register interest

Dr Philippa Matthews

Research Area: Immunology
Scientific Themes: Immunology & Infectious Disease and Genetics & Genomics
Keywords: hepatitis b virus, adaptive immunity, HLA, HBV, epidemiology, genetics and sequencing
Web Links:
'Hepitopes' is a project to identify protein fragments (epitopes) of the hepatitis B virus that are recognised by the immune system, helping to control or clear the infection. You can access the database on-line via our publication (Lumley et al, Wellcome Open Research 2016, 1:9. doi: 10.12688/wellcomeopenres.9952.1).

'Hepitopes' is a project to identify protein fragments (epitopes) of the hepatitis B virus that are ...

This graph shows the effect of important genes in the human immune system on HBV infection. We used a marker of viral infectivity called Hepatitis B e-antigen. The position of the blue line (representing HLA-A genes) shows a significant effect, while the genes in red and green (HLA-B and HLA-C) do not have an effect. This helps us to focus our attention on the immune responses that are most likely to control the infection. This result is published in the Journal of Infectious Diseases (doi: 10.1093/infdis/jiv592).

This graph shows the effect of important genes in the human immune system on HBV infection. We used ...

The disused diamond mine in Kimberley, South Africa. Kimberley is one of our research sites, from where we have studied children with HIV and HBV infection. The study will now expand to include sites in Bloemfontein and Cape Town.

The disused diamond mine in Kimberley, South Africa. Kimberley is one of our research sites, from ...

A child's depiction of hepatitis B virus. I am running a project 'viral footprints', using themes from our research to inspire and engage members of the public, including hospital patients and students from Oxfordshire schools.

A child's depiction of hepatitis B virus. I am running a project 'viral footprints', using themes ...

I am a research fellow in Clinical Infection funded by the Wellcome Trust to work on a study of chronic hepatitis B virus (HBV) infection, with a particular focus on populations in southern Africa.

Together with a group of collaborators at the Wellcome Trust Centre for Human Genetics, I am pioneering a new pipeline to generate full length deep HBV sequences, alongside collecting human demographic, clinical and genetic data. The aim of the study is to identify factors that impact on the outcomes of chronic HBV infection, and specifically to characterise the adaptive immune response.

In the long-term, advancing this knowledge will feed into optimising therapy and developing strategies for cure.

I have a background in HIV immunology, and also have research interests in other chronic viral infections including CMV, herpes viruses and human parvovirus-4 (PARV4), and virus discovery.

I am interested in data visualisation, which includes promoting Open Access publication, and also designing my own resources for use in primary and secondary school workshops to inspire school students in topics around science and medicine.

I continue to contribute to clinical work, and teaching graduate and undergraduate medical students in Microbiology and Infectious Diseases at Oxford University Hospitals. My particular clinical interests include the management of bone and joint infection, and antimicrobial prescribing and stewardship.

Affiliations:

  • Honorary Consultant in Clinical Infection; Oxford University Hospitals NHS Foundation Trust Department of Microbiology and Infectious Diseases.
  • Wellcome Trust Research Fellow, Nuffield Department of Medicine, University of Oxford and Peter Medawar Building for Pathogen Research, University of Oxford.
  • Senior Research Fellow; Harris Manchester College, University of Oxford.

Funding:

  • NIHR - Research Capability Funding (2015-2016).
  • Rosetrees Trust (small project grant, 2014-2016).
  • British Infection Association (small project grant, 2014-2016).
  • University of Oxford Medical Research Fund (small project grant, 2014-2016).
  • Wellcome Trust (Intermediate Fellowship 2016-2021).
  • Royal College of Pathologists and Wellcome Trust grants for Public Engagement (2015 onwards).

Name Department Institution Country
Professor Paul Klenerman Experimental Medicine Division Oxford University, Peter Medawar Building United Kingdom
Professor Ellie (Eleanor) Barnes Experimental Medicine Division Oxford University, Peter Medawar Building United Kingdom
Dr Rory Bowden Wellcome Trust Centre for Human Genetics Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Professor Mary Carrington National Cancer Institute United States
Dr Katie Jeffery FRCPath Department of Microbiology and Infectious DIseases Oxford University Hospitals NHS Foundation Trust United Kingdom
Dr Jonathan Carlson Microsoft Research United States
Professor Philip Goulder Department of Paediatrics University of Oxford United Kingdom
Dr Monique Andersson MRCP FRCPath Department of Microbiology and Infectious DIseases Oxford University Hospitals NHS Foundation Trust United Kingdom
Dr Dominique Goedhals Department of Microbiology University Hospital Bloemfontein South Africa
Matthews PC, Barnes E. 2017. Hepatitis B vaccine shortage: another symptom of chronic neglect? BMJ, 359 pp. j4686. | Read more

Leitman EM, Thobakgale CF, Adland E, Ansari MA, Raghwani J, Prendergast AJ, Tudor-Williams G, Kiepiela P, Hemelaar J, Brener J et al. 2017. Role of HIV-specific CD8+ T cells in pediatric HIV cure strategies after widespread early viral escape. J Exp Med, 214 (11), pp. 3239-3261. | Show Abstract | Read more

Recent studies have suggested greater HIV cure potential among infected children than adults. A major obstacle to HIV eradication in adults is that the viral reservoir is largely comprised of HIV-specific cytotoxic T lymphocyte (CTL) escape variants. We here evaluate the potential for CTL in HIV-infected slow-progressor children to play an effective role in "shock-and-kill" cure strategies. Two distinct subgroups of children were identified on the basis of viral load. Unexpectedly, in both groups, as in adults, HIV-specific CTL drove the selection of escape variants across a range of epitopes within the first weeks of infection. However, in HIV-infected children, but not adults, de novo autologous variant-specific CTL responses were generated, enabling the pediatric immune system to "corner" the virus. Thus, even when escape variants are selected in early infection, the capacity in children to generate variant-specific anti-HIV CTL responses maintains the potential for CTL to contribute to effective shock-and-kill cure strategies in pediatric HIV infection.

O'Hara GA, McNaughton AL, Maponga T, Jooste P, Ocama P, Chilengi R, Mokaya J, Liyayi MI, Wachira T, Gikungi DM et al. 2017. Hepatitis B virus infection as a neglected tropical disease. PLoS Negl Trop Dis, 11 (10), pp. e0005842. | Read more

Stockdale AJ, Chaponda M, Beloukas A, Phillips RO, Matthews PC, Papadimitropoulos A, King S, Bonnett L, Geretti AM. 2017. Prevalence of hepatitis D virus infection in sub-Saharan Africa: a systematic review and meta-analysis. Lancet Glob Health, 5 (10), pp. e992-e1003. | Show Abstract | Read more

BACKGROUND: Hepatitis D virus (also known as hepatitis delta virus) can establish a persistent infection in people with chronic hepatitis B, leading to accelerated progression of liver disease. In sub-Saharan Africa, where HBsAg prevalence is higher than 8%, hepatitis D virus might represent an important additive cause of chronic liver disease. We aimed to establish the prevalence of hepatitis D virus among HBsAg-positive populations in sub-Saharan Africa. METHODS: We systematically reviewed studies of hepatitis D virus prevalence among HBsAg-positive populations in sub-Saharan Africa. We searched PubMed, Embase, and Scopus for papers published between Jan 1, 1995, and Aug 30, 2016, in which patient selection criteria and geographical setting were described. Search strings included sub-Saharan Africa, the countries therein, and permutations of hepatitis D virus. Cohort data were also added from HIV-positive populations in Malawi and Ghana. Populations undergoing assessment in liver disease clinics and those sampled from other populations (defined as general populations) were analysed. We did a meta-analysis with a DerSimonian-Laird random-effects model to calculate a pooled estimate of hepatitis D virus seroprevalence. FINDINGS: Of 374 studies identified by our search, 30 were included in our study, only eight of which included detection of hepatitis D virus RNA among anti-hepatitis D virus seropositive participants. In west Africa, the pooled seroprevalence of hepatitis D virus was 7·33% (95% CI 3·55-12·20) in general populations and 9·57% (2·31-20·43) in liver-disease populations. In central Africa, seroprevalence was 25·64% (12·09-42·00) in general populations and 37·77% (12·13-67·54) in liver-disease populations. In east and southern Africa, seroprevalence was 0·05% (0·00-1·78) in general populations. The odds ratio for anti-hepatitis D virus detection among HBsAg-positive patients with liver fibrosis or hepatocellular carcinoma was 5·24 (95% CI 2·74-10·01; p<0·0001) relative to asymptomatic controls. INTERPRETATION: Findings suggest localised clusters of hepatitis D virus endemicity across sub-Saharan Africa. Epidemiological data are needed from southern and east Africa, and from patients with established liver disease. Further studies should aim to define the reliability of hepatitis D virus testing methods, identify risk factors for transmission, and characterise the natural history of the infection in the region. FUNDING: Wellcome Trust, Royal Society.

Leitman EM, Willberg CB, Tsai M-H, Chen H, Buus S, Chen F, Riddell L, Haas D, Fellay J, Goedert JJ et al. 2017. HLA-B*14:02-Restricted Env-Specific CD8+ T-Cell Activity Has Highly Potent Antiviral Efficacy Associated with Immune Control of HIV Infection. J Virol, 91 (22), pp. e00544-17-e00544-17. | Show Abstract | Read more

Immune control of human immunodeficiency virus type 1 (HIV) infection is typically associated with effective Gag-specific CD8+ T-cell responses. We here focus on HLA-B*14, which protects against HIV disease progression, but the immunodominant HLA-B*14-restricted anti-HIV response is Env specific (ERYLKDQQL, HLA-B*14-EL9). A subdominant HLA-B*14-restricted response targets Gag (DRYFKTLRA, HLA-B*14-DA9). Using HLA-B*14/peptide-saporin-conjugated tetramers, we show that HLA-B*14-EL9 is substantially more potent at inhibiting viral replication than HLA-B*14-DA9. HLA-B*14-EL9 also has significantly higher functional avidity (P < 0.0001) and drives stronger selection pressure on the virus than HLA-B*14-DA9. However, these differences were HLA-B*14 subtype specific, applying only to HLA-B*14:02 and not to HLA-B*14:01. Furthermore, the HLA-B*14-associated protection against HIV disease progression is significantly greater for HLA-B*14:02 than for HLA-B*14:01, consistent with the superior antiviral efficacy of the HLA-B*14-EL9 response. Thus, although Gag-specific CD8+ T-cell responses may usually have greater anti-HIV efficacy, factors independent of protein specificity, including functional avidity of individual responses, are also critically important to immune control of HIV.IMPORTANCE In HIV infection, although cytotoxic T lymphocytes (CTL) play a potentially critical role in eradication of viral reservoirs, the features that constitute an effective response remain poorly defined. We focus on HLA-B*14, unique among HLAs associated with control of HIV in that the dominant CTL response is Env specific, not Gag specific. We demonstrate that Env-specific HLA-B*14-restricted activity is substantially more efficacious than the subdominant HLA-B*14-restricted Gag response. Env immunodominance over Gag and strong Env-mediated selection pressure on HIV are observed only in subjects expressing HLA-B*14:02, and not HLA-B*14:01. This reflects the increased functional avidity of the Env response over Gag, substantially more marked for HLA-B*14:02. Finally, we show that HLA-B*14:02 is significantly more strongly associated with viremic control than HLA-B*14:01. These findings indicate that, although Gag-specific CTL may usually have greater anti-HIV efficacy than Env responses, factors independent of protein specificity, including functional avidity, may carry greater weight in mediating effective control of HIV.

Li A, Gow N, Atkins BL, Taylor A, Peto T, McNally MA, Matthews PC. 2017. Metalware-associated orthopaedic infections caused by Staphylococcus lugdunensis: An emerging pathogen. J Infect, 75 (4), pp. 368-370. | Read more

Sharp CP, Gregory WF, Hattingh L, Malik A, Adland E, Daniels S, van Zyl A, Carlson JM, Wareing S, Ogwu A et al. 2017. PARV4 prevalence, phylogeny, immunology and coinfection with HIV, HBV and HCV in a multicentre African cohort. Wellcome Open Res, 2 pp. 26. | Show Abstract | Read more

Background: The seroprevalence of human parvovirus-4 (PARV4) varies considerably by region. In sub-Saharan Africa, seroprevalence is high in the general population, but little is known about the transmission routes or the prevalence of coinfection with blood-borne viruses, HBV, HCV and HIV.  Methods: To further explore the characteristics of PARV4 in this setting, with a particular focus on the prevalence and significance of coinfection, we screened a cohort of 695 individuals recruited from Durban and Kimberley (South Africa) and Gaborone (Botswana) for PARV4 IgG and DNA, as well as documenting HIV, HBV and HCV status.  Results: Within these cohorts, 69% of subjects were HIV-positive. We identified no cases of HCV by PCR, but 7.4% were positive for HBsAg. PARV4 IgG was positive in 42%; seroprevalence was higher in adults (69%) compared to children (21%) (p<0.0001) and in HIV-positive (52%) compared to HIV-negative individuals (24%) (p<0.0001), but there was no association with HBsAg status. We developed an on-line tool to allow visualization of coinfection data (https://purl.oclc.org/coinfection-viz). We identified five subjects who were PCR-positive for PARV4 genotype-3. Ex vivo CD8+ T cell responses spanned the entire PARV4 proteome and we propose a novel HLA-B*57:03-restricted epitope within the NS protein.  Conclusions: This characterisation of PARV4 infection provides enhanced insights into the epidemiology of infection and co-infection in African cohorts, and provides the foundations for planning further focused studies to elucidate transmission pathways, immune responses, and the clinical significance of this organism.

Leitman EM, Palmer CD, Buus S, Chen F, Riddell L, Sims S, Klenerman P, Sáez-Cirión A, Walker BD, Hess PR et al. 2017. Saporin-conjugated tetramers identify efficacious anti-HIV CD8+ T-cell specificities. PLoS One, 12 (10), pp. e0184496. | Show Abstract | Read more

Antigen-specific T-cells are highly variable, spanning potent antiviral efficacy and damaging auto-reactivity. In virus infections, identifying the most efficacious responses is critical to vaccine design. However, current methods depend on indirect measures or on ex vivo expanded CTL clones. We here describe a novel application of cytotoxic saporin-conjugated tetramers to kill antigen-specific T-cells without significant off-target effects. The relative efficacy of distinct antiviral CD8+ T-cell specificity can be directly assessed via antigen-specific CD8+ T-cell depletion. The utility of these reagents is demonstrated here in identifying the CD8+ T-cell specificity most effective in preventing HIV progression in HIV-infected HLA-B*27-positive immune controllers.

Matthews PC, Sharp C, Simmonds P, Klenerman P. 2017. Human parvovirus 4 'PARV4' remains elusive despite a decade of study. F1000Res, 6 pp. 82. | Show Abstract | Read more

Human parvovirus 4 ('PARV4') is a small DNA tetraparvovirus, first reported in 2005. In some populations, PARV4 infection is uncommon, and evidence of exposure is found only in individuals with risk factors for parenteral infection who are infected with other blood-borne viruses. In other settings, seroprevalence studies suggest an endemic, age-associated transmission pattern, independent of any specific risk factors. The clinical impact of PARV4 infection remains uncertain, but reported disease associations include an influenza-like syndrome, encephalitis, acceleration of HIV disease, and foetal hydrops. In this review, we set out to report progress updates from the recent literature, focusing on the investigation of cohorts in different geographical settings, now including insights from Asia, the Middle East, and South America, and discussing whether attributes of viral or host populations underpin the striking differences in epidemiology. We review progress in understanding viral phylogeny and biology, approaches to diagnostics, and insights that might be gained from studies of closely related animal pathogens. Crucial questions about pathogenicity remain unanswered, but we highlight new evidence supporting a possible link between PARV4 and an encephalitis syndrome. The unequivocal evidence that PARV4 is endemic in certain populations should drive ongoing research efforts to understand risk factors and routes of transmission and to gain new insights into the impact of this virus on human health.

Matthews PC. 2016. Fairness in scientific publishing. F1000Res, 5 pp. 2816. | Show Abstract | Read more

Major changes are afoot in the world of academic publishing, exemplified by innovations in publishing platforms, new approaches to metrics, improvements in our approach to peer review, and a focus on developing and encouraging open access to scientific literature and data. The FAIR acronym recommends that authors and publishers should aim to make their output Findable, Accessible, Interoperable and Reusable. In this opinion article, I explore the parallel view that we should take a collective stance on making the dissemination of scientific data fair in the conventional sense, by being mindful of equity and justice for patients, clinicians, academics, publishers, funders and academic institutions. The views I represent are founded on oral and written dialogue with clinicians, academics and the publishing industry. Further progress is needed to improve collaboration and dialogue between these groups, to reduce misinterpretation of metrics, to minimise inequity that arises as a consequence of geographic setting, to improve economic sustainability, and to broaden the spectrum, scope, and diversity of scientific publication.

Jooste P, van Zyl A, Adland E, Daniels S, Hattingh L, Brits A, Wareing S, Goedhals D, Jeffery K, Andersson M et al. 2016. Screening, characterisation and prevention of Hepatitis B virus (HBV) co-infection in HIV-positive children in South Africa. J Clin Virol, 85 pp. 71-74. | Show Abstract | Read more

BACKGROUND: In South Africa, the first HBV vaccine dose is administered at age 6 weeks, leaving a potential window for vertical transmission. Insights into HBV seroprevalence in the vulnerable HIV-infected group are important to drive improvements in surveillance, treatment and prevention. OBJECTIVES: We set out to implement a screening program for HBV among HIV-infected children and adolescents in Kimberley, South Africa. Our aims were to demonstrate that screening is feasible and sustainable, to establish the prevalence of HBV, to characterise the HBV cases we identified, and to inform discussion about the infant vaccination schedule. STUDY DESIGN: We tested all HIV positive children (age 0-16) for Hepatitis B surface antigen (HBsAg), delivering this testing as part of routine state-funded care. We followed up HBsAg-positive cases with an extended panel of HBV serology tests, and HBV DNA viral load quantification. RESULTS: Our screening campaign was successfully incorporated into routine out-patient care. Among 625 patients tested, we found five positive for HBsAg (0.8%), of whom three were Hepatitis B e-antigen positive. Two additional children initially tested HBsAg-positive but were negative on repeat testing. Antiviral therapy in the HBsAg children was reviewed and adjusted if required. CONCLUSIONS: The results testify to the overall success of the HBV vaccine campaign. However, we have demonstrated that ongoing vigilance is required to detect cases and prevent transmission events. Further evaluation of the optimum timing of the first vaccine HBV vaccine dose is required; a vaccine dose at birth could reduce prevalence further.

Lumley S, Noble H, Hadley MJ, Callow L, Malik A, Chua YY, Duffey OJ, Grolmusova N, Kumar A, Ravenscroft S et al. 2016. Hepitopes: A live interactive database of HLA class I epitopes in hepatitis B virus. Wellcome Open Res, 1 pp. 9. | Show Abstract | Read more

Increased clinical and scientific scrutiny is being applied to hepatitis B virus (HBV), with focus on the development of new therapeutic approaches, ultimately aiming for cure. Defining the optimum natural CD8+ T cell immune responses that arise in HBV, mediated by HLA class I epitope presentation, may help to inform novel immunotherapeutic strategies. Therefore, we have set out to develop a comprehensive database of these epitopes in HBV, coined 'Hepitopes'. This undertaking has its foundations in a systematic literature review to identify the sites and sequences of all published class I epitopes in HBV. We also collected information regarding the methods used to define each epitope, and any reported associations between an immune response to this epitope and disease outcome. The results of this search have been collated into a new open-access interactive database that is available at http://www.expmedndm.ox.ac.uk/hepitopes. Over time, we will continue to refine and update this resource, as well as inviting contributions from others in the field to support its development. This unique new database is an important foundation for ongoing investigations into the nature and impact of the CD8+ T cell response to HBV.

Matthews PC, Barrett LK, Warren S, Stoesser N, Snelling M, Scarborough M, Jones N. 2016. Oral fosfomycin for treatment of urinary tract infection: a retrospective cohort study. BMC Infect Dis, 16 (1), pp. 556. | Show Abstract | Read more

BACKGROUND: Fosfomycin is increasingly called upon for the treatment of multi drug-resistant (MDR) organisms causing urinary tract infection (UTI). We reviewed oral fosfomycin use for UTI treatment in a large UK hospital. The primary goal was to audit our clinical practice against current national guidelines. Secondary aims were to identify factors associated with treatment failure, and to investigate the potential for using fosfomycin in patients with co-morbidities. METHODS: We retrospectively studied 75 adult patients with UTI who received 151 episodes of treatment with fosfomycin from March 2013 to June 2015. We collected clinical data from our electronic patient record, and microbiology data pre- and post- fosfomycin treatment. We recorded additional data for patients receiving prolonged courses in order to make a preliminary assessment of safety and efficacy. We also reviewed >18,000 urinary tract isolates of Escherichia coli and Klebsiella spp. processed by our laboratory over the final year of our study period to determine the prevalence of fosfomycin resistance. RESULTS: There was a significant increase in fosfomycin treatment episodes over the course of the study period. Co-morbidities were present in 71 % of patients. The majority had E. coli infection (69 %), of which 59 % were extended spectrum beta-lactamase (ESBL)-producers. Klebsiella infections were more likely than E. coli to fail treatment, and more likely to be reported as fosfomycin resistant in cases of relapse following treatment. There were no adverse events in five patients treated with prolonged fosfomycin. Among all urinary isolates collected over a year, fosfomycin resistance was documented in 1 % of E. coli vs. 19 % of Klebsiella spp. (p < 0.0001). CONCLUSIONS: We report an important role for oral fosfomycin for MDR UTI treatment in a UK hospital population, and based on the findings from this study, we present our own local guidelines for its use. We present preliminary data suggesting that fosfomycin is safe and effective for use in patients with complex comorbidities and over prolonged time periods, but may be less effective against Klebsiella than E. coli.

Leitman EM, Willberg CB, De Burgh-Thomas A, Streeck H, Goulder PJR, Matthews PC. 2016. Subdominant Gag-specific anti-HIV efficacy in an HLA-B*57-positive elite controller. AIDS, 30 (6), pp. 972-974. | Read more

Leitman EM, Hurst J, Mori M, Kublin J, Ndung'u T, Walker BD, Carlson J, Gray GE, Matthews PC, Frahm N, Goulder PJR. 2016. Lower Viral Loads and Slower CD4+ T-Cell Count Decline in MRKAd5 HIV-1 Vaccinees Expressing Disease-Susceptible HLA-B*58:02. J Infect Dis, 214 (3), pp. 379-389. | Show Abstract | Read more

BACKGROUND: HLA strongly influences human immunodeficiency virus type 1 (HIV-1) disease progression. A major contributory mechanism is via the particular HLA-presented HIV-1 epitopes that are recognized by CD8(+) T-cells. Different populations vary considerably in the HLA alleles expressed. We investigated the HLA-specific impact of the MRKAd5 HIV-1 Gag/Pol/Nef vaccine in a subset of the infected Phambili cohort in whom the disease-susceptible HLA-B*58:02 is highly prevalent. METHODS: Viral loads, CD4(+) T-cell counts, and enzyme-linked immunospot assay-determined anti-HIV-1 CD8(+) T-cell responses for a subset of infected antiretroviral-naive Phambili participants, selected according to sample availability, were analyzed. RESULTS: Among those expressing disease-susceptible HLA-B*58:02, vaccinees had a lower chronic viral set point than placebo recipients (median, 7240 vs 122 500 copies/mL; P = .01), a 0.76 log10 lower longitudinal viremia level (P = .01), and slower progression to a CD4(+) T-cell count of <350 cells/mm(3) (P = .02). These differences were accompanied by a higher Gag-specific breadth (4.5 vs 1 responses; P = .04) and magnitude (2300 vs 70 spot-forming cells/10(6) peripheral blood mononuclear cells; P = .06) in vaccinees versus placebo recipients. CONCLUSIONS: In addition to the known enhancement of HIV-1 acquisition resulting from the MRKAd5 HIV-1 vaccine, these findings in a nonrandomized subset of enrollees show an HLA-specific vaccine effect on the time to CD4(+) T-cell count decline and viremia level after infection and the potential for vaccines to differentially alter disease outcome according to population HLA composition. CLINICAL TRIALS REGISTRATION: NCT00413725, DOH-27-0207-1539.

Matthews PC, Carlson JM, Beloukas A, Malik A, Jooste P, Ogwu A, Shapiro R, Riddell L, Chen F, Luzzi G et al. 2016. HLA-A is a Predictor of Hepatitis B e Antigen Status in HIV-Positive African Adults. J Infect Dis, 213 (8), pp. 1248-1252. | Show Abstract | Read more

Outcomes of chronic infection with hepatitis B virus (HBV) are varied, with increased morbidity reported in the context of human immunodeficiency virus (HIV) coinfection. The factors driving different outcomes are not well understood, but there is increasing interest in an HLA class I effect. We therefore studied the influence of HLA class I on HBV in an African HIV-positive cohort. We demonstrated that virologic markers of HBV disease activity (hepatitis B e antigen status or HBV DNA level) are associated with HLA-A genotype. This finding supports the role of the CD8(+) T-cell response in HBV control, and potentially informs future therapeutic T-cell vaccine strategies.

Matthews P, Beloukas A, Malik A, Carlson J, Jooste P, Ogwu A, Shapiro R, Riddell L, Chen F, Luzzi G et al. 2015. HLA CONTRIBUTES TO IMMUNE CONTROL OF HEPATITIS B IN HIV-POSITIVE AFRICAN ADULTS JOURNAL OF INFECTION, 71 (6), pp. 685-686. | Read more

Adland E, Klenerman P, Goulder P, Matthews PC. 2015. Ongoing burden of disease and mortality from HIV/CMV coinfection in Africa in the antiretroviral therapy era. Front Microbiol, 6 (SEP), pp. 1016. | Show Abstract | Read more

Human Cytomegalovirus (CMV) is a well-recognized pathogen in the context of HIV infection, but since the roll out of ART, clinical and scientific interest in the problem of HIV/CMV coinfection has diminished. However, CMV remains a significant cofactor in HIV disease, with an influence on HIV acquisition, disease progression, morbidity, and mortality. Disease manifestations may be a result of direct interplay between the two viruses, or may arise as a secondary consequence of immune dysregulation and systemic inflammation. The problem is most relevant when the rates of coinfection are high, most notably in sub-Saharan Africa, and in children at risk of acquiring both infections early in life. Understanding the interplay between these viruses and developing strategies to diagnose, treat and prevent CMV should be a priority.

Leitman EM, Hurst J, Mori M, Matthews PC, Frahm N, Kublin J, Gray GE, Goulder PJR. 2015. HLA-B*58:02-specific benefit of MRKAd5 Gag/Pol/Nef vaccine in an African population JOURNAL OF THE INTERNATIONAL AIDS SOCIETY, 18 | Read more

Brener J, Gall A, Batorsky R, Riddell L, Buus S, Leitman E, Kellam P, Allen T, Goulder P, Matthews PC. 2015. Disease progression despite protective HLA expression in an HIV-infected transmission pair Retrovirology, | Show Abstract | Read more

© 2015 Brener et al.Background: The precise immune responses mediated by HLA class I molecules such as HLA-B*27:05 and HLA-B*57:01 that protect against HIV disease progression remain unclear. We studied a CRF01_AE clade HIV infected donor-recipient transmission pair in which the recipient expressed both HLA-B*27:05 and HLA-B*57:01. Results: Within 4.5 years of diagnosis, the recipient had progressed to meet criteria for antiretroviral therapy initiation. We employed ultra-deep sequencing of the full-length virus genome in both donor and recipient as an unbiased approach by which to identify specific viral mutations selected in association with progression. Using a heat map method to highlight differences in the viral sequences between donor and recipient, we demonstrated that the majority of the recipient's mutations outside of Env were within epitopes restricted by HLA-B*27:05 and HLA-B*57:01, including the well-studied Gag epitopes. The donor, who also expressed HLA alleles associated with disease protection, HLA-A*32:01/B*13:02/B*14:01, showed selection of mutations in parallel with disease progression within epitopes restricted by these protective alleles. Conclusions: These studies of full-length viral sequences in a transmission pair, both of whom expressed protective HLA alleles but nevertheless failed to control viremia, are consistent with previous reports pointing to the critical role of Gag-specific CD8+ T cell responses restricted by protective HLA molecules in maintaining immune control of HIV infection. The transmission of subtype CRF01_AE clade infection may have contributed to accelerated disease progression in this pair as a result of clade-specific sequence differences in immunodominant epitopes.

Matthews PC. 2015. Rolling back malaria ELIFE, 4 | Read more

Matthews PC, Sharp CP, Malik A, Gregory WF, Adland E, Jooste P, Goulder PJR, Simmonds P, Klenerman P. 2015. Human parvovirus 4 infection among mothers and children in South Africa. Emerg Infect Dis, 21 (4), pp. 713-715. | Read more

Matthews PC, Jeffery K, Klenerman P, Barnes E, Cooke G. 2015. Screening and treatment for hepatitis C: a balanced perspective. BMJ, 350 (feb24 10), pp. h644. | Read more

Matthews PC. 2015. Rolling back malaria. Elife, 4 (4), | Read more

Brener J, Gall A, Batorsky R, Riddell L, Buus S, Leitman E, Kellam P, Allen T, Goulder P, Matthews PC. 2015. Disease progression despite protective HLA expression in an HIV-infected transmission pair. Retrovirology, 12 (1), pp. 55. | Show Abstract | Read more

BACKGROUND: The precise immune responses mediated by HLA class I molecules such as HLA-B*27:05 and HLA-B*57:01 that protect against HIV disease progression remain unclear. We studied a CRF01_AE clade HIV infected donor-recipient transmission pair in which the recipient expressed both HLA-B*27:05 and HLA-B*57:01. RESULTS: Within 4.5 years of diagnosis, the recipient had progressed to meet criteria for antiretroviral therapy initiation. We employed ultra-deep sequencing of the full-length virus genome in both donor and recipient as an unbiased approach by which to identify specific viral mutations selected in association with progression. Using a heat map method to highlight differences in the viral sequences between donor and recipient, we demonstrated that the majority of the recipient's mutations outside of Env were within epitopes restricted by HLA-B*27:05 and HLA-B*57:01, including the well-studied Gag epitopes. The donor, who also expressed HLA alleles associated with disease protection, HLA-A*32:01/B*13:02/B*14:01, showed selection of mutations in parallel with disease progression within epitopes restricted by these protective alleles. CONCLUSIONS: These studies of full-length viral sequences in a transmission pair, both of whom expressed protective HLA alleles but nevertheless failed to control viremia, are consistent with previous reports pointing to the critical role of Gag-specific CD8+ T cell responses restricted by protective HLA molecules in maintaining immune control of HIV infection. The transmission of subtype CRF01_AE clade infection may have contributed to accelerated disease progression in this pair as a result of clade-specific sequence differences in immunodominant epitopes.

Mori M, Adland E, Paioni P, Swordy A, Mori L, Laker L, Muenchhoff M, Matthews PC, Tudor-Williams G, Lavandier N et al. 2015. Sex Differences in Antiretroviral Therapy Initiation in Pediatric HIV Infection. PLoS One, 10 (7), pp. e0131591. | Show Abstract | Read more

The incidence and severity of infections in childhood is typically greater in males. The basis for these observed sex differences is not well understood, and potentially may facilitate novel approaches to reducing disease from a range of conditions. We here investigated sex differences in HIV-infected children in relation to antiretroviral therapy (ART) initiation and post-treatment outcome. In a South African cohort of 2,101 HIV-infected children, we observed that absolute CD4+ count and CD4% were significantly higher in ART-naïve female, compared to age-matched male, HIV-infected children. Absolute CD4 count and CD4% were also significantly higher in HIV-uninfected female versus male neonates. We next showed that significantly more male than female children were initiated on ART (47% female); and children not meeting criteria to start ART by >5 yrs were more frequently female (59%; p<0.001). Among ART-treated children, immune reconstitution of CD4 T-cells was more rapid and more complete in female children, even after adjustment for pre-ART absolute CD4 count or CD4% (p=0.011, p=0.030, respectively). However, while ART was initiated as a result of meeting CD4 criteria less often in females (45%), ART initiation as a result of clinical disease in children whose CD4 counts were above treatment thresholds occurred more often in females (57%, p<0.001). The main sex difference in morbidity observed in children initiating ART above CD4 thresholds, above that of TB disease, was as a result of wasting and stunting observed in females with above-threshold CD4 counts (p=0.002). These findings suggest the possibility that optimal treatment of HIV-infected children might incorporate differential CD4 treatment thresholds for ART initiation according to sex.

Matthews PC, Beloukas A, Malik A, Carlson JM, Jooste P, Ogwu A, Shapiro R, Riddell L, Chen F, Luzzi G et al. 2015. Prevalence and Characteristics of Hepatitis B Virus (HBV) Coinfection among HIV-Positive Women in South Africa and Botswana. PLoS One, 10 (7), pp. e0134037. | Show Abstract | Read more

There is progressive concern about the evolving burden of morbidity and mortality caused by coinfection with HIV-1 and hepatitis B virus (HBV) in sub-Saharan Africa, but the epidemiology and impact of this problem are not well defined. We therefore set out to assimilate more information about the nature of HBV/HIV coinfection in this region by undertaking a retrospective observational study of southern African adult women. We used samples from previously recruited HIV-1 positive women attending antenatal clinics in three settings in South Africa and Botswana (n = 950) and added a small cohort of HIV-negative antenatal South African women for comparison (n = 72). We tested for HBsAg and followed up HBsAg-positive samples by testing for HBeAg, HBV DNA, HBV genotype, presence of drug-resistance associated mutations (RAMs) and HDV. We identified HBsAg in 72 individuals (7% of the whole cohort), of whom 27% were HBeAg-positive, and the majority HBV genotypes A1 and A2. We did not detect any HDV coinfection. HBV prevalence was significantly different between geographically distinct cohorts, but did not differ according to HIV status. Among adults from South Africa, HBV/HIV coinfected patients had lower CD4+ T cell counts compared to those with HIV-monoinfection (p = 0.02), but this finding was not replicated in the cohort from Botswana. Overall, these data provide a snapshot of the coinfection problem at the heart of the HIV/HBV co-epidemic, and are important to inform public health policy, resource allocation, education, surveillance and clinical care.

Payne R, Muenchhoff M, Mann J, Roberts HE, Matthews P, Adland E, Hempenstall A, Huang K-H, Brockman M, Brumme Z et al. 2014. Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence. Proc Natl Acad Sci U S A, 111 (50), pp. E5393-E5400. | Show Abstract | Read more

It is widely believed that epidemics in new hosts diminish in virulence over time, with natural selection favoring pathogens that cause minimal disease. However, a tradeoff frequently exists between high virulence shortening host survival on the one hand but allowing faster transmission on the other. This is the case in HIV infection, where high viral loads increase transmission risk per coital act but reduce host longevity. We here investigate the impact on HIV virulence of HIV adaptation to HLA molecules that protect against disease progression, such as HLA-B*57 and HLA-B*58:01. We analyzed cohorts in Botswana and South Africa, two countries severely affected by the HIV epidemic. In Botswana, where the epidemic started earlier and adult seroprevalence has been higher, HIV adaptation to HLA including HLA-B*57/58:01 is greater compared with South Africa (P = 7 × 10(-82)), the protective effect of HLA-B*57/58:01 is absent (P = 0.0002), and population viral replicative capacity is lower (P = 0.03). These data suggest that viral evolution is occurring relatively rapidly, and that adaptation of HIV to the most protective HLA alleles may contribute to a lowering of viral replication capacity at the population level, and a consequent reduction in HIV virulence over time. The potential role in this process played by increasing antiretroviral therapy (ART) access is also explored. Models developed here suggest distinct benefits of ART, in addition to reducing HIV disease and transmission, in driving declines in HIV virulence over the course of the epidemic, thereby accelerating the effects of HLA-mediated viral adaptation.

Brener J, Gall A, Batorsky R, Kellam P, Allen T, Matthews P, Goulder P. 2014. HIV Minor Variants Detected by Next Generation Sequencing: Impact on Immune Control of HIV in the Context of HLA-B*27:05 and HLA-B*57:01. AIDS Res Hum Retroviruses, 30 Suppl 1 (S1), pp. A180-A181. | Read more

Matthews PC, Geretti AM, Goulder PJR, Klenerman P. 2014. Epidemiology and impact of HIV coinfection with hepatitis B and hepatitis C viruses in Sub-Saharan Africa. J Clin Virol, 61 (1), pp. 20-33. | Show Abstract | Read more

Human immunodeficiency virus (HIV), Hepatitis B (HBV) and Hepatitis C (HCV) are blood-borne viruses with potentially shared routes of transmission. In high-income settings, the impact of antiretroviral therapy (ART) on survival has unmasked chronic liver disease from viral hepatitis B or hepatitis C as a leading cause of morbidity and mortality in individuals with HIV infection. It is now feared that progressive liver disease may threaten the success of ART programmes in developing countries, where HCV or HBV testing and monitoring are not yet systematic among HIV-infected patients and ART use is generally blind to these co-infections. We set out to review recent data from Sub-Saharan Africa, in order to build a detailed and up-to-date picture of the epidemiology and emerging impact of HBV and HCV coinfection in countries at the heart of the HIV pandemic. There is a preponderance of HIV/HBV coinfection compared to HIV/HCV in this region, and significant caveats exist regarding the accuracy of published HCV seroprevalence surveys. Morbidity and mortality of coinfection is significant, and may be further enhanced in African populations due to the influence of host, viral and environmental factors. Careful scrutiny of the coinfection problem is vital to inform an approach to directing resources, planning public health initiatives, providing clinical care, and guiding future research.

Matthews PC, Malik A, Simmons R, Sharp C, Simmonds P, Klenerman P. 2014. PARV4: an emerging tetraparvovirus. PLoS Pathog, 10 (5), pp. e1004036. | Read more

Matthews PC, Wangrangsimakul T, Borthwick M, Williams C, Byren I, Wilkinson D. 2014. Electronic prescribing: Reducing delay to first dose of antibiotics for patients in intensive care. BMJ Qual Improv Rep, 2 (2), pp. u202241.w1120-u202241.w1120. | Show Abstract | Read more

Delays in antibiotic therapy in the context of severe sepsis are associated with increased mortality. One way to reduce such delays may be through modifications to electronic prescribing (EP) systems. The research team evaluated the role of one such EP system in reducing delays in antibiotic administration in an Intensive Care Unit (ICU). First, the delays in antibiotic administration in adult ICU patients was quantified. The EP system was then modified to remove deafult time settings for antibiotic doses, which ensured that all antibiotic doses were scheduled for administration within an hour of the prescription being generated. Enhanced training for clinicians and nurses was also implemented, focusing on the EP system and highlighting the importance of prompt antimicrobial prescribing and delivery to the patient. The antibiotic administration was re-audited, and a significant reduction in delays (p=0.002, Mann-Whitney U test) was found. This study demonstrates how prudent use of EP systems can help to reduce delays in antibiotic administration in an ICU setting, thus potentially contributing to reducing mortality in patients with sepsis.

Payne RP, Branch S, Kløverpris H, Matthews PC, Koofhethile CK, Strong T, Adland E, Leitman E, Frater J, Ndung'u T et al. 2014. Differential escape patterns within the dominant HLA-B*57:03-restricted HIV Gag epitope reflect distinct clade-specific functional constraints. J Virol, 88 (9), pp. 4668-4678. | Show Abstract | Read more

UNLABELLED: HLA-B*57:01 and HLA-B*57:03, the most prevalent HLA-B*57 subtypes in Caucasian and African populations, respectively, are the HLA alleles most protective against HIV disease progression. Understanding the mechanisms underlying this immune control is of critical importance, yet they remain unclear. Unexplained differences are observed in the impact of the dominant cytotoxic T lymphocyte (CTL) response restricted by HLA-B*57:01 and HLA-B*57:03 in chronic infection on the Gag epitope KAFSPEVIPMF (KF11; Gag 162 to 172). We previously showed that the HLA-B*57:03-KF11 response is associated with a >1-log-lower viral setpoint in C clade virus infection and that this response selects escape mutants within the epitope. We first examined the relationship of KF11 responses in B clade virus-infected subjects with HLA-B*57:01 to immune control and observed that a detectable KF11 response was associated with a >1-log-higher viral load (P = 0.02). No evidence of HLA-B*57:01-KF11-associated selection pressure was identified in previous comprehensive analyses of >1,800 B clade virus-infected subjects. We then studied a B clade virus-infected cohort in Barbados, where HLA-B*57:03 is highly prevalent. In contrast to findings for B clade virus-infected subjects expressing HLA-B*57:01, we observed strong selection pressure driven by the HLA-B*57:03-KF11 response for the escape mutation S173T. This mutation reduces recognition of virus-infected cells by HLA-B*57:03-KF11 CTLs and is associated with a >1-log increase in viral load in HLA-B*57:03-positive subjects (P = 0.009). We demonstrate functional constraints imposed by HIV clade relating to the residue at Gag 173 that explain the differential clade-specific escape patterns in HLA-B*57:03 subjects. Further studies are needed to evaluate the role of the KF11 response in HLA-B*57:01-associated HIV disease protection. IMPORTANCE: HLA-B*57 is the HLA class I molecule that affords the greatest protection against disease progression in HIV infection. Understanding the key mechanism(s) underlying immunosuppression of HIV is of importance in guiding therapeutic and vaccine-related approaches to improve the levels of HIV control occurring in nature. Numerous mechanisms have been proposed to explain the HLA associations with differential HIV disease outcome, but no consensus exists. These studies focus on two subtypes of HLA-B*57 prevalent in Caucasian and African populations, HLA-B*57:01 and HLA-B*57:03, respectively. These alleles appear equally protective against HIV disease progression. The CTL epitopes presented are in many cases identical, and the dominant response in chronic infection in each case is to the Gag epitope KF11. However, there the similarity ends. This study sought to better understand the reasons for these differences and what they teach us about which immune responses contribute to immune control of HIV infection.

Cited:

45

Scopus

Matthews PC, Geretti AM, Goulder PJR, Klenerman P. 2014. Epidemiology and impact of HIV coinfection with Hepatitis B and Hepatitis C viruses in Sub-Saharan Africa Journal of Clinical Virology, 61 (1), pp. 20-33. | Show Abstract | Read more

Human immunodeficiency virus (HIV), Hepatitis B (HBV) and Hepatitis C (HCV) are blood-borne viruses with potentially shared routes of transmission. In high-income settings, the impact of antiretroviral therapy (ART) on survival has unmasked chronic liver disease from viral hepatitis B or hepatitis C as a leading cause of morbidity and mortality in individuals with HIV infection. It is now feared that progressive liver disease may threaten the success of ART programmes in developing countries, where HCV or HBV testing and monitoring are not yet systematic among HIV-infected patients and ART use is generally blind to these co-infections. We set out to review recent data from Sub-Saharan Africa, in order to build a detailed and up-to-date picture of the epidemiology and emerging impact of HBV and HCV coinfection in countries at the heart of the HIV pandemic. There is a preponderance of HIV/HBV coinfection compared to HIV/HCV in this region, and significant caveats exist regarding the accuracy of published HCV seroprevalence surveys. Morbidity and mortality of coinfection is significant, and may be further enhanced in African populations due to the influence of host, viral and environmental factors. Careful scrutiny of the coinfection problem is vital to inform an approach to directing resources, planning public health initiatives, providing clinical care, and guiding future research. © 2014 Elsevier B.V.

Matthews PC, Chue AL, Wyllie D, Barnett A, Isinkaye T, Jefferies L, Lovering A, Scarborough M. 2014. Increased teicoplanin doses are associated with improved serum levels but not drug toxicity Journal of Infection, 68 (1), pp. 43-49. | Show Abstract | Read more

Objective: Teicoplanin is widely used for the treatment of severe gram-positive infection, aiming to achieve trough serum levels of 20-60mg/L for patients with severe infection. A standard 400mg daily dose is frequently associated with sub-therapeutic levels, and we have therefore changed our routine approach to 600mg daily (following loading doses in each case). We set out to investigate the impact of this dose increase on drug levels and potential side-effects. Methods: We undertook a retrospective study of 549 consecutive adult Out-Patient Antimicrobial Treatment (OPAT) episodes treated with intravenous teicoplanin. Results: Therapeutic teicoplanin levels were more frequently achieved in patients treated with 600mg compared to 400mg daily (68% vs. 37% respectively, p < 0.0001), without an increased frequency of potentially toxic levels, defined as > 60mg/L (6% vs. 8% respectively, p=0.4). There was no difference in the incidence of neutropaenia, eosinophilia, thrombocytopaenia, acute renal injury or treatment cessation in patients treated with the higher teicoplanin dose. Conclusions: In the majority of stable adult patients with normal renal function, we advocate a loading regimen (600mg b.d. for two doses) followed by a 600mg daily teicoplanin dose in order to achieve therapeutic trough levels. © 2013 The British Infection Association.

Kløverpris HN, Adland E, Koyanagi M, Stryhn A, Harndahl M, Matthews PC, Shapiro R, Walker BD, Ndung'u T, Brander C et al. 2014. HIV subtype influences HLA-B*07:02-associated HIV disease outcome. AIDS Res Hum Retroviruses, 30 (5), pp. 468-475. | Show Abstract | Read more

Genetic polymorphisms within the MHC encoding region have the strongest impact on HIV disease progression of any in the human genome and provide important clues to the mechanisms of HIV immune control. Few analyses have been undertaken of HLA alleles associated with rapid disease progression. HLA-B*07:02 is an HLA class I molecule that is prevalent in most populations worldwide and that has previously been consistently linked to accelerated disease progression in B-clade infection. This study investigates the observation that HLA-B*07:02 is not associated with a high viral setpoint in C-clade infection. We examine the hypothesis that this clade-specific difference in association with disease outcome may be related to distinct targeting of CD8(+) T cell epitopes. We observed that C-clade-infected individuals with HLA-B*07:02 target a broader range of Gag epitopes, and to higher magnitudes, than do individuals infected with B-clade infection. In particular, a novel p17-Gag (Gag22-30, RPGGKKHYM) epitope is targeted in >50% of HLA-B*07:02-positive C-clade-infected individuals but clade-specific differences in this epitope result in nonimmunogenicity in B-clade infection. Only the C-clade p24-Gag "GL9" (Gag355-363, GPSHKARVL) epitope-specific CD8(+) T cell response out of 16 studied was associated with a low viral setpoint. Although this epitope was also targeted in B-clade infection, the escape mutant S357S is present at higher frequency in B-clade infection than in C-clade infection (70% versus 43% in HLA-B*07:02-negative subjects). These data support earlier studies suggesting that increased breadth of the Gag-specific CD8(+) T cell response may contribute to improved HIV immune control irrespective of the particular HLA molecules expressed.

Matthews PC, Chue AL, Wyllie D, Barnett A, Isinkaye T, Jefferies L, Lovering A, Scarborough M. 2014. Increased teicoplanin doses are associated with improved serum levels but not drug toxicity. J Infect, 68 (1), pp. 43-49. | Show Abstract | Read more

OBJECTIVE: Teicoplanin is widely used for the treatment of severe gram-positive infection, aiming to achieve trough serum levels of 20-60 mg/L for patients with severe infection. A standard 400 mg daily dose is frequently associated with sub-therapeutic levels, and we have therefore changed our routine approach to 600 mg daily (following loading doses in each case). We set out to investigate the impact of this dose increase on drug levels and potential side-effects. METHODS: We undertook a retrospective study of 549 consecutive adult Out-Patient Antimicrobial Treatment (OPAT) episodes treated with intravenous teicoplanin. RESULTS: Therapeutic teicoplanin levels were more frequently achieved in patients treated with 600 mg compared to 400 mg daily (68% vs. 37% respectively, p < 0.0001), without an increased frequency of potentially toxic levels, defined as >60 mg/L (6% vs. 8% respectively, p = 0.4). There was no difference in the incidence of neutropaenia, eosinophilia, thrombocytopaenia, acute renal injury or treatment cessation in patients treated with the higher teicoplanin dose. CONCLUSIONS: In the majority of stable adult patients with normal renal function, we advocate a loading regimen (600 mg b.d. for two doses) followed by a 600 mg daily teicoplanin dose in order to achieve therapeutic trough levels.

Adland E, Carlson JM, Paioni P, Kløverpris H, Shapiro R, Ogwu A, Riddell L, Luzzi G, Chen F, Balachandran T et al. 2013. Nef-specific CD8+ T cell responses contribute to HIV-1 immune control. PLoS One, 8 (9), pp. e73117. | Show Abstract | Read more

Recent studies in the SIV-macaque model of HIV infection suggest that Nef-specific CD8+ T-cell responses may mediate highly effective immune control of viraemia. In HIV infection Nef recognition dominates in acute infection, but in large cohort studies of chronically infected subjects, breadth of T cell responses to Nef has not been correlated with significant viraemic control. Improved disease outcomes have instead been associated with targeting Gag and, in some cases, Pol. However analyses of the breadth of Nef-specific T cell responses have been confounded by the extreme immunogenicity and multiple epitope overlap within the central regions of Nef, making discrimination of distinct responses impossible via IFN-gamma ELISPOT assays. Thus an alternative approach to assess Nef as an immune target is needed. Here, we show in a cohort of >700 individuals with chronic C-clade infection that >50% of HLA-B-selected polymorphisms within Nef are associated with a predicted fitness cost to the virus, and that HLA-B alleles that successfully drive selection within Nef are those linked with lower viral loads. Furthermore, the specific CD8+ T cell epitopes that are restricted by protective HLA Class I alleles correspond substantially to effective SIV-specific epitopes in Nef. Distinguishing such individual HIV-specific responses within Nef requires specific peptide-MHC I tetramers. Overall, these data suggest that CD8+ T cell targeting of certain specific Nef epitopes contributes to HIV suppression. These data suggest that a re-evaluation of the potential use of Nef in HIV T-cell vaccine candidates would be justified.

Matthews PC, Listgarten J, Carlson JM, Payne R, Huang K-HG, Frater J, Goedhals D, Steyn D, van Vuuren C, Paioni P et al. 2012. Co-operative additive effects between HLA alleles in control of HIV-1. PLoS One, 7 (10), pp. e47799. | Show Abstract | Read more

BACKGROUND: HLA class I genotype is a major determinant of the outcome of HIV infection, and the impact of certain alleles on HIV disease outcome is well studied. Recent studies have demonstrated that certain HLA class I alleles that are in linkage disequilibrium, such as HLA-A*74 and HLA-B*57, appear to function co-operatively to result in greater immune control of HIV than mediated by either single allele alone. We here investigate the extent to which HLA alleles--irrespective of linkage disequilibrium--function co-operatively. METHODOLOGY/PRINCIPAL FINDINGS: We here refined a computational approach to the analysis of >2000 subjects infected with C-clade HIV first to discern the individual effect of each allele on disease control, and second to identify pairs of alleles that mediate 'co-operative additive' effects, either to improve disease suppression or to contribute to immunological failure. We identified six pairs of HLA class I alleles that have a co-operative additive effect in mediating HIV disease control and four hazardous pairs of alleles that, occurring together, are predictive of worse disease outcomes (q<0.05 in each case). We developed a novel 'sharing score' to quantify the breadth of CD8+ T cell responses made by pairs of HLA alleles across the HIV proteome, and used this to demonstrate that successful viraemic suppression correlates with breadth of unique CD8+ T cell responses (p = 0.03). CONCLUSIONS/SIGNIFICANCE: These results identify co-operative effects between HLA Class I alleles in the control of HIV-1 in an extended Southern African cohort, and underline complementarity and breadth of the CD8+ T cell targeting as one potential mechanism for this effect.

Matthews PC, Koyanagi M, Kløverpris HN, Harndahl M, Stryhn A, Akahoshi T, Gatanaga H, Oka S, Juarez Molina C, Valenzuela Ponce H et al. 2012. Differential clade-specific HLA-B*3501 association with HIV-1 disease outcome is linked to immunogenicity of a single Gag epitope. J Virol, 86 (23), pp. 12643-12654. | Show Abstract | Read more

The strongest genetic influence on immune control in HIV-1 infection is the HLA class I genotype. Rapid disease progression in B-clade infection has been linked to HLA-B*35 expression, in particular to the less common HLA-B*3502 and HLA-B*3503 subtypes but also to the most prevalent subtype, HLA-B*3501. In these studies we first demonstrated that whereas HLA-B*3501 is associated with a high viral set point in two further B-clade-infected cohorts, in Japan and Mexico, this association does not hold in two large C-clade-infected African cohorts. We tested the hypothesis that clade-specific differences in HLA associations with disease outcomes may be related to distinct targeting of critical CD8(+) T-cell epitopes. We observed that only one epitope was significantly targeted differentially, namely, the Gag-specific epitope NPPIPVGDIY (NY10, Gag positions 253 to 262) (P = 2 × 10(-5)). In common with two other HLA-B*3501-restricted epitopes, in Gag and Nef, that were not targeted differentially, a response toward NY10 was associated with a significantly lower viral set point. Nonimmunogenicity of NY10 in B-clade-infected subjects derives from the Gag-D260E polymorphism present in ∼90% of B-clade sequences, which critically reduces recognition of the Gag NY10 epitope. These data suggest that in spite of any inherent HLA-linked T-cell receptor repertoire differences that may exist, maximizing the breadth of the Gag-specific CD8(+) T-cell response, by the addition of even a single epitope, may be of overriding importance in achieving immune control of HIV infection. This distinction is of direct relevance to development of vaccines designed to optimize the anti-HIV CD8(+) T-cell response in all individuals, irrespective of HLA type.

Kloverpris HN, Stryhn A, Harndahl M, van der Stok M, Payne RP, Matthews PC, Chen F, Riddell L, Walker BD, Ndung'u T et al. 2012. HLA-B*57 Micropolymorphism shapes HLA allele-specific epitope immunogenicity, selection pressure, and HIV immune control. J Virol, 86 (2), pp. 919-929. | Show Abstract | Read more

The genetic polymorphism that has the greatest impact on immune control of human immunodeficiency virus (HIV) infection is expression of HLA-B*57. Understanding of the mechanism for this strong effect remains incomplete. HLA-B*57 alleles and the closely related HLA-B*5801 are often grouped together because of their similar peptide-binding motifs and HIV disease outcome associations. However, we show here that the apparently small differences between HLA-B*57 alleles, termed HLA-B*57 micropolymorphisms, have a significant impact on immune control of HIV. In a study cohort of >2,000 HIV C-clade-infected subjects from southern Africa, HLA-B*5703 is associated with a lower viral-load set point than HLA-B*5702 and HLA-B*5801 (medians, 5,980, 15,190, and 19,000 HIV copies/ml plasma; P = 0.24 and P = 0.0005). In order to better understand these observed differences in HLA-B*57/5801-mediated immune control of HIV, we undertook, in a study of >1,000 C-clade-infected subjects, a comprehensive analysis of the epitopes presented by these 3 alleles and of the selection pressure imposed on HIV by each response. In contrast to previous studies, we show that each of these three HLA alleles is characterized both by unique CD8(+) T-cell specificities and by clear-cut differences in selection pressure imposed on the virus by those responses. These studies comprehensively define for the first time the CD8(+) T-cell responses and immune selection pressures for which these protective alleles are responsible. These findings are consistent with HLA class I alleles mediating effective immune control of HIV through the number of p24 Gag-specific CD8(+) T-cell responses generated that can drive significant selection pressure on the virus.

Matthews PC, Lazarus R, Protheroe A, Milford C, Bowler ICJW. 2011. Acute necrotizing sinusitis caused by Staphylococcus lugdunensis. J Clin Microbiol, 49 (7), pp. 2740-2742. | Show Abstract | Read more

Staphylococcus lugdunensis is most commonly associated with infections arising from the inguinal region, but here we report this organism as a cause of bacterial sinusitis, highlighting its potential niche as a commensal of the upper airways. The severity of necrosis demonstrates the potential for destructive pathology mimicking Staphylococcus aureus disease.

Matthews PC, Leslie AJ, Katzourakis A, Crawford H, Payne R, Prendergast A, Power K, Kelleher AD, Klenerman P, Carlson J et al. 2011. HLA Footprints on Human Immunodeficiency Virus Type 1 Are Associated with Interclade Polymorphisms and Intraclade Phylogenetic Clustering (vol 83, pg 4605, 2009) JOURNAL OF VIROLOGY, 85 (9), pp. 4635-4635. | Read more

Matthews PC, Adland E, Listgarten J, Leslie A, Mkhwanazi N, Carlson JM, Harndahl M, Stryhn A, Payne RP, Ogwu A et al. 2011. HLA-A*7401-mediated control of HIV viremia is independent of its linkage disequilibrium with HLA-B*5703. J Immunol, 186 (10), pp. 5675-5686. | Show Abstract | Read more

The potential contribution of HLA-A alleles to viremic control in chronic HIV type 1 (HIV-1) infection has been relatively understudied compared with HLA-B. In these studies, we show that HLA-A*7401 is associated with favorable viremic control in extended southern African cohorts of >2100 C-clade-infected subjects. We present evidence that HLA-A*7401 operates an effect that is independent of HLA-B*5703, with which it is in linkage disequilibrium in some populations, to mediate lowered viremia. We describe a novel statistical approach to detecting additive effects between class I alleles in control of HIV-1 disease, highlighting improved viremic control in subjects with HLA-A*7401 combined with HLA-B*57. In common with HLA-B alleles that are associated with effective control of viremia, HLA-A*7401 presents highly targeted epitopes in several proteins, including Gag, Pol, Rev, and Nef, of which the Gag epitopes appear immunodominant. We identify eight novel putative HLA-A*7401-restricted epitopes, of which three have been defined to the optimal epitope. In common with HLA-B alleles linked with slow progression, viremic control through an HLA-A*7401-restricted response appears to be associated with the selection of escape mutants within Gag epitopes that reduce viral replicative capacity. These studies highlight the potentially important contribution of an HLA-A allele to immune control of HIV infection, which may have been concealed by a stronger effect mediated by an HLA-B allele with which it is in linkage disequilibrium. In addition, these studies identify a factor contributing to different HIV disease outcomes in individuals expressing HLA-B*5703.

Matthews DR, Matthews PC. 2011. Banting Memorial Lecture: reply from Matthews and Matthews. Type2 diabetes as an 'infectious'disease: is this the Black Death of the 21st century? Diabet Med, 28 (7), pp. 880. | Read more

Matthews DR, Matthews PC. 2011. Banting Memorial Lecture 2010^. Type 2 diabetes as an 'infectious' disease: is this the Black Death of the 21st century? Diabet Med, 28 (1), pp. 2-9. | Show Abstract | Read more

We are currently facing a global pandemic of obesity and Type 2 diabetes. In some settings, the population prevalence of Type 2 diabetes is 50%, and half of those affected will die from diabetes-related complications. Eight centuries ago, an epidemic of bubonic plague swept across Europe, killing at least half of its victims. We here draw comparisons between these two pandemics, proposing close analogies between the 'Black Death' of the 14th century and the modern-day equivalent of Type 2 diabetes. Both diseases can be considered in terms of an aetiological agent, a reservoir, a vector and a predisposing toxic environment; populations can be considered as highly susceptible to the transmissable agents of Type 2 diabetes in the setting of calorie excess, inadequate food labelling, poorly regulated advertising and sedentary lifestyles. As for tackling a pandemic of a contagious microbial pathogen, we believe that breaking the cycle of transmission in the diabetes epidemic must be underpinned by political will and prompt, decisive legislation backed by the medical community. Far from fearing that such measures edge us towards a 'nanny state', we believe individuals should expect a responsible government to safeguard them from the toxic milieu that puts them at risk of obesity and its complications, and that communities and populations have the right to have their health protected.

Crawford H, Matthews PC, Schaefer M, Carlson JM, Leslie A, Kilembe W, Allen S, Ndung'u T, Heckerman D, Hunter E, Goulder PJR. 2011. The hypervariable HIV-1 capsid protein residues comprise HLA-driven CD8+ T-cell escape mutations and covarying HLA-independent polymorphisms. J Virol, 85 (3), pp. 1384-1390. | Show Abstract | Read more

One proposed HIV vaccine strategy is to induce Gag-specific CD8(+) T-cell responses that can corner the virus, through fitness cost of viral escape and unavailability of compensatory mutations. We show here that the most variable capsid residues principally comprise escape mutants driven by protective alleles HLA-B*57, -5801, and -8101 and covarying HLA-independent polymorphisms that arise in conjunction with these escape mutations. These covarying polymorphisms are potentially compensatory and are concentrated around three tropism-determining loops of p24, suggesting structural interdependencies. Our results demonstrate complex patterns of adaptation of HIV under immune selection pressure, the understanding of which should aid vaccine design.

Leslie A, Matthews PC, Listgarten J, Carlson JM, Kadie C, Ndung'u T, Brander C, Coovadia H, Walker BD, Heckerman D, Goulder PJR. 2010. Additive contribution of HLA class I alleles in the immune control of HIV-1 infection. J Virol, 84 (19), pp. 9879-9888. | Show Abstract | Read more

Previous studies have identified a central role for HLA-B alleles in influencing control of HIV infection. An alternative possibility is that a small number of HLA-B alleles may have a very strong impact on HIV disease outcome, dominating the contribution of other HLA alleles. Here, we find that even following the exclusion of subjects expressing any of the HLA-B class I alleles (B*57, B*58, and B*18) identified to have the strongest influence on control, the dominant impact of HLA-B alleles on virus set point and absolute CD4 count variation remains significant. However, we also find that the influence of HLA on HIV control in this C-clade-infected cohort from South Africa extends beyond HLA-B as HLA-Cw type remains a significant predictor of virus and CD4 count following exclusion of the strongest HLA-B associations. Furthermore, there is evidence of interdependent protective effects of the HLA-Cw*0401-B*8101, HLA-Cw*1203-B*3910, and HLA-A*7401-B*5703 haplotypes that cannot be explained solely by linkage to a protective HLA-B allele. Analysis of individuals expressing both protective and detrimental alleles shows that even the strongest HLA alleles appear to have an additive rather than dominant effect on HIV control at the individual level. Finally, weak but significant frequency-dependent effects in this cohort can be detected only by looking at an individual's combined HLA allele frequencies. Taken together, these data suggest that although individual HLA alleles, particularly HLA-B, can have a strong impact, HIV control overall is likely to be influenced by the additive effect of some or all of the other HLA alleles present.

Matthews P, Prendergast A, Kawashima Y, Pfafferott K, Frater J, Heckerman D, Takiguchi M, Goulder P. 2009. INTER-CONTINENTAL PATTERNS OF HIV-1 CONTROL: HLA AND THE QUEST FOR A T CELL VACCINE JOURNAL OF INFECTION, 59 (6), pp. S430-S431.

Matthews PC, Berendt AR, McNally MA, Byren I. 2009. Diagnosis and management of prosthetic joint infection. BMJ, 338 (may29 1), pp. b1773. | Read more

Matthews PC, Leslie AJ, Katzourakis A, Crawford H, Payne R, Prendergast A, Power K, Kelleher AD, Klenerman P, Carlson J et al. 2009. HLA footprints on human immunodeficiency virus type 1 are associated with interclade polymorphisms and intraclade phylogenetic clustering. J Virol, 83 (9), pp. 4605-4615. | Show Abstract | Read more

The selection of escape mutations has a major impact on immune control of infections with viruses such as human immunodeficiency virus (HIV). Viral evasion of CD8(+) T-cell responses leaves predictable combinations of escape mutations, termed HLA "footprints." The most clearly defined footprints are those associated with HLA alleles that are linked with successful control of HIV, such as HLA-B*57. Here we investigated the extent to which HLA footprint sites in HIV type 1 (HIV-1) are associated with viral evolution among and within clades. First, we examined the extent to which amino acid differences between HIV-1 clades share identity with sites of HLA-mediated selection pressure and observed a strong association, in particular with respect to sites of HLA-B selection (P < 10(-6)). Similarly, the sites of amino acid variability within a clade were found to overlap with sites of HLA-selected mutation. Second, we studied the impact of HLA selection on interclade phylogeny. Removing the sites of amino acid variability did not significantly affect clade-specific clustering, reflecting the central role of founder effects in establishing distinct clades. However, HLA footprints may underpin founder strains, and we show that amino acid substitutions between clades alter phylogeny, underlining a potentially substantial role for HLA in driving ongoing viral evolution. Finally, we investigated the impact of HLA selection on within-clade phylogeny and demonstrate that even a single HLA allele footprint can result in significant phylogenetic clustering of sequences. In conclusion, these data highlight the fact that HLA can be a strong selection force for both intra- and interclade HIV evolution at a population level.

Kawashima Y, Pfafferott K, Frater J, Matthews P, Payne R, Addo M, Gatanaga H, Fujiwara M, Hachiya A, Koizumi H et al. 2009. Adaptation of HIV-1 to human leukocyte antigen class I. Nature, 458 (7238), pp. 641-645. | Show Abstract | Read more

The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host-pathogen co-evolution involving humans. A focal point is the interaction between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8(+) T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection. Mutation within these epitopes can allow viral escape from CD8(+) T-cell recognition. Here we analysed viral sequences and HLA alleles from >2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128-135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts (P = 0.0001). Extending these analyses to incorporate other well-defined CD8(+) T-cell epitopes, including those restricted by HLA-B*57 and HLA-B*27, showed that the frequency of these epitope variants (n = 14) was consistently correlated with the prevalence of the restricting HLA allele in the different cohorts (together, P < 0.0001), demonstrating strong evidence of HIV adaptation to HLA at a population level. This process of viral adaptation may dismantle the well-established HLA associations with control of HIV infection that are linked to the availability of key epitopes, and highlights the challenge for a vaccine to keep pace with the changing immunological landscape presented by HIV.

English S, Katzourakis A, Flanagan P, Duda A, Francis J, Matthews P, Prendergast A, Goulder P, Fidler S, Weber J et al. 2009. Contemporaneous transmission of genetically distinct HIV variants from a single donor to two recipients RETROVIROLOGY, 6

Payne RP, Matthews PC, Prado JG, Goulder PJR. 2009. Chapter 1 HLA-Mediated Control of HIV and HIV Adaptation to HLA Advances in Parasitology, 68 pp. 1-20. | Show Abstract | Read more

The human immunodeficiency virus (HIV) epidemic provides a rare opportunity to examine in detail the initial stages of a host-pathogen co-evolutionary struggle in humans. The genes encoding the human leukocyte antigen (HLA) class I molecules have a critical influence in the success or failure of the immune response against HIV. The particular HLA class I molecules expressed by each individual defines the type of cytotoxic T-lymphocyte (CTL) response that is made against the virus. This chapter describes the role of HLA class I and the CTL response in controlling HIV replication, and discusses the extent to which HIV has already adapted to those HLA class I molecules and CTL responses that are most effective in viral suppression. It is evident that viral mutations that enable HIV to evade the CTL response are indeed already accumulating in populations where the selecting HLA molecules are highly prevalent, indicating the dynamic and shifting nature of the evolutionary interplay between HIV and human populations. © 2009 Elsevier Ltd. All rights reserved.

Bansal A, Carlson J, Matthews P, Akinsiku O, Yan J, Sabbaj S, Heath S, Goulder P, Heckerman D, Goepfert P. 2009. Cryptic CTL epitopes derived from antisense transcription are frequently recognized in HIV-1 infection RETROVIROLOGY, 6

Hempel U, Buranapraditkun S, Chatkulkawin P, Pitakpolrat P, Phillips LC, Allgaier RL, Lorenzen S, Hildebrand WH, Leitner T, Matthews P et al. 2009. HLA-B1302 is associated with viral control in clade CRF01_AE HIV-1 infection in Thailand RETROVIROLOGY, 6

Payne RP, Matthews PC, Prado JG, Goulder PJR. 2009. HLA-mediated control of HIV and HIV adaptation to HLA. Adv Parasitol, 68 pp. 1-20. | Show Abstract | Read more

The human immunodeficiency virus (HIV) epidemic provides a rare opportunity to examine in detail the initial stages of a host-pathogen co-evolutionary struggle in humans. The genes encoding the human leukocyte antigen (HLA) class I molecules have a critical influence in the success or failure of the immune response against HIV. The particular HLA class I molecules expressed by each individual defines the type of cytotoxic T-lymphocyte (CTL) response that is made against the virus. This chapter describes the role of HLA class I and the CTL response in controlling HIV replication, and discusses the extent to which HIV has already adapted to those HLA class I molecules and CTL responses that are most effective in viral suppression. It is evident that viral mutations that enable HIV to evade the CTL response are indeed already accumulating in populations where the selecting HLA molecules are highly prevalent, indicating the dynamic and shifting nature of the evolutionary interplay between HIV and human populations.

Hempel U, Buranapraditkun S, Chatkulkawin P, Pitakpolrat P, Phillips LC, Allgaier RL, Lorenzen S, Hildebrand WH, Leitner T, Matthews P et al. 2009. P16-07. HLA-B1302 is associated with viral control in clade CRF01_AE HIV-1 infection in Thailand Retrovirology, 6 (Suppl 3), pp. P236-P236. | Read more

English S, Katzourakis A, Flanagan P, Duda A, Francis J, Matthews P, Prendergast A, Goulder P, Fidler S, Weber J et al. 2009. P07-09. Contemporaneous transmission of genetically distinct HIV variants from a single donor to two recipients Retrovirology, 6 (Suppl 3), pp. P107-P107. | Read more

Matthews PC, Missouris CG, Jordaan J, Lessing MPA. 2008. Staphylococcus lugdunensis endocarditis following cardiac catheterisation. Int J Cardiol, 130 (1), pp. 87-88. | Show Abstract | Read more

We report the case of a 77 year old with Staphylococcus lugdunensis endocarditis following cardiac catheterisation via a femoral approach. We underline the association between this pathogen and inguinal skin breaks, and discuss the potential diagnostic pitfalls in clinical and laboratory diagnosis.

Matthews PC, Jeans A, Squier W, Kini U, Byren I, Atkins BL. 2008. Muscle hemorrhage in a paraplegic adult with neurofibromatosis type 1 and an associated vasculopathy. Am J Med Genet A, 146A (18), pp. 2424-2426. | Read more

Matthews PC, Dean BJF, Medagoda K, Gundle R, Atkins BL, Berendt AR, Byren I. 2008. Native hip joint septic arthritis in 20 adults: delayed presentation beyond three weeks predicts need for excision arthroplasty. J Infect, 57 (3), pp. 185-190. | Show Abstract | Read more

OBJECTIVES: Septic arthritis of native hip joints is an uncommon condition in adults in Western Europe, but continues to present a challenge to medical and surgical management. We set out to study the natural history and bacteriology of the disease in this group, with a particular focus on patients requiring excision arthroplasty (EA). METHODS: We retrospectively studied 26 secondary referral cases (20 adults) managed by a specialist bone infection unit over a 12 year period. RESULTS: Our patient cohort was diverse, affecting all age groups in the presence and absence of co-morbid conditions. The commonest pathogen was Staphylococcus aureus. Of 20 adults studied, five (25%) required EA. Symptom duration prior to presentation was a statistical predictor of the requirement for EA (p<0.003); in particular, symptom duration of over three weeks was strongly associated with requirement for this procedure (p<0.0003). CONCLUSIONS: In cases that present promptly, combined surgical drainage and intravenous antibiotics should be expected to eradicate infection and to salvage the femoral head. Cases presenting following a delay are more likely to require EA and subsequent hip reconstruction.

Matthews PC, Jeans A, Squier W, Kini U, Byren I, Atkins BL. 2008. Muscle hemorrhage in a paraplegic adult with neurofibromatosis type 1 and an associated vasculopathy American Journal of Medical Genetics, Part A, 146 (18), pp. 2424-2426. | Read more

Carlson JM, Brumme ZL, Rousseau CM, Brumme CJ, Matthews P, Kadie C, Mullins JI, Walker BD, Harrigan PR, Goulder PJR, Heckerman D. 2008. Phylogenetic dependency networks: inferring patterns of CTL escape and codon covariation in HIV-1 Gag. PLoS Comput Biol, 4 (11), pp. e1000225. | Show Abstract | Read more

HIV avoids elimination by cytotoxic T-lymphocytes (CTLs) through the evolution of escape mutations. Although there is mounting evidence that these escape pathways are broadly consistent among individuals with similar human leukocyte antigen (HLA) class I alleles, previous population-based studies have been limited by the inability to simultaneously account for HIV codon covariation, linkage disequilibrium among HLA alleles, and the confounding effects of HIV phylogeny when attempting to identify HLA-associated viral evolution. We have developed a statistical model of evolution, called a phylogenetic dependency network, that accounts for these three sources of confounding and identifies the primary sources of selection pressure acting on each HIV codon. Using synthetic data, we demonstrate the utility of this approach for identifying sites of HLA-mediated selection pressure and codon evolution as well as the deleterious effects of failing to account for all three sources of confounding. We then apply our approach to a large, clinically-derived dataset of Gag p17 and p24 sequences from a multicenter cohort of 1144 HIV-infected individuals from British Columbia, Canada (predominantly HIV-1 clade B) and Durban, South Africa (predominantly HIV-1 clade C). The resulting phylogenetic dependency network is dense, containing 149 associations between HLA alleles and HIV codons and 1386 associations among HIV codons. These associations include the complete reconstruction of several recently defined escape and compensatory mutation pathways and agree with emerging data on patterns of epitope targeting. The phylogenetic dependency network adds to the growing body of literature suggesting that sites of escape, order of escape, and compensatory mutations are largely consistent even across different clades, although we also identify several differences between clades. As recent case studies have demonstrated, understanding both the complexity and the consistency of immune escape has important implications for CTL-based vaccine design. Phylogenetic dependency networks represent a major step toward systematically expanding our understanding of CTL escape to diverse populations and whole viral genes.

Goepfert PA, Lumm W, Farmer P, Matthews P, Prendergast A, Carlson JM, Derdeyn CA, Tang J, Kaslow RA, Bansal A et al. 2008. Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients. J Exp Med, 205 (5), pp. 1009-1017. | Show Abstract | Read more

In a study of 114 epidemiologically linked Zambian transmission pairs, we evaluated the impact of human leukocyte antigen class I (HLA-I)-associated amino acid polymorphisms, presumed to reflect cytotoxic T lymphocyte (CTL) escape in Gag and Nef of the virus transmitted from the chronically infected donor, on the plasma viral load (VL) in matched recipients 6 mo after infection. CTL escape mutations in Gag and Nef were seen in the donors, which were subsequently transmitted to recipients, largely unchanged soon after infection. We observed a significant correlation between the number of Gag escape mutations targeted by specific HLA-B allele-restricted CTLs and reduced VLs in the recipients. This negative correlation was most evident in newly infected individuals, whose HLA alleles were unable to effectively target Gag and select for CTL escape mutations in this gene. Nef mutations in the donor had no impact on VL in the recipient. Thus, broad Gag-specific CTL responses capable of driving virus escape in the donor may be of clinical benefit to both the donor and recipient. In addition to their direct implications for HIV-1 vaccine design, these data suggest that CTL-induced viral polymorphisms and their associated in vivo viral fitness costs could have a significant impact on HIV-1 pathogenesis.

Rousseau CM, Daniels MG, Carlson JM, Kadie C, Crawford H, Prendergast A, Matthews P, Payne R, Rolland M, Raugi DN et al. 2008. HLA class I-driven evolution of human immunodeficiency virus type 1 subtype c proteome: immune escape and viral load. J Virol, 82 (13), pp. 6434-6446. | Show Abstract | Read more

Human immunodeficiency virus type 1 (HIV-1) mutations that confer escape from cytotoxic T-lymphocyte (CTL) recognition can sometimes result in lower viral fitness. These mutations can then revert upon transmission to a new host in the absence of CTL-mediated immune selection pressure restricted by the HLA alleles of the prior host. To identify these potentially critical recognition points on the virus, we assessed HLA-driven viral evolution using three phylogenetic correction methods across full HIV-1 subtype C proteomes from a cohort of 261 South Africans and identified amino acids conferring either susceptibility or resistance to CTLs. A total of 558 CTL-susceptible and -resistant HLA-amino acid associations were identified and organized into 310 immunological sets (groups of individual associations related to a single HLA/epitope combination). Mutations away from seven susceptible residues, including four in Gag, were associated with lower plasma viral-RNA loads (q < 0.2 [where q is the expected false-discovery rate]) in individuals with the corresponding HLA alleles. The ratio of susceptible to resistant residues among those without the corresponding HLA alleles varied in the order Vpr > Gag > Rev > Pol > Nef > Vif > Tat > Env > Vpu (Fisher's exact test; P < or = 0.0009 for each comparison), suggesting the same ranking of fitness costs by genes associated with CTL escape. Significantly more HLA-B (chi(2); P = 3.59 x 10(-5)) and HLA-C (chi(2); P = 4.71 x 10(-6)) alleles were associated with amino acid changes than HLA-A, highlighting their importance in driving viral evolution. In conclusion, specific HIV-1 residues (enriched in Vpr, Gag, and Rev) and HLA alleles (particularly B and C) confer susceptibility to the CTL response and are likely to be important in the development of vaccines targeted to decrease the viral load.

Matthews PC, Prendergast A, Leslie A, Crawford H, Payne R, Rousseau C, Rolland M, Honeyborne I, Carlson J, Kadie C et al. 2008. Central role of reverting mutations in HLA associations with human immunodeficiency virus set point. J Virol, 82 (17), pp. 8548-8559. | Show Abstract | Read more

Much uncertainty still exists over what T-cell responses need to be induced by an effective human immunodeficiency virus (HIV) vaccine. Previous studies have hypothesized that the effective CD8(+) T-cell responses are those driving the selection of escape mutations that reduce viral fitness and therefore revert post-transmission. In this study, we adopted a novel approach to define better the role of reverting escape mutations in immune control of HIV infection. This analysis of sequences from 710 study subjects with chronic C-clade HIV type 1 infection demonstrates the importance of mutations that impose a fitness cost in the control of viremia. Consistent with previous studies, the viral set points associated with each HLA-B allele are strongly correlated with the number of Gag-specific polymorphisms associated with the relevant HLA-B allele (r = -0.56, P = 0.0034). The viral set points associated with each HLA-C allele were also strongly correlated with the number of Pol-specific polymorphisms associated with the relevant HLA-C allele (r = -0.67, P = 0.0047). However, critically, both these correlations were dependent solely on the polymorphisms identified as reverting. Therefore, despite the inevitable evolution of viral escape, viremia can be controlled through the selection of mutations that are detrimental to viral fitness. The significance of these results is in highlighting the rationale for an HIV vaccine that can induce these broad responses.

Matthews PC, Taylor A, Byren I, Atkins BL. 2007. Teicoplanin levels in bone and joint infections: are standard doses subtherapeutic? J Infect, 55 (5), pp. 408-413. | Show Abstract | Read more

OBJECTIVES: Previously published data suggest that a trough serum teicoplanin level of > or = 20 mg/l is predictive of improved outcomes in serious staphylococcal infection. We investigated how dose regimen and patient characteristics impact on trough teicoplanin levels in patients with musculoskeletal infection, in order to help standardise teicoplanin use. METHODS: We prospectively collected data for 141 clinically stable adults with bone and joint infection treated as outpatients with teicoplanin. Patients with end stage renal failure were excluded. RESULTS: The most frequently used teicoplanin dose regimens were 400 mg or 600 mg i.v. once daily. Trough levels were available for 78% of episodes, of which 51% were > or = 20 mg/l. Unsurprisingly, a level of > or = 20 mg/l occurred more often with a dose of 600 mg than with lower doses (p=0.005). There was no significant relationship between teicoplanin level and age, body weight or creatinine clearance, but male gender was associated with lower trough levels than female gender (p=0.03). CONCLUSIONS: These data suggest that teicoplanin levels of > or = 20 mg/l for bone and joint infection in stable adult patients are best achieved with a daily dose of at least 600 mg.

Matthews PC, Conlon CP, Berendt AR, Kayley J, Jefferies L, Atkins BL, Byren I. 2007. Outpatient parenteral antimicrobial therapy (OPAT): is it safe for selected patients to self-administer at home? A retrospective analysis of a large cohort over 13 years. J Antimicrob Chemother, 60 (2), pp. 356-362. | Show Abstract | Read more

OBJECTIVES: Provision of outpatient parenteral antimicrobial therapy (OPAT) is an evolving field, facilitating discharge from hospital for selected patients with serious infections. We report on a large OPAT cohort focusing on the practice of supervised parenteral antibiotic administration in the community by patients and relatives, which we collectively term 'self-administration'. To distinguish between healthcare professional OPAT and self-administered OPAT, we have coined the terms H-OPAT and S-OPAT, respectively. PATIENTS AND METHODS: We analysed data on 2059 OPAT episodes collected prospectively over a 13 year time period from 1993 to 2005. RESULTS: Clinical diagnosis, microbiology and antibiotics in this OPAT series are comparable to those previously reported. We identified no excess complications or hospital re-admissions in the S-OPAT group compared with the H-OPAT group. CONCLUSIONS: Self-administration of intravenous antimicrobial therapy, in selected patients under the supervision of a specialist team, is a safe and feasible strategy.

Brent AJ, Matthews PC, Dance DA, Pitt TL, Handy R. 2007. Misdiagnosing melioidosis. Emerg Infect Dis, 13 (2), pp. 349-351. | Read more

Matthews PC, Berendt AR, Lipsky BA. 2007. Clinical management of diabetic foot infection: diagnostics, therapeutics and the future. Expert Rev Anti Infect Ther, 5 (1), pp. 117-127. | Show Abstract | Read more

Diabetic foot infection accounts for a substantial global burden of morbidity, psychosocial disruption and economic cost. Recommendations for best practice are continuously evolving in parallel with improvements in imaging modalities, development and clinical use of new antimicrobial agents and data surrounding novel adjunctive strategies. We discuss this complex group of infections with a particular emphasis on medical management of osteomyelitis, while also highlighting the importance of a broad multidisciplinary approach to eradicating infection.

Matthews PC, Van den Abbeele K, Dawson S, McIntyre M. 2006. HIV testing for adult patients with Streptococcus pneumoniae bacteraemia. Clin Med (Lond), 6 (5), pp. 512. | Read more

Matthews PC, Pickles J, Berry J, Salisbury JR, Barker RD, Ervine M. 2006. Airway emergency in tuberculosis. J Infect, 52 (5), pp. e147-e150. | Show Abstract | Read more

We report a case of acute fatal stridor in a patient newly diagnosed with pulmonary tuberculosis and human immunodeficiency virus (HIV) infection. No evidence of direct airway encroachment was identified at autopsy. We review mechanisms by which tuberculosis may cause stridor and discuss the implications of co-existent HIV infection with reference to the recent literature. The report highlights the need for recognition of acute or evolving airway compromise as an uncommon manifestation of tuberculosis.

Martinez-Picado J, Prado JG, Fry EE, Pfafferott K, Leslie A, Chetty S, Thobakgale C, Honeyborne I, Crawford H, Matthews P et al. 2006. Fitness cost of escape mutations in p24 Gag in association with control of human immunodeficiency virus type 1. J Virol, 80 (7), pp. 3617-3623. | Show Abstract | Read more

Mutational escape by human immunodeficiency virus (HIV) from cytotoxic T-lymphocyte (CTL) recognition is a major challenge for vaccine design. However, recent studies suggest that CTL escape may carry a sufficient cost to viral replicative capacity to facilitate subsequent immune control of a now attenuated virus. In order to examine how limitations can be imposed on viral escape, the epitope TSTLQEQIGW (TW10 [Gag residues 240 to 249]), presented by two HLA alleles associated with effective control of HIV, HLA-B*57 and -B*5801, was investigated. The in vitro experiments described here demonstrate that the dominant TW10 escape mutation, T242N, reduces viral replicative capacity. Structural analysis reveals that T242 plays a critical role in defining the start point and in stabilizing helix 6 within p24 Gag, ensuring that escape occurs at a significant cost. A very similar role is played by Thr-180, which is also an escape residue, but within a second p24 Gag epitope associated with immune control. Analysis of HIV type 1 gag in 206 B*57/5801-positive subjects reveals three principle alternative TW10-associated variants, and each is strongly linked to concomitant additional variants within p24 Gag, suggesting that functional constraints operate against their occurrence alone. The extreme conservation of p24 Gag and the predictable nature of escape variation resulting from these tight functional constraints indicate that p24 Gag may be a critical immunogen in vaccine design and suggest novel vaccination strategies to limit viral escape options from such epitopes.

Leitman EM, Willberg CB, De Burgh-Thomas A, Streeck H, Goulder PJR, Matthews PC. 2016. Subdominant Gag-specific anti-HIV efficacy in an HLA-B*57-positive elite controller. AIDS, 30 (6), pp. 972-974. | Read more

Leitman EM, Hurst J, Mori M, Kublin J, Ndung'u T, Walker BD, Carlson J, Gray GE, Matthews PC, Frahm N, Goulder PJR. 2016. Lower Viral Loads and Slower CD4+ T-Cell Count Decline in MRKAd5 HIV-1 Vaccinees Expressing Disease-Susceptible HLA-B*58:02. J Infect Dis, 214 (3), pp. 379-389. | Show Abstract | Read more

BACKGROUND: HLA strongly influences human immunodeficiency virus type 1 (HIV-1) disease progression. A major contributory mechanism is via the particular HLA-presented HIV-1 epitopes that are recognized by CD8(+) T-cells. Different populations vary considerably in the HLA alleles expressed. We investigated the HLA-specific impact of the MRKAd5 HIV-1 Gag/Pol/Nef vaccine in a subset of the infected Phambili cohort in whom the disease-susceptible HLA-B*58:02 is highly prevalent. METHODS: Viral loads, CD4(+) T-cell counts, and enzyme-linked immunospot assay-determined anti-HIV-1 CD8(+) T-cell responses for a subset of infected antiretroviral-naive Phambili participants, selected according to sample availability, were analyzed. RESULTS: Among those expressing disease-susceptible HLA-B*58:02, vaccinees had a lower chronic viral set point than placebo recipients (median, 7240 vs 122 500 copies/mL; P = .01), a 0.76 log10 lower longitudinal viremia level (P = .01), and slower progression to a CD4(+) T-cell count of <350 cells/mm(3) (P = .02). These differences were accompanied by a higher Gag-specific breadth (4.5 vs 1 responses; P = .04) and magnitude (2300 vs 70 spot-forming cells/10(6) peripheral blood mononuclear cells; P = .06) in vaccinees versus placebo recipients. CONCLUSIONS: In addition to the known enhancement of HIV-1 acquisition resulting from the MRKAd5 HIV-1 vaccine, these findings in a nonrandomized subset of enrollees show an HLA-specific vaccine effect on the time to CD4(+) T-cell count decline and viremia level after infection and the potential for vaccines to differentially alter disease outcome according to population HLA composition. CLINICAL TRIALS REGISTRATION: NCT00413725, DOH-27-0207-1539.

Matthews PC, Carlson JM, Beloukas A, Malik A, Jooste P, Ogwu A, Shapiro R, Riddell L, Chen F, Luzzi G et al. 2016. HLA-A is a Predictor of Hepatitis B e Antigen Status in HIV-Positive African Adults. J Infect Dis, 213 (8), pp. 1248-1252. | Show Abstract | Read more

Outcomes of chronic infection with hepatitis B virus (HBV) are varied, with increased morbidity reported in the context of human immunodeficiency virus (HIV) coinfection. The factors driving different outcomes are not well understood, but there is increasing interest in an HLA class I effect. We therefore studied the influence of HLA class I on HBV in an African HIV-positive cohort. We demonstrated that virologic markers of HBV disease activity (hepatitis B e antigen status or HBV DNA level) are associated with HLA-A genotype. This finding supports the role of the CD8(+) T-cell response in HBV control, and potentially informs future therapeutic T-cell vaccine strategies.

Matthews P, Beloukas A, Malik A, Carlson J, Jooste P, Ogwu A, Shapiro R, Riddell L, Chen F, Luzzi G et al. 2015. HLA CONTRIBUTES TO IMMUNE CONTROL OF HEPATITIS B IN HIV-POSITIVE AFRICAN ADULTS JOURNAL OF INFECTION, 71 (6), pp. 685-686. | Read more

Adland E, Klenerman P, Goulder P, Matthews PC. 2015. Ongoing burden of disease and mortality from HIV/CMV coinfection in Africa in the antiretroviral therapy era. Front Microbiol, 6 (SEP), pp. 1016. | Show Abstract | Read more

Human Cytomegalovirus (CMV) is a well-recognized pathogen in the context of HIV infection, but since the roll out of ART, clinical and scientific interest in the problem of HIV/CMV coinfection has diminished. However, CMV remains a significant cofactor in HIV disease, with an influence on HIV acquisition, disease progression, morbidity, and mortality. Disease manifestations may be a result of direct interplay between the two viruses, or may arise as a secondary consequence of immune dysregulation and systemic inflammation. The problem is most relevant when the rates of coinfection are high, most notably in sub-Saharan Africa, and in children at risk of acquiring both infections early in life. Understanding the interplay between these viruses and developing strategies to diagnose, treat and prevent CMV should be a priority.

Leitman EM, Hurst J, Mori M, Matthews PC, Frahm N, Kublin J, Gray GE, Goulder PJR. 2015. HLA-B*58:02-specific benefit of MRKAd5 Gag/Pol/Nef vaccine in an African population JOURNAL OF THE INTERNATIONAL AIDS SOCIETY, 18 | Read more

Brener J, Gall A, Batorsky R, Riddell L, Buus S, Leitman E, Kellam P, Allen T, Goulder P, Matthews PC. 2015. Disease progression despite protective HLA expression in an HIV-infected transmission pair Retrovirology, | Show Abstract | Read more

© 2015 Brener et al.Background: The precise immune responses mediated by HLA class I molecules such as HLA-B*27:05 and HLA-B*57:01 that protect against HIV disease progression remain unclear. We studied a CRF01_AE clade HIV infected donor-recipient transmission pair in which the recipient expressed both HLA-B*27:05 and HLA-B*57:01. Results: Within 4.5 years of diagnosis, the recipient had progressed to meet criteria for antiretroviral therapy initiation. We employed ultra-deep sequencing of the full-length virus genome in both donor and recipient as an unbiased approach by which to identify specific viral mutations selected in association with progression. Using a heat map method to highlight differences in the viral sequences between donor and recipient, we demonstrated that the majority of the recipient's mutations outside of Env were within epitopes restricted by HLA-B*27:05 and HLA-B*57:01, including the well-studied Gag epitopes. The donor, who also expressed HLA alleles associated with disease protection, HLA-A*32:01/B*13:02/B*14:01, showed selection of mutations in parallel with disease progression within epitopes restricted by these protective alleles. Conclusions: These studies of full-length viral sequences in a transmission pair, both of whom expressed protective HLA alleles but nevertheless failed to control viremia, are consistent with previous reports pointing to the critical role of Gag-specific CD8+ T cell responses restricted by protective HLA molecules in maintaining immune control of HIV infection. The transmission of subtype CRF01_AE clade infection may have contributed to accelerated disease progression in this pair as a result of clade-specific sequence differences in immunodominant epitopes.

Matthews PC. 2015. Rolling back malaria ELIFE, 4 | Read more

Matthews PC, Sharp CP, Malik A, Gregory WF, Adland E, Jooste P, Goulder PJR, Simmonds P, Klenerman P. 2015. Human parvovirus 4 infection among mothers and children in South Africa. Emerg Infect Dis, 21 (4), pp. 713-715. | Read more

Matthews PC, Beloukas A, Malik A, Carlson JM, Jooste P, Ogwu A, Shapiro R, Riddell L, Chen F, Luzzi G et al. 2015. Prevalence and Characteristics of Hepatitis B Virus (HBV) Coinfection among HIV-Positive Women in South Africa and Botswana. PLoS One, 10 (7), pp. e0134037. | Show Abstract | Read more

There is progressive concern about the evolving burden of morbidity and mortality caused by coinfection with HIV-1 and hepatitis B virus (HBV) in sub-Saharan Africa, but the epidemiology and impact of this problem are not well defined. We therefore set out to assimilate more information about the nature of HBV/HIV coinfection in this region by undertaking a retrospective observational study of southern African adult women. We used samples from previously recruited HIV-1 positive women attending antenatal clinics in three settings in South Africa and Botswana (n = 950) and added a small cohort of HIV-negative antenatal South African women for comparison (n = 72). We tested for HBsAg and followed up HBsAg-positive samples by testing for HBeAg, HBV DNA, HBV genotype, presence of drug-resistance associated mutations (RAMs) and HDV. We identified HBsAg in 72 individuals (7% of the whole cohort), of whom 27% were HBeAg-positive, and the majority HBV genotypes A1 and A2. We did not detect any HDV coinfection. HBV prevalence was significantly different between geographically distinct cohorts, but did not differ according to HIV status. Among adults from South Africa, HBV/HIV coinfected patients had lower CD4+ T cell counts compared to those with HIV-monoinfection (p = 0.02), but this finding was not replicated in the cohort from Botswana. Overall, these data provide a snapshot of the coinfection problem at the heart of the HIV/HBV co-epidemic, and are important to inform public health policy, resource allocation, education, surveillance and clinical care.

Matthews PC, Geretti AM, Goulder PJR, Klenerman P. 2014. Epidemiology and impact of HIV coinfection with hepatitis B and hepatitis C viruses in Sub-Saharan Africa. J Clin Virol, 61 (1), pp. 20-33. | Show Abstract | Read more

Human immunodeficiency virus (HIV), Hepatitis B (HBV) and Hepatitis C (HCV) are blood-borne viruses with potentially shared routes of transmission. In high-income settings, the impact of antiretroviral therapy (ART) on survival has unmasked chronic liver disease from viral hepatitis B or hepatitis C as a leading cause of morbidity and mortality in individuals with HIV infection. It is now feared that progressive liver disease may threaten the success of ART programmes in developing countries, where HCV or HBV testing and monitoring are not yet systematic among HIV-infected patients and ART use is generally blind to these co-infections. We set out to review recent data from Sub-Saharan Africa, in order to build a detailed and up-to-date picture of the epidemiology and emerging impact of HBV and HCV coinfection in countries at the heart of the HIV pandemic. There is a preponderance of HIV/HBV coinfection compared to HIV/HCV in this region, and significant caveats exist regarding the accuracy of published HCV seroprevalence surveys. Morbidity and mortality of coinfection is significant, and may be further enhanced in African populations due to the influence of host, viral and environmental factors. Careful scrutiny of the coinfection problem is vital to inform an approach to directing resources, planning public health initiatives, providing clinical care, and guiding future research.

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