explored. To investigate this, we analyzed the TCR Vbeta usage of CD8+ T cells populations which were expanded following vaccination with modified vaccinia virus Ankara expressing a HIV-1 gag/multiepitope immunogen (MVA.HIVA) in HIV-1-infected patients receiving highly active antiretroviral therapy. Vaccinations induced the re-expansion of HIV-1-specific CD8+ T cells and these showed broad TCR Vbeta usage which was maintained for at least 1 year in some individuals. By contrast, virus-specific CD8+ T cell populations in the same donors which failed to expand after vaccination and in unvaccinated controls were oligoclonal. Simultaneously, we observed that CD8+ T cells recognizing vaccine-derived HIV-1 epitopes displayed enhanced capacity to proliferate and to inhibit HIV-1 replication in vitro, following MVA.HIVA immunizations. Taken together, these data indicate that an attenuated viral-vectored vaccine can modulate adaptive CD8+ T cell responses to HIV-1 and improve their antiviral functional capacity. The potential therapeutic benefit of this vaccination approach warrants further investigation.

Dorrell L, Williams P, Suttill A, Brown D, Roberts J, Conlon C, Hanke T, McMichael A. 2007. Safety and tolerability of recombinant modified vaccinia virus Ankara expressing an HIV-1 gag/multiepitope immunogen (MVA.HIVA) in HIV-1-infected persons receiving combination antiretroviral therapy. Vaccine, 25 (17), pp. 3277-3283. | Show Abstract | Read more

The safety of attenuated poxviruses in HIV-1-infected individuals is an important consideration in their application as vaccine vectors, first, because new HIV-1 infections may occur in vaccine trials involving persons at high risk of infection and secondly, therapeutic vaccinations are a potential means to enhance virus-specific immune responses once infection has occurred. We administered a candidate modified vaccinia virus Ankara-vectored HIV-1 vaccine, MVA.HIVA, by intradermal injection to 16 chronically infected adults during highly active antiretroviral therapy. Vaccinations were well tolerated and there were no serious adverse events. No breakthrough viraemia occurred after immunisations or throughout follow-up. These data confirm the safety of MVA.HIVA in HIV-1-infected individuals and provide support for further evaluation of MVA-vectored vaccines in prophylactic and therapeutic immunisation strategies.

Hanke T, Goonetilleke N, McMichael AJ, Dorrell L. 2007. Clinical experience with plasmid DNA- and modified vaccinia virus Ankara-vectored human immunodeficiency virus type 1 clade A vaccine focusing on T-cell induction. J Gen Virol, 88 (Pt 1), pp. 1-12. | Show Abstract | Read more

Candidate human immunodeficiency virus type 1 (HIV-1) vaccines focusing on T-cell induction, constructed as pTHr.HIVA DNA and modified vaccinia virus Ankara (MVA).HIVA, were delivered in a heterologous prime-boost regimen. The vaccines were tested in several hundred healthy or HIV-1-infected volunteers in Europe and Africa. Whilst larger trials of hundreds of volunteers suggested induction of HIV-1-specific T-cell responses in <15 % of healthy vaccinees, a series of small, rapid trials in 12-24 volunteers at a time with a more in-depth analysis of vaccine-elicited T-cell responses proved to be highly informative and provided more encouraging results. These trials demonstrated that the pTHr.HIVA vaccine alone primed consistently weak and mainly CD4(+), but also CD8(+) T-cell responses, and the MVA.HIVA vaccine delivered a consistent boost to both CD4(+) and CD8(+) T cells, which was particularly strong in HIV-1-infected patients. Thus, whilst the search is on for ways to enhance T-cell priming, MVA is a useful boosting vector for human subunit genetic vaccines.

Létourneau S, Im EJ, Mashishi T, Brereton C, Bridgeman A, Yang H, Dorrell L, Dong T, Korber B, McMichael AJ, Hanke T. 2007. Design and pre-clinical evaluation of a universal HIV-1 vaccine. PLoS One, 2 (10), pp. e984. | Show Abstract | Read more

BACKGROUND: One of the big roadblocks in development of HIV-1/AIDS vaccines is the enormous diversity of HIV-1, which could limit the value of any HIV-1 vaccine candidate currently under test. METHODOLOGY AND FINDINGS: To address the HIV-1 variation, we designed a novel T cell immunogen, designated HIV(CONSV), by assembling the 14 most conserved regions of the HIV-1 proteome into one chimaeric protein. Each segment is a consensus sequence from one of the four major HIV-1 clades A, B, C and D, which alternate to ensure equal clade coverage. The gene coding for the HIV(CONSV) protein was inserted into the three most studied vaccine vectors, plasmid DNA, human adenovirus serotype 5 and modified vaccine virus Ankara (MVA), and induced HIV-1-specific T cell responses in mice. We also demonstrated that these conserved regions prime CD8(+) and CD4(+) T cell to highly conserved epitopes in humans and that these epitopes, although usually subdominant, generate memory T cells in patients during natural HIV-1 infection. SIGNIFICANCE: Therefore, this vaccine approach provides an attractive and testable alternative for overcoming the HIV-1 variability, while focusing T cell responses on regions of the virus that are less likely to mutate and escape. Furthermore, this approach has merit in the simplicity of design and delivery, requiring only a single immunogen to provide extensive coverage of global HIV-1 population diversity.

Ondondo BO, Yang H, Dong T, di Gleria K, Suttill A, Conlon C, Brown D, Williams P 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.

Dorrell L. 2006. Therapeutic immunization for the control of HIV-1: where are we now? Int J STD AIDS, 17 (7), pp. 436-441. | Show Abstract | Read more

Highly active antiretroviral therapy (HAART) has transformed HIV-1 infection from an invariably fatal disease into a chronic infection requiring lifelong treatment. However, the challenges we still face are the urgent need to provide affordable sustainable therapy to the millions of infected individuals who live in resource-poor countries, and the limitations posed by serious drug toxicity and viral resistance associated with long-term therapy. Augmentation of HIV-specific immunity by therapeutic vaccination is a possible alternative to continuous HAART. In this review, progress in the development of therapeutic immunization strategies is discussed.

Dorrell L. 2006. Therapeutic immunization for the control of HIV-1: where are we now? INTERNATIONAL JOURNAL OF STD & AIDS, 17 (7), pp. 436-442. | Read more

Dorrell L, Yang H, Ondondo B, Dong T, di Gleria K, Suttill A, Conlon C, Brown D 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.

Goonetilleke N, Moore S, Dally L, Winstone N, Cebere I, Mahmoud A, Pinheiro S, Gillespie G et al. 2006. Induction of multifunctional human immunodeficiency virus type 1 (HIV-1)-specific T cells capable of proliferation in healthy subjects by using a prime-boost regimen of DNA- and modified vaccinia virus Ankara-vectored vaccines expressing HIV-1 Gag coupled to CD8+ T-cell epitopes. J Virol, 80 (10), pp. 4717-4728. | Show Abstract | Read more

A double-blind randomized phase I trial was conducted in human immunodeficiency virus type 1 (HIV-1)-negative subjects receiving vaccines vectored by plasmid DNA and modified vaccinia virus Ankara (MVA) expressing HIV-1 p24/p17 gag linked to a string of CD8(+) T-cell epitopes. The trial had two groups. One group received either two doses of MVA.HIVA (2x MVA.HIVA) (n=8) or two doses of placebo (2x placebo) (n=4). The second group received 2x pTHr.HIVA followed by one dose of MVA.HIVA (n=8) or 3x placebo (n=4). In the pTHr.HIVA-MVA.HIVA group, HIV-1-specific T-cell responses peaked 1 week after MVA.HIVA vaccination in both ex vivo gamma interferon (IFN-gamma) ELISPOT (group mean, 210 spot-forming cells/10(6) cells) and proliferation (group mean stimulation index, 37), with assays detecting positive responses in four out of eight and five out of eight subjects, respectively. No HIV-1-specific T-cell responses were detected in either assay in the 2x MVA.HIVA group or subjects receiving placebo. Using a highly sensitive and reproducible cultured IFN-gamma ELISPOT assay, positive responses mainly mediated by CD4(+) T cells were detected in eight out of eight vaccinees in the pTHr.HIVA-MVA.HIVA group and four out of eight vaccinees in the 2x MVA.HIVA group. Importantly, no false-positive responses were detected in the eight subjects receiving placebo. Of the 12 responders, 11 developed responses to previously identified immunodominant CD4(+) T-cell epitopes, with 6 volunteers having responses to more than one epitope. Five out of 12 responders also developed CD8(+) T-cell responses to the epitope string. Induced T cells produced a variety of anti-viral cytokines, including tumor necrosis factor alpha and macrophage inflammatory protein 1 beta. These data demonstrate that prime-boost vaccination with recombinant DNA and MVA vectors can induce multifunctional HIV-1-specific T cells in the majority of vaccinees.

Sutherland R, Yang H, Scriba TJ, Ondondo B, Robinson N, Conlon C, Suttill A, McShane H, Fidler S, McMichael A, Dorrell L. 2006. Impaired IFN-gamma-secreting capacity in mycobacterial antigen-specific CD4 T cells during chronic HIV-1 infection despite long-term HAART. AIDS, 20 (6), pp. 821-829. | Show Abstract | Read more

OBJECTIVE: To determine whether long-term HAART in chronic HIV-1 infection restores fully functional Mycobacterium tuberculosis (MTB)-specific CD4 T-cell responses. DESIGN: A cross-sectional study of HIV-1-seropositive subjects on continuous HAART for over one year with CD4 cell counts greater than 300 cells/microl and undetectable viraemia, antiretroviral-naive individuals with primary HIV-1 infection (PHI), and healthy bacillus Calmette-Guérin-vaccinated low-risk controls. METHODS: Purified protein derivative (PPD)-specific cytokine-secreting CD4 T cells were quantified ex vivo by enzyme-linked immunospot assay and intracellular cytokine staining. Lymphoproliferation was detected by [3H]-thymidine incorporation. RESULTS: PPD-specific IFN-gamma-secreting CD4 T cells were markedly reduced in chronic HAART-treated HIV-1-positive and PHI subjects compared with healthy controls [medians 30, 155 and 582 spot-forming cells/million peripheral blood mononuclear cells (PBMC), respectively, P < 0.0001 and P < 0.002], but the frequency of these cells was, nonetheless, significantly greater in viraemic PHI subjects than in aviraemic chronic HIV-1-positive subjects (P < 0.01). In the latter, low frequencies of PPD-specific IL-2 and IL-4-secreting CD4 T cells were also observed. However, lymphoproliferation was evident after the in-vitro stimulation of PBMC with PPD, indicating that MTB-specific T cells were present. The defect in IFN-gamma secretion could be overcome by culture with IL-12. CONCLUSION: Despite an improvement in CD4 T-cell counts after HAART, MTB-specific CD4 T cells from chronically infected patients have impaired IFN-gamma-secreting capacity. The early initiation of HAART might preserve functional CD4 T-cell responses to MTB, and warrants evaluation in populations with a high risk of dual infection.

Cebere I, Dorrell L, McShane H, Simmons A, McCormack S, Schmidt C, Smith C, Brooks M 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.

Ondondo B, Yang H, Dong T, de Gleria K, Suttill A, Conlon C, Brown D, Williams P et al. 2006. Detection of broad functional gag-specific CD4+T cell responses in HIV-1-infected subjects following therapeutic immunization with rMVA expressing an HIV-1 gag immunogen RETROVIROLOGY, 3

Ondondo BO, Yang H, Rowland-Jones SL, Hanke T, McMichael A, Dorrell L. 2005. pTHr.HIVA and MVA.HIVA vaccines (gag p24/p17) augment CD4+T cell responses in chronically infected HIV-1 patients on HAART IMMUNOLOGY, 116 pp. 108-108.

Dorrell L, Yang H, Iversen AK, Conlon C, Suttill A, Lancaster M, Dong T, Cebere I 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.

Dorrell L. 2005. Therapeutic immunization strategies for the control of HIV-1. Expert Rev Vaccines, 4 (4), pp. 513-520. | Show Abstract | Read more

Highly active antiretroviral therapy (HAART) is currently the only means to halt or prevent progression to AIDS. However, lack of access to medications for the vast majority of HIV-1-infected individuals in immediate need, together with the requirement for lifelong adherence and potential for serious toxicity, are significant limitations which have yet to be overcome. Augmentation of HIV-specific immunity by therapeutic vaccination is being explored as a possible alternative to continuous HAART. A few candidate HIV-1 vaccines have entered clinical trials involving an assessment of viremia control during an analytic therapy interruption, but even the most promising of these achieve a short-lived suppression of HIV-1 without HAART. Nevertheless, these studies are guiding the development of better immune augmentation strategies, which could extend the time off therapy and will also contribute to a better understanding of the immune correlates of protection against AIDS. The status of therapeutic vaccines that are currently undergoing preclinical and clinical evaluation is reviewed.

Gillespie GM, Pinheiro S, Sayeid-Al-Jamee M, Alabi A, Kaye S, Sabally S, Sarge-Njie R, Njai H 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.

Lee JK, Stewart-Jones G, Dong T, Harlos K, Di Gleria K, Dorrell L, Douek DC, van der Merwe PA, Jones EY, McMichael AJ. 2004. T cell cross-reactivity and conformational changes during TCR engagement. J Exp Med, 200 (11), pp. 1455-1466. | Show Abstract | Read more

All thymically selected T cells are inherently cross-reactive, yet many data indicate a fine specificity in antigen recognition, which enables virus escape from immune control by mutation in infections such as the human immunodeficiency virus (HIV). To address this paradox, we analyzed the fine specificity of T cells recognizing a human histocompatibility leukocyte antigen (HLA)-A2-restricted, strongly immunodominant, HIV gag epitope (SLFNTVATL). The majority of 171 variant peptides tested bound HLA-A2, but only one third were recognized. Surprisingly, one recognized variant (SLYNTVATL) showed marked differences in structure when bound to HLA-A2. T cell receptor (TCR) recognition of variants of these two peptides implied that they adopted the same conformation in the TCR-peptide-major histocompatibility complex (MHC) complex. However, the on-rate kinetics of TCR binding were identical, implying that conformational changes at the TCR-peptide-MHC binding interface occur after an initial permissive antigen contact. These findings have implications for the rational design of vaccines targeting viruses with unstable genomes.

Mwau M, Cebere I, Sutton J, Chikoti P, Winstone N, Wee EG, Beattie T, Chen YH 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.

Lopes AR, Jaye A, Dorrell L, Sabally S, Alabi A, Jones NA, Flower DR, De Groot A et al. 2003. Greater CD8+ TCR heterogeneity and functional flexibility in HIV-2 compared to HIV-1 infection. J Immunol, 171 (1), pp. 307-316. | Show Abstract

Virus-specific CD8(+) T cells are known to play an important role in the control of HIV infection. In this study we investigated whether there may be qualitative differences in the CD8(+) T cell response in HIV-1- and HIV-2-infected individuals that contribute to the relatively efficient control of the latter infection. A molecular comparison of global TCR heterogeneity showed a more oligoclonal pattern of CD8 cells in HIV-1- than HIV-2-infected patients. This was reflected in restricted and conserved TCR usage by CD8(+) T cells recognizing individual HLA-A2- and HLA-B57-restricted viral epitopes in HIV-1, with limited plasticity in their response to amino acid substitutions within these epitopes. The more diverse TCR usage observed for HIV-2-specific CD8(+) T cells was associated with an enhanced potential for CD8 expansion and IFN-gamma production on cross-recognition of variant epitopes. Our data suggest a mechanism that could account for any possible cross-protection that may be mediated by HIV-2-specific CD8(+) T cells against HIV-1 infection. Furthermore, they have implications for HIV vaccine development, demonstrating an association between a polyclonal, virus-specific CD8(+) T cell response and an enhanced capacity to tolerate substitutions within T cell epitopes.

Dorrell L, Edwards A. 2002. Vulvovaginitis due to fluconazole resistant Candida albicans following self treatment with non-prescribed triazoles. Sex Transm Infect, 78 (4), pp. 308-309. | Read more

Dorrell L, Willcox BE, Jones EY, Gillespie G, Njai H, Sabally S, Jaye A, DeGleria K 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.

Dorrell L, O'Callaghan CA, Britton W, Hambleton S, McMichael A, Smith GL, Rowland-Jones S, Blanchard TJ. 2000. Recombinant modified vaccinia virus Ankara efficiently restimulates human cytotoxic T lymphocytes in vitro. Vaccine, 19 (2-3), pp. 327-336. | Show Abstract | Read more

The immunogenicity of recombinant modified vaccinia Ankara, a highly attenuated vaccinia virus, expressing influenza nucleoprotein (MVA-NP) and HIV-1 gag (MVA-gag) was investigated. Restimulation of peripheral blood lymphocytes of healthy subjects with MVA-NP led to expansion of CTL with specificity for known NP epitopes. These CTL efficiently lysed NP peptide-pulsed targets and released interferon-gamma (IFN-gamma) on contact with epitope peptide. MVA-NP-stimulated CTL specific for the HLA-B8 epitope, NP380-88, stained with a tetrameric complex of HLA-B8 refolded with the NP380-88 peptide and anti-CD8 antibody on flow cytometry. CTL were also elicited from two HIV-1 seropositive donors by restimulation with MVA-HIV-1 gag and showed specificity for immunodominant gag epitopes. These data indicate that restimulation of human CTL with recombinant MVA is effective and suggest that MVA will elicit CTL responses in humans in vivo.

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.

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.

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

Veenstra J, Williams IG, Colebunders R, Dorrell L, Tchamouroff SE, Patou G, Lange JM, Weller IV et al. 1996. Immunization with recombinant p17/p24:Ty virus-like particles in human immunodeficiency virus-infected persons. J Infect Dis, 174 (4), pp. 862-866. | Show Abstract

In studies of the natural history of human immunodeficiency virus type 1 (HIV-1) infection, it has been repeatedly shown that higher-titer antibody responses to the HIV gag p24 protein correlate with less rapid disease progression. In HIV-negative persons, immunization with HIV-1 p17/p24:Ty virus-like particles (p24-VLP) induced humoral and cellular immune responses to p24. This construct was therefore studied as a potential immunotherapeutic agent with the objective of augmenting the immune response to p24 in a double-blind placebo-controlled trial involving 74 p24 antibody-positive, asymptomatic HIV-1-infected subjects with CD4 cell counts > 350/mm3. Immunization with p24-VLP was generally well tolerated. Immunization with p24-VLP did not increase p24 antibody levels and had no effect on CD4 cell counts or virus load. The failure to increase p24 antibody titers cannot entirely be explained by the subjects' immunodeficiency because most generated an antibody response to Ty, a yeast component of the immunogen.

Yang H, Buisson S, Bossi G, Wallace Z, Hancock G, So C, Ashfield R, Vuidepot A et al. 2016. Elimination of Latently HIV-infected Cells from Antiretroviral Therapy-suppressed Subjects by Engineered Immune-mobilizing T-cell Receptors. Mol Ther, | Show Abstract | Read more

Persistence of human immunodeficiency virus (HIV) in a latent state in long-lived CD4+ T-cells is a major barrier to eradication. Latency-reversing agents that induce direct or immune-mediated cell death upon reactivation of HIV are a possible solution. However, clearance of reactivated cells may require immunotherapeutic agents that are fine-tuned to detect viral antigens when expressed at low levels. We tested the antiviral efficacy of immune-mobilizing monoclonal T-cell receptors against viruses (ImmTAVs), bispecific molecules that redirect CD8+ T-cells to kill HIV-infected CD4+ T-cells. T-cell receptors specific for an immunodominant Gag epitope, SL9, and its escape variants were engineered to achieve supraphysiological affinity and fused to a humanised CD3-specific single chain antibody fragment. Ex vivo polyclonal CD8+ T-cells were efficiently redirected by immune-mobilising monoclonal T-cell receptors against viruses to eliminate CD4+ T-cells from human histocompatibility leukocyte antigen (HLA)-A*0201-positive antiretroviral therapy-treated patients after reactivation of inducible HIV in vitro. The efficiency of infected cell elimination correlated with HIV Gag expression. Immune-mobilising monoclonal T-cell receptors against viruses have potential as a therapy to facilitate clearance of reactivated HIV reservoir cells.Molecular Therapy (2016); doi:10.1038/mt.2016.114.

Ewer KJ, Lambe T, Rollier CS, Spencer AJ, Hill AV, Dorrell L. 2016. Viral vectors as vaccine platforms: from immunogenicity to impact. Curr Opin Immunol, 41 pp. 47-54. | Show Abstract | Read more

Viral vectors are the vaccine platform of choice for many pathogens that have thwarted efforts towards control using conventional vaccine approaches. Although the STEP trial encumbered development of recombinant human adenovirus vectors only a few years ago, replication-deficient simian adenoviruses have since emerged as a crucial component of clinically effective prime-boost regimens. The vectors discussed here elicit functionally relevant cellular and humoral immune responses, at extremes of age and in diverse populations. The recent Ebola virus outbreak highlighted the utility of viral vectored vaccines in facilitating a rapid response to public health emergencies. Meanwhile, technological advances in manufacturing to support scale-up of viral vectored vaccines have helped to consolidate their position as a leading approach to tackling 'old' and emerging infections.

Kinloch-de Loes S, Dorrell L, Yang H, Hardy GA, Yerly S, Cellerai C, Vandekerckhove L, De Spielgelaere W, Malatinkova E, Wee Lee Koh W, Johnson MA. 2015. Aviremia 10 Years Postdiscontinuation of Antiretroviral Therapy Initiated During Primary Human Immunodeficiency Virus-1 Infection and Association With Gag-Specific T-Cell Responses. Open Forum Infect Dis, 2 (4), pp. ofv144. | Show Abstract | Read more

Combination antiretroviral therapy during primary human immunodeficiency virus-1 infection may enable long-term drug-free virological control in rare individuals. We describe a female who maintained aviremia and a normal CD4(+)/CD8(+) T cell ratio for 10 years after stopping therapy, despite a persistent viral reservoir. Cellular immune responses may have contributed to this outcome.

Ternette N, Yang H, Partridge T, Llano A, Cedeño S, Fischer R, Charles PD, Dudek NL et al. 2016. Defining the HLA class I-associated viral antigen repertoire from HIV-1-infected human cells. Eur J Immunol, 46 (1), pp. 60-69. | Show Abstract | Read more

Recognition and eradication of infected cells by cytotoxic T lymphocytes is a key defense mechanism against intracellular pathogens. High-throughput definition of HLA class I-associated immunopeptidomes by mass spectrometry is an increasingly important analytical tool to advance our understanding of the induction of T-cell responses against pathogens such as HIV-1. We utilized a liquid chromatography tandem mass spectrometry workflow including de novo-assisted database searching to define the HLA class I-associated immunopeptidome of HIV-1-infected human cells. We here report for the first time the identification of 75 HIV-1-derived peptides bound to HLA class I complexes that were purified directly from HIV-1-infected human primary CD4(+) T cells and the C8166 human T-cell line. Importantly, one-third of eluted HIV-1 peptides had not been previously known to be presented by HLA class I. Over 82% of the identified sequences originated from viral protein regions for which T-cell responses have previously been reported but for which the precise HLA class I-binding sequences have not yet been defined. These results validate and expand the current knowledge of virus-specific antigenic peptide presentation during HIV-1 infection and provide novel targets for T-cell vaccine development.

Ternette N, Block PD, Sánchez-Bernabéu Á, Borthwick N, Pappalardo E, Abdul-Jawad S, Ondondo B, Charles PD, Dorrell L, Kessler BM, Hanke T. 2015. Early Kinetics of the HLA Class I-Associated Peptidome of MVA.HIVconsv-Infected Cells. J Virol, 89 (11), pp. 5760-5771. | Show Abstract | Read more

UNLABELLED: Cytotoxic T cells substantially contribute to the control of intracellular pathogens such as human immunodeficiency virus type 1 (HIV-1). Here, we evaluated the immunopeptidome of Jurkat cells infected with the vaccine candidate MVA.HIVconsv, which delivers HIV-1 conserved antigenic regions by using modified vaccinia virus Ankara (MVA). We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to identify 6,358 unique peptides associated with the class I human leukocyte antigen (HLA), of which 98 peptides were derived from the MVA vector and 7 were derived from the HIVconsv immunogen. Human vaccine recipients responded to the peptide sequences identified by LC-MS/MS. Peptides derived from the conserved HIV-1 regions were readily detected as early as 1.5 h after MVA.HIVconsv infection. Four of the seven conserved peptides were monitored between 0 and 3.5 h of infection by using quantitative mass spectrometry (Q-MS), and their abundance in HLA class I associations reflected levels of the whole HIVconsv protein in the cell. While immunopeptides delivered by the incoming MVA vector proteins could be detected, all early HIVconsv-derived immunopeptides were likely synthesized de novo. MVA.HIVconsv infection generally altered the composition of HLA class I-associated human (self) peptides, but these changes corresponded only partially to changes in the whole cell host protein abundance. IMPORTANCE: The vast changes in cellular antigen presentation after infection of cells with a vectored vaccine, as shown here for MVA.HIVconsv, highlight the complexity of factors that need to be considered for efficient antigen delivery and presentation. Identification and quantitation of HLA class I-associated peptides by Q-MS will not only find broad application in T-cell epitope discovery but also inform vaccine design and allow evaluation of efficient epitope presentation using different delivery strategies.

Clutton G, Bridgeman A, Reyes-Sandoval A, Hanke T, Dorrell L. 2015. Transient IL-10 receptor blockade can enhance CD8(+) T cell responses to a simian adenovirus-vectored HIV-1 conserved region immunogen. Hum Vaccin Immunother, 11 (4), pp. 1030-1035. | Show Abstract | Read more

Viral vector vaccines designed to elicit CD8(+) T cells in non-human primates exert potent control of immunodeficiency virus infections; however, similar approaches have been unsuccessful in humans. Adenoviral vectors elicit potent T cell responses but also induce production of immunosuppressive interleukin-10 (IL-10), which can limit the expansion of T cell responses. We investigated whether inhibiting IL-10 signaling prior to immunization with a candidate adenovirus vectored-HIV-1 vaccine, ChAdV63.HIVconsv, could modulate innate and adaptive immune responses in BALB/c mice. Transient IL-10 receptor blockade led to a modest but significant increase in the total magnitude CD8(+) T cell response to HIVconsv, but did not affect T cell responses to immunodominant epitopes. Anti-IL-10R-treated animals also exhibited greater expression of CD86 on CD11c(+) dendritic cells. Our data support further investigation and optimization of IL-10 blocking strategies to improve the immunogenicity of vaccines based on replication-defective adenoviruses.

Hancock G, Yang H, Yorke E, Wainwright E, Bourne V, Frisbee A, Payne TL, Berrong M et al. 2015. Identification of effective subdominant anti-HIV-1 CD8+ T cells within entire post-infection and post-vaccination immune responses. PLoS Pathog, 11 (2), pp. e1004658. | Show Abstract | Read more

Defining the components of an HIV immunogen that could induce effective CD8+ T cell responses is critical to vaccine development. We addressed this question by investigating the viral targets of CD8+ T cells that potently inhibit HIV replication in vitro, as this is highly predictive of virus control in vivo. We observed broad and potent ex vivo CD8+ T cell-mediated viral inhibitory activity against a panel of HIV isolates among viremic controllers (VC, viral loads <5000 copies/ml), in contrast to unselected HIV-infected HIV Vaccine trials Network (HVTN) participants. Viral inhibition of clade-matched HIV isolates was strongly correlated with the frequency of CD8+ T cells targeting vulnerable regions within Gag, Pol, Nef and Vif that had been identified in an independent study of nearly 1000 chronically infected individuals. These vulnerable and so-called "beneficial" regions were of low entropy overall, yet several were not predicted by stringent conservation algorithms. Consistent with this, stronger inhibition of clade-matched than mismatched viruses was observed in the majority of subjects, indicating better targeting of clade-specific than conserved epitopes. The magnitude of CD8+ T cell responses to beneficial regions, together with viral entropy and HLA class I genotype, explained up to 59% of the variation in viral inhibitory activity, with magnitude of the T cell response making the strongest unique contribution. However, beneficial regions were infrequently targeted by CD8+ T cells elicited by vaccines encoding full-length HIV proteins, when the latter were administered to healthy volunteers and HIV-positive ART-treated subjects, suggesting that immunodominance hierarchies undermine effective anti-HIV CD8+ T cell responses. Taken together, our data support HIV immunogen design that is based on systematic selection of empirically defined vulnerable regions within the viral proteome, with exclusion of immunodominant decoy epitopes that are irrelevant for HIV control.

Borthwick N, Ahmed T, Ondondo B, Hayes P, Rose A, Ebrahimsa U, Hayton EJ, Black A et al. 2014. Vaccine-elicited human T cells recognizing conserved protein regions inhibit HIV-1. Mol Ther, 22 (2), pp. 464-475. | Show Abstract | Read more

Virus diversity and escape from immune responses are the biggest challenges to the development of an effective vaccine against HIV-1. We hypothesized that T-cell vaccines targeting the most conserved regions of the HIV-1 proteome, which are common to most variants and bear fitness costs when mutated, will generate effectors that efficiently recognize and kill virus-infected cells early enough after transmission to potentially impact on HIV-1 replication and will do so more efficiently than whole protein-based T-cell vaccines. Here, we describe the first-ever administration of conserved immunogen vaccines vectored using prime-boost regimens of DNA, simian adenovirus and modified vaccinia virus Ankara to uninfected UK volunteers. The vaccine induced high levels of effector T cells that recognized virus-infected autologous CD4(+) cells and inhibited HIV-1 replication by up to 5.79 log10. The virus inhibition was mediated by both Gag- and Pol- specific effector CD8(+) T cells targeting epitopes that are typically subdominant in natural infection. These results provide proof of concept for using a vaccine to target T cells at conserved epitopes, showing that these T cells can control HIV-1 replication in vitro.

Cited:

25

Scopus

Holloway CJ, Ntusi N, Suttie J, Mahmod M, Wainwright E, Clutton G, Hancock G, Beak P et al. 2013. Comprehensive cardiac magnetic resonance imaging and spectroscopy reveal a high burden of myocardial disease in HIV patients Circulation, 128 (8), pp. 814-822. | Show Abstract | Read more

BACKGROUND - : HIV infection continues to be endemic worldwide. Although treatments are successful, it remains controversial whether patients receiving optimal therapy have structural, functional, or biochemical cardiac abnormalities that may underlie their increased cardiac morbidity and mortality. The purpose of this study was to characterize myocardial abnormalities in a contemporary group of HIV-infected individuals undergoing combination antiretroviral therapy. METHODS AND RESULTS - : Volunteers with HIV who were undergoing combination antiretroviral therapy and age-matched control subjects without a history of cardiovascular disease underwent cardiac magnetic resonance imaging and spectroscopy for the determination of cardiac function, myocardial fibrosis, and myocardial lipid content. A total of 129 participants were included in this analysis. Compared with age-matched control subjects (n=39; 30.23%), HIV-infected subjects undergoing combination antiretroviral therapy (n=90; 69.77%) had 47% higher median myocardial lipid levels (P <0.003) and 74% higher median plasma triglyceride levels (both P<0.001). Myocardial fibrosis, predominantly in the basal inferolateral wall of the left ventricle, was observed in 76% of HIV-infected subjects compared with 13% of control subjects (P<0.001). Peak myocardial systolic and diastolic longitudinal strain were also lower in HIV-infected individuals than in control subjects and remained statistically significant after adjustment for available confounders. CONCLUSIONS - : Comprehensive cardiac imaging revealed cardiac steatosis, alterations in cardiac function, and a high prevalence of myocardial fibrosis in a contemporary group of asymptomatic HIV-infected subjects undergoing combination antiretroviral therapy. Cardiac steatosis and fibrosis may underlie cardiac dysfunction and increased cardiovascular morbidity and mortality in subjects with HIV. © 2013 American Heart Association, Inc.

Clutton G, Yang H, Hancock G, Sande N, Holloway C, Angus B, von Delft A, Barnes E et al. 2013. Emergence of a distinct HIV-specific IL-10-producing CD8+ T-cell subset with immunomodulatory functions during chronic HIV-1 infection. Eur J Immunol, 43 (11), pp. 2875-2885. | Show Abstract | Read more

Interleukin-10 (IL-10) plays a key role in regulating proinflammatory immune responses to infection but can interfere with pathogen clearance. Although IL-10 is upregulated throughout HIV-1 infection in multiple cell subsets, whether this is a viral immune evasion strategy or an appropriate response to immune activation is unresolved. Analysis of IL-10 production at the single cell level in 51 chronically infected subjects (31 antiretroviral (ART) naïve and 20 ART treated) showed that a subset of CD8(+) T cells with a CD25(neg) FoxP3(neg) phenotype contributes substantially to IL-10 production in response to HIV-1 gag stimulation. The frequencies of gag-specific IL-10- and IFN-γ-producing T cells in ART-naïve subjects were strongly correlated and the majority of these IL-10(+) CD8(+) T cells co-produced IFN-γ; however, patients with a predominant IL-10(+) /IFN-γ(neg) profile showed better control of viraemia. Depletion of HIV-specific CD8(+) IL-10(+) cells from PBMCs led to upregulation of CD38 on CD14(+) monocytes together with increased IL-6 production, in response to gag stimulation. Increased CD38 expression was positively correlated with the frequency of the IL-10(+) population and was also induced by exposure of monocytes to HIV-1 in vitro. Production of IL-10 by HIV-specific CD8(+) T cells may represent an adaptive regulatory response to monocyte activation during chronic infection.

Schiffner T, Sattentau QJ, Dorrell L. 2013. Development of prophylactic vaccines against HIV-1. Retrovirology, 10 (1), pp. 72. | Show Abstract | Read more

The focus of most current HIV-1 vaccine development is on antibody-based approaches. This is because certain antibody responses correlated with protection from HIV-1 acquisition in the RV144 phase III trial, and because a series of potent and broad spectrum neutralizing antibodies have been isolated from infected individuals. Taken together, these two findings suggest ways forward to develop a neutralizing antibody-based vaccine. However, understanding of the correlates of protection from disease in HIV-1 and other infections strongly suggests that we should not ignore CTL-based research. Here we review recent progress in the field and highlight the challenges implicit in HIV-1 vaccine design and some potential solutions.

Holloway CJ, Ntusi N, Suttie J, Mahmod M, Wainwright E, Clutton G, Hancock G, Beak P et al. 2013. Comprehensive cardiac magnetic resonance imaging and spectroscopy reveal a high burden of myocardial disease in HIV patients. Circulation, 128 (8), pp. 814-822. | Show Abstract | Read more

BACKGROUND: HIV infection continues to be endemic worldwide. Although treatments are successful, it remains controversial whether patients receiving optimal therapy have structural, functional, or biochemical cardiac abnormalities that may underlie their increased cardiac morbidity and mortality. The purpose of this study was to characterize myocardial abnormalities in a contemporary group of HIV-infected individuals undergoing combination antiretroviral therapy. METHODS AND RESULTS: Volunteers with HIV who were undergoing combination antiretroviral therapy and age-matched control subjects without a history of cardiovascular disease underwent cardiac magnetic resonance imaging and spectroscopy for the determination of cardiac function, myocardial fibrosis, and myocardial lipid content. A total of 129 participants were included in this analysis. Compared with age-matched control subjects (n=39; 30.23%), HIV-infected subjects undergoing combination antiretroviral therapy (n=90; 69.77%) had 47% higher median myocardial lipid levels (P <0.003) and 74% higher median plasma triglyceride levels (both P<0.001). Myocardial fibrosis, predominantly in the basal inferolateral wall of the left ventricle, was observed in 76% of HIV-infected subjects compared with 13% of control subjects (P<0.001). Peak myocardial systolic and diastolic longitudinal strain were also lower in HIV-infected individuals than in control subjects and remained statistically significant after adjustment for available confounders. CONCLUSIONS: Comprehensive cardiac imaging revealed cardiac steatosis, alterations in cardiac function, and a high prevalence of myocardial fibrosis in a contemporary group of asymptomatic HIV-infected subjects undergoing combination antiretroviral therapy. Cardiac steatosis and fibrosis may underlie cardiac dysfunction and increased cardiovascular morbidity and mortality in subjects with HIV.

An exploration of the characteristics of vaccine-induced T cell responses to novel HIV-1 and HCV vaccines and their contribution to protective immunity

HIV-1 and hepatitis C virus (HCV) are major global pathogens with high rates of morbidity and mortality. Co-infection is common, due to overlapping transmission risks. PEACHI (Prevention of hepatitis C and HIV co-infections) is an Oxford-led EU FP7-funded project that aims to develop effective viral vectored vaccines for prevention of HIV-1, HCV and co-infection. The vaccines exploit potent replication-defective viral vectors (simian adenovirus, ChAd and modified vaccinia virus Ankara, MVA) and ...

View project

Development of new vaccines for therapy of high-risk Human Papillomavirus infections

Human papillomaviruses (HPV) are responsible for virtually all cases of cervical cancer and a significant proportion of other anogenital and oropharyngeal cancers. Half a million cases of cervical cancer occur each year in low and middle income countries, largely due to the lack of cytological screening programmes. Licensed HPV vaccines are highly effective in preventing incident infection and consequent pre-malignant disease and could substantially reduce cervical cancers in resource-poor ...

View project

Development of new vaccines for therapy of high-risk Human Papillomavirus infections

In collaboration with Prof. Lucy Dorrell at the Jenner Institute, we are aiming to screen MHC-associated peptide sequences presented on primary HPV-driven anogenital cancer tissues for suitable T cell targets. Identified antigen candidates will then be selected and evaluated for their suitability in immunotherapeutic approaches for distinct HR genotypes by implementing them into viral vectors in collaboration with Dr Arturo Reyes-Sandoval at the Jenner Institute.

View project

109

Thank you for registering your interest

We were unable to record your request to register for interest in future opportunities. Please try again and if problems persist contact us at webteam@ndm.ox.ac.uk