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ABSTRACT: The rates of escape and reversion in response to selection pressure arising
from the host immune system, notably the cytotoxic T-lymphocyte (CTL) response,
are key factors determining the evolution of HIV. Existing methods for
estimating these parameters from cross-sectional population data using ordinary
differential equations (ODE) ignore information about the genealogy of sampled
HIV sequences, which has the potential to cause systematic bias and
over-estimate certainty. Here, we describe an integrated approach, validated
through extensive simulations, which combines genealogical inference and
epidemiological modelling, to estimate rates of CTL escape and reversion in HIV
epitopes. We show that there is substantial uncertainty about rates of viral
escape and reversion from cross-sectional data, which arises from the inherent
stochasticity in the evolutionary process. By application to empirical data, we
find that point estimates of rates from a previously published ODE model and
the integrated approach presented here are often similar, but can also differ
several-fold depending on the structure of the genealogy. The model-based
approach we apply provides a framework for the statistical analysis of escape
and reversion in population data and highlights the need for longitudinal and
denser cross-sectional sampling to enable accurate estimate of these key
parameters.
02/2013;
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Sarah Fidler,
Kholoud Porter,
Fiona Ewings, John Frater,
Gita Ramjee,
David Cooper,
Helen Rees,
Martin Fisher,
Mauro Schechter,
Pontiano Kaleebu,
Giuseppe Tambussi,
Sabine Kinloch,
Jose M Miro,
Anthony Kelleher,
Myra McClure,
Steve Kaye,
Michelle Gabriel,
Rodney Phillips,
Jonathan Weber,
Abdel Babiker
[show abstract]
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ABSTRACT: Short-course antiretroviral therapy (ART) in primary human immunodeficiency virus (HIV) infection may delay disease progression but has not been adequately evaluated.
We randomly assigned adults with primary HIV infection to ART for 48 weeks, ART for 12 weeks, or no ART (standard of care), with treatment initiated within 6 months after seroconversion. The primary end point was a CD4+ count of less than 350 cells per cubic millimeter or long-term ART initiation.
A total of 366 participants (60% men) underwent randomization to 48-week ART (123 participants), 12-week ART (120), or standard care (123), with an average follow-up of 4.2 years. The primary end point was reached in 50% of the 48-week ART group, as compared with 61% in each of the 12-week ART and standard-care groups. The average hazard ratio was 0.63 (95% confidence interval [CI], 0.45 to 0.90; P=0.01) for 48-week ART as compared with standard care and was 0.93 (95% CI, 0.67 to 1.29; P=0.67) for 12-week ART as compared with standard care. The proportion of participants who had a CD4+ count of less than 350 cells per cubic millimeter was 28% in the 48-week ART group, 40% in the 12-week group, and 40% in the standard-care group. Corresponding values for long-term ART initiation were 22%, 21%, and 22%. The median time to the primary end point was 65 weeks (95% CI, 17 to 114) longer with 48-week ART than with standard care. Post hoc analysis identified a trend toward a greater interval between ART initiation and the primary end point the closer that ART was initiated to estimated seroconversion (P=0.09), and 48-week ART conferred a reduction in the HIV RNA level of 0.44 log(10) copies per milliliter (95% CI, 0.25 to 0.64) 36 weeks after the completion of short-course therapy. There were no significant between-group differences in the incidence of the acquired immunodeficiency syndrome, death, or serious adverse events.
A 48-week course of ART in patients with primary HIV infection delayed disease progression, although not significantly longer than the duration of the treatment. There was no evidence of adverse effects of ART interruption on the clinical outcome. (Funded by the Wellcome Trust; SPARTAC Controlled-Trials.com number, ISRCTN76742797, and EudraCT number, 2004-000446-20.).
New England Journal of Medicine 01/2013; 368(3):207-17. · 53.30 Impact Factor
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ABSTRACT: OBJECTIVE:: To fully define cytotoxic T-lymphocyte (CTL) escape variants of an HLA-B*51-restricted integrase epitope in early HIV-1 infection. DESIGN:: 94 longitudinally-sampled acute/early HIV-1 subtype B-infected subjects were assessed to determine HLA-B*51-restricted LPPVVAKEI (LI9) escape variants. METHODS:: LI9 was sequenced at baseline and subsequent time-points. Interferon-γ ELISpot assays were performed using serial log dilutions of variant LI9 peptides to determine the cellular response and functional avidity. RESULTS:: There is a significant association between HLA-B*51 expression and an evolving LI9 sequence from baseline to year 1 (P < 0.0001). We detected that the V32I and P30X polymorphisms emerged within HLA-B*51 subjects over time. Reversion of the P30S polymorphism was observed by year 1 in one HLA-B*51 subject. LPPIIAKEI and LPSIVAKEI had significantly lower functional avidity compared to LPPVVAKEI and so may be less well recognised by LI9-specific CTLs; a positive IFNγ response to IPSVVAKEI was rarely seen. Functional avidity to wildtype LI9 inversely correlated with viral load (R = 0.448, P = 0.0485). CONCLUSIONS:: Our results provide support for the role of HLA-B*51-restricted CTLs and functional avidity in the control of early HIV-1 infection.
AIDS (London, England) 10/2012; · 4.91 Impact Factor
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Henrik N Kløverpris,
Mikkel Harndahl,
Alasdair J Leslie,
Jonathan M Carlson,
Nasreen Ismail,
Mary van der Stok,
Kuan-Hsiang Gary Huang,
Fabian Chen,
Lynn Riddell,
Dewald Steyn,
Dominique Goedhals,
Cloete van Vuuren, John Frater,
Bruce D Walker,
Mary Carrington,
Thumbi Ndung'u,
Søren Buus,
Philip Goulder
[show abstract]
[hide abstract]
ABSTRACT: Genetic variation within the HLA-B locus has the strongest impact on HIV disease progression of any polymorphisms within the human genome. However, identifying the exact mechanism involved is complicated by several factors. HLA-Bw4 alleles provide ligands for NK cells and for CD8 T cells, and strong linkage disequilibrium between HLA class I alleles complicates the discrimination of individual HLA allelic effects from those of other HLA and non-HLA alleles on the same haplotype. Here, we exploit an experiment of nature involving two recently diverged HLA alleles, HLA-B*42:01 and HLA-B*42:02, which differ by only a single amino acid. Crucially, they occur primarily on identical HLA class I haplotypes and, as Bw6 alleles, do not act as NK cell ligands and are therefore largely unconfounded by other genetic factors. We show that in an outbred cohort (n = 2,093) of HIV C-clade-infected individuals, a single amino acid change at position 9 of the HLA-B molecule critically affects peptide binding and significantly alters the cytotoxic T lymphocyte (CTL) epitopes targeted, measured directly ex vivo by gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay (P = 2 × 10(-10)) and functionally through CTL escape mutation (P = 2 × 10(-8)). HLA-B*42:01, which presents multiple Gag epitopes, is associated with a 0.52 log(10) lower viral-load set point than HLA-B*42:02 (P = 0.02), which presents no p24 Gag epitopes. The magnitude of this effect from a single amino acid difference in the HLA-A*30:01/B*42/Cw*17:01 haplotype is equivalent to 75% of that of HLA-B*57:03, the most protective HLA class I allele in this population. This naturally controlled experiment represents perhaps the clearest demonstration of the direct impact of a particular HIV-specific CTL on disease control.
Journal of Virology 08/2012; 86(21):11493-500. · 5.40 Impact Factor
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[show abstract]
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ABSTRACT: Identifying human immunodeficiency virus (HIV) immune escape mutations has implications for understanding the impact of host immunity on pathogen evolution and guiding the choice of vaccine antigens. One means of identifying cytotoxic-T-lymphocyte (CTL) escape mutations is to search for statistical associations between mutations and host human leukocyte antigen (HLA) class I alleles at the population level. The impact of evolutionary rates on the strength of such associations is not well defined. Here, we address this topic using a mathematical model of within-host evolution and between-host transmission of CTL escape mutants that predicts the prevalence of escape mutants at the population level. We ask how the rates at which an escape mutation emerges in a host who bears the restricting HLA and reverts when transmitted to a host who does not bear the HLA affect the strength of an association. We consider the impact of these factors when using a standard statistical method to test for an association and when using an adaptation of that method that corrects for phylogenetic relationships. We show that with both methods, the average sample size required to identify an escape mutation is smaller if the mutation escapes and reverts quickly. Thus, escape mutations identified as HLA associated systematically favor those that escape and revert rapidly. We also present expressions that can be used to infer escape and reversion rates from cross-sectional escape prevalence data.
Journal of Virology 06/2012; 86(16):8568-80. · 5.40 Impact Factor
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Jonathan M Carlson,
Jennifer Listgarten,
Nico Pfeifer,
Vincent Tan,
Carl Kadie,
Bruce D Walker,
Thumbi Ndung'u,
Roger Shapiro, John Frater,
Zabrina L Brumme,
Philip J R Goulder,
David Heckerman
[show abstract]
[hide abstract]
ABSTRACT: The promiscuous presentation of epitopes by similar HLA class I alleles holds promise for a universal T-cell-based HIV-1 vaccine. However, in some instances, cytotoxic T lymphocytes (CTL) restricted by HLA alleles with similar or identical binding motifs are known to target epitopes at different frequencies, with different functional avidities and with different apparent clinical outcomes. Such differences may be illuminated by the association of similar HLA alleles with distinctive escape pathways. Using a novel computational method featuring phylogenetically corrected odds ratios, we systematically analyzed differential patterns of immune escape across all optimally defined epitopes in Gag, Pol, and Nef in 2,126 HIV-1 clade C-infected adults. Overall, we identified 301 polymorphisms in 90 epitopes associated with HLA alleles belonging to shared supertypes. We detected differential escape in 37 of 38 epitopes restricted by more than one allele, which included 278 instances of differential escape at the polymorphism level. The majority (66 to 97%) of these resulted from the selection of unique HLA-specific polymorphisms rather than differential epitope targeting rates, as confirmed by gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISPOT) data. Discordant associations between HLA alleles and viral load were frequently observed between allele pairs that selected for differential escape. Furthermore, the total number of associated polymorphisms strongly correlated with average viral load. These studies confirm that differential escape is a widespread phenomenon and may be the norm when two alleles present the same epitope. Given the clinical correlates of immune escape, such heterogeneity suggests that certain epitopes will lead to discordant outcomes if applied universally in a vaccine.
Journal of Virology 02/2012; 86(9):5230-43. · 5.40 Impact Factor
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ABSTRACT: CXCR4-tropic (X4) HIV-1 variants are associated with faster disease progression compared with CCR5-tropic variants; however, the mechanism for this is unclear. We measured T-cell activation in 120 individuals with primary HIV-1 infection. X4-utilizing variants, determined genotypically, were present in 8.3% of the participants and were associated with higher levels of CD4 T-cell activation, even after adjusting for other prognostic factors. Increased CD4 T-cell activation may influence the more rapid immunological decline associated with X4 virus.
AIDS (London, England) 02/2012; 26(7):887-90. · 4.91 Impact Factor
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01/2012; , ISBN: 978-953-307-871-7
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Advances in Virology 01/2012; 2012:490549.
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Philippa C Matthews,
Jennifer Listgarten,
Jonathan M Carlson,
Rebecca Payne,
Kuan-Hsiang Gary Huang, John Frater,
Dominique Goedhals,
Dewald Steyn,
Cloete van Vuuren,
Paolo Paioni,
Pieter Jooste,
Anthony Ogwu,
Roger Shapiro,
Zenele Mncube,
Thumbi Ndung'u,
Bruce D Walker,
David Heckerman,
Philip J R Goulder
[show abstract]
[hide abstract]
ABSTRACT: 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.
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).
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.
PLoS ONE 01/2012; 7(10):e47799. · 4.09 Impact Factor
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John Frater
[show abstract]
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ABSTRACT: Despite the proven efficacy of highly active antiretroviral therapy in reducing mortality and morbidity of HIV infection, longer-term strategies are less well defined and there is renewed interest in HIV eradication. This review will describe the major obstacles that need to be overcome and the key new advances and strategies designed to achieve an HIV cure.
Characterization of the HIV viral reservoir over the past few years has led to a better understanding of which approaches might successfully lead to eradication. A number of approaches such as histone modification, immunotoxins, gene therapy and gene knockout strategies have resulted and have been explored initially in vitro. There has been progression from both laboratory and animal model studies, and clinical trials are now underway using new approaches such as histone deacetylase inhibitors and zinc finger nucleases.
Although there is currently no cure for HIV infection, there has been a resurgence of interest in the field with the development of a number of potential new approaches, some of which have entered clinical trials.
Current Opinion in Infectious Diseases 12/2011; 24(6):593-8. · 4.93 Impact Factor
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11/2011; , ISBN: 978-953-307-719-2
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[show abstract]
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ABSTRACT: Deliberate redirection of T cell responses to human immunodeficiency virus-1 might enhance immunity and thus aid viral containment. Dahirel et al. (2011) identify candidate antigens to achieve this with a theory derived from physics.
Immunity 07/2011; 35(1):10-2. · 21.64 Impact Factor
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ABSTRACT: To combat the pandemic of human immunodeficiency virus 1 (HIV-1), a successful vaccine will need to cope with the variability of transmissible viruses. Human hosts infected with HIV-1 potentially harbour many viral variants but very little is known about viruses that are likely to be transmitted, or even if there are viral characteristics that predict enhanced transmission in vivo. We show for the first time that genetic divergence consistent with a single transmission event in vivo can represent several years of pre-transmission evolution.
We describe a highly unusual case consistent with a single donor transmitting highly related but distinct HIV-1 variants to two individuals on the same evening. We confirm that the clustering of viral genetic sequences, present within each recipient, is consistent with the history of a single donor across the viral env, gag and pol genes by maximum likelihood and bayesian Markov Chain Monte Carlo based phylogenetic analyses. Based on an uncorrelated, lognormal relaxed clock of env gene evolution calibrated with other datasets, the time since the most recent common ancestor is estimated as 2.86 years prior to transmission (95% confidence interval 1.28 to 4.54 years).
Our results show that an effective design for a preventative vaccine will need to anticipate extensive HIV-1 diversity within an individual donor as well as diversity at the population level.
Retrovirology 07/2011; 8:54. · 6.47 Impact Factor
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Philippa C Matthews,
Emily Adland,
Jennifer Listgarten,
Alasdair Leslie,
Nompumelelo Mkhwanazi,
Jonathan M Carlson,
Mikkel Harndahl,
Anette Stryhn,
Rebecca P Payne,
Anthony Ogwu, [......],
Lynn Riddell,
Fabian Chen,
Graz Luzzi,
Thambiah Balachandran,
Thumbi Ndung'u,
Søren Buus,
Mary Carrington,
Roger Shapiro,
David Heckerman,
Philip J R Goulder
[show abstract]
[hide abstract]
ABSTRACT: 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.
The Journal of Immunology 05/2011; 186(10):5675-86. · 5.79 Impact Factor
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Kuan-Hsiang Gary Huang,
Dominique Goedhals,
Jonathan M Carlson,
Mark A Brockman,
Swati Mishra,
Zabrina L Brumme,
Stephen Hickling,
Christopher S W Tang,
Toshiyuki Miura,
Chris Seebregts,
David Heckerman,
Thumbi Ndung'u,
Bruce Walker,
Paul Klenerman,
Dewald Steyn,
Philip Goulder,
Rodney Phillips,
Cloete van Vuuren, John Frater
[show abstract]
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ABSTRACT: We lack the understanding of why HIV-infected individuals in South Africa progress to AIDS. We hypothesised that in end-stage disease there is a shifting dynamic between T cell imposed immunity and viral immune escape, which, through both compensatory and reverting viral mutations, results in increased viral fitness, elevated plasma viral loads and disease progression. We explored how T cell responses, viral adaptation and viral fitness inter-relate in South African cohorts recruited from Bloemfontein, the Free State (n = 278) and Durban, KwaZulu-Natal (n = 775). Immune responses were measured by γ-interferon ELISPOT assays. HLA-associated viral polymorphisms were determined using phylogenetically corrected techniques, and viral replication capacity (VRC) was measured by comparing the growth rate of gag-protease recombinant viruses against recombinant NL4-3 viruses. We report that in advanced disease (CD4 counts <100 cells/µl), T cell responses narrow, with a relative decline in Gag-directed responses (p<0.0001). This is associated with preserved selection pressure at specific viral amino acids (e.g., the T242N polymorphism within the HLA-B*57/5801 restricted TW10 epitope), but with reversion at other sites (e.g., the T186S polymorphism within the HLA-B*8101 restricted TL9 epitope), most notably in Gag and suggestive of "immune relaxation". The median VRC from patients with CD4 counts <100 cells/µl was higher than from patients with CD4 counts ≥ 500 cells/µl (91.15% versus 85.19%, p = 0.0004), potentially explaining the rise in viral load associated with disease progression. Mutations at HIV Gag T186S and T242N reduced VRC, however, in advanced disease only the T242N mutants demonstrated increasing VRC, and were associated with compensatory mutations (p = 0.013). These data provide novel insights into the mechanisms of HIV disease progression in South Africa. Restoration of fitness correlates with loss of viral control in late disease, with evidence for both preserved and relaxed selection pressure across the HIV genome. Interventions that maintain viral fitness costs could potentially slow progression.
PLoS ONE 01/2011; 6(4):e19018. · 4.09 Impact Factor
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Eleanor Barnes,
Peter Flanagan,
Anthony Brown,
Nicola Robinson,
Helen Brown,
Myra McClure,
Annette Oxenius,
Jane Collier,
Jonathan Weber,
Huldrych F Günthard,
Bernard Hirschel,
Sarah Fidler,
Rodney Phillips, John Frater
[show abstract]
[hide abstract]
ABSTRACT: A xenotropic murine leukemia virus-related virus (XMRV) has recently been reported in association with prostate cancer and chronic fatigue syndrome, with a prevalence of up to 3.7% in the healthy population. We looked for XMRV in 230 patients with human immunodeficiency virus type 1 or hepatitis C infection. XMRV was undetectable in plasma or peripheral blood mononuclear cells by polymerase chain reaction targeting XMRV gag or env. T cell responses to XMRV Gag were undetectable in peripheral blood mononuclear cells by ex vivo gamma interferon enzyme-linked immunospot assay. In our cohorts, XMRV was not enriched in patients with blood-borne or sexually transmitted infections from the United Kingdom and Western Europe.
The Journal of Infectious Diseases 10/2010; 202(10):1482-5. · 6.41 Impact Factor
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[show abstract]
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ABSTRACT: During infection with human immunodeficiency virus (HIV), immune pressure from cytotoxic T-lymphocytes (CTLs) selects for viral mutants that confer escape from CTL recognition. These escape variants can be transmitted between individuals where, depending upon their cost to viral fitness and the CTL responses made by the recipient, they may revert. The rates of within-host evolution and their concordant impact upon the rate of spread of escape mutants at the population level are uncertain. Here we present a mathematical model of within-host evolution of escape mutants, transmission of these variants between hosts and subsequent reversion in new hosts. The model is an extension of the well-known SI model of disease transmission and includes three further parameters that describe host immunogenetic heterogeneity and rates of within host viral evolution. We use the model to explain why some escape mutants appear to have stable prevalence whilst others are spreading through the population. Further, we use it to compare diverse datasets on CTL escape, highlighting where different sources agree or disagree on within-host evolutionary rates. The several dozen CTL epitopes we survey from HIV-1 gag, RT and nef reveal a relatively sedate rate of evolution with average rates of escape measured in years and reversion in decades. For many epitopes in HIV, occasional rapid within-host evolution is not reflected in fast evolution at the population level.
PLoS Pathogens 01/2010; 6(11):e1001196. · 9.13 Impact Factor
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Kuan-Hsiang Gary Huang,
Dominique Goedhals,
Helen Fryer,
Cloete van Vuuren,
Aris Katzourakis,
Tulio De Oliveira,
Helen Brown,
Sharon Cassol,
Chris Seebregts,
Angela McLean,
Paul Klenerman,
Rodney Phillips, John Frater
[show abstract]
[hide abstract]
ABSTRACT: We aimed to characterize the molecular epidemiology of HIV type-1 (HIV-1) and the prevalence of drug-associated mutations prior to initiating highly active antiretroviral therapy (HAART) in the Free State province, South Africa. The Free State has a population of 3 million, an antenatal HIV prevalence of approximately 34% and a well established infrastucture for antiretroviral (ARV) provision.
HIV-1 polymerase genes were sequenced from 425 HAART-naive HIV-1-positive patients at voluntary primary healthcare HIV testing centres, who were subsequently attending district centres for assessment for commencing ARVs. Patients (>18 years) were sampled randomly with no exclusion for gender or clinical criteria. Sequences were analysed according to phylogeny and drug resistance.
Phylogenetic clustering within the cohort was suggestive of multiple introductions of subtype C virus into the region. Drug resistance mutations (according to the International AIDS Society-USA classification) were distributed randomly across the cohort phylogeny with an overall prevalence of 2.3% in the sampled patients. When stratified according to CD4(+) T-cell count, the prevalence of resistance was 3.6%, 0.9% and 1.2% for CD4(+) T-cell counts <100, 200-350 and >500 cells/microl, respectively, and was most common for non-nucleoside reverse transcriptase inhibitor resistance (3.1% in patients with CD4(+) T-cell count <100 cells/microl). We surveyed all drug-selected mutations and found further significant clustering among patients with low CD4(+) T-cell counts (P=0.003), suggesting unrecognized exposure to ARVs.
In the Free State population, there was a statistical association between low CD4(+) T-cell counts and drug-associated viral polymorphisms. Our data advocate the benefit of detailed history taking from patients starting HAART at low CD4(+) T-cell counts with close follow-up of the virological response.
Antiviral therapy 01/2009; 14(7):975-84. · 3.16 Impact Factor
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Peter Zimbwa,
Anita Milicic, John Frater,
Thomas J Scriba,
Antony Willis,
Philip J R Goulder,
Tilly Pillay,
Huldrych Gunthard,
Jonathan N Weber,
Hua-Tang Zhang,
Rodney E Phillips
[show abstract]
[hide abstract]
ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) evokes a strong immune response, but the virus persists. Polymorphisms within known antigenic sites result in loss of immune recognition and can be positively selected. Amino acid variation outside known HLA class I restricted epitopes can also enable immune escape by interfering with the processing of the optimal peptide antigen. However, the lack of precise rules dictating epitope generation and the enormous genetic diversity of HIV make prediction of processing mutants very difficult. Polymorphism E169D in HIV-1 reverse transcriptase (RT) is significantly associated with HLA-B*0702 in HIV-1-infected individuals. This polymorphism does not map within a known HLA-B*0702 epitope; instead, it is located five residues downstream of a HLA-B*0702-restricted epitope SPAIFQSSM (SM9). Here we investigate the association between E169D and HLA-B*0702 for immune escape via the SM9 epitope. We show that this single amino acid variation prevents the immune recognition of the flanked SM9 epitope by cytotoxic T cells through lack of generation of the epitope, which is a result of aberrant proteasomal cleavage. The E169D polymorphism also maps within and abrogates the recognition of an HLA-A*03-restricted RT epitope MR9. This study highlights the potential for using known statistical associations as indicators for viral escape but also the complexity involved in interpreting the immunological consequences of amino acid changes in HIV sequences.
Journal of Virology 03/2007; 81(4):2031-8. · 5.40 Impact Factor
