Two new papers add to the recent welter of studies indicating that T cell immune responses can pressure HIV into mutating in ways that compromise viral fitness. Much of this data has been generated by a productive and novel collaboration between immunologists affiliated with Bruce Walker’s lab at Partners AIDS Researcher Center in Boston and a team of data crunchers at Microsoft led by David Heckerman. Heckerman was interviewed by CNET about the project last year.
JVI Accepts, published online ahead of print on 2 July 2008
J. Virol. doi:10.1128/JVI.00580-08
CENTRAL ROLE OF REVERTING MUTATIONS IN HLA ASSOCIATIONS WITH HIV VIRAL SETPOINT
Philippa C Matthews*, Andrew Prendergast, Alasdair Leslie, Hayley Crawford, Rebecca Payne, Christine Rousseau, Morgane Rolland, Isobella Honeyborne, Jonathan Carlson, Carl Kadie, Christian Brander, Karen Bishop, Nonkululeko Mlotshwa, James D Mullins, Hoosen Coovadia, Thumbi Ndung'u, Bruce D Walker, David Heckerman, and Philip JR Goulder*
Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Rd, Oxford OX1 3SY, UK; Department of Microbiology, University of Washington School of Medicine, Seattle, Washington 98195-8070, USA; Miscrosoft Research, One Microsoft Way, Redmond, WA 9805; Partners AIDS Research Center, Massachusetts General Hospital, 13th St, Bldg 149, Charlestown, Boston, MA 02129, USA; HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa; Howard Hughes Medical Institute, Chevy Chase, MD, USA
Much uncertainty still exists over what T cell responses need to be induced by an effective HIV vaccine. Previous studies have hypothesised 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-1 infection demonstrates the importance of mutations that impose a fitness cost on control of viraemia. Consistent with previous studies, the viral setpoints 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 setpoints 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, viraemia 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.
AIDS. 22(11):1277-1286, July 11, 2008.
Brumme, Zabrina L; Tao, Iris; Szeto, Sharon; Brumme, Chanson J; Carlson, Jonathan M; Chan, Dennison; Kadie, Carl; Frahm, Nicole; Brander, Christian; Walker, Bruce; Heckerman, David; Harrigan, P Richard
Objective: Selection of specific human leukocyte antigen (HLA)-restricted cytotoxic T-lymphocyte (CTL) escape mutations in key Gag epitopes has been associated with loss of HIV immune control on an individual basis. Here we undertake a population-based identification of HLA-associated polymorphisms in Gag and investigate their relationship with plasma viral load.
Design: Cross-sectional analysis of 567 chronically HIV subtype B-infected, treatment-naive individuals.
Methods: HLA class I-associated Gag substitutions were identified using phylogenetically corrected analysis methods featuring a multivariate adjustment for HLA linkage disequilibrium and a q-value correction for multiple tests. Presence of HLA-associated substitutions and markers of HIV disease status were correlated using Spearman's rank test.
Results: We have created a gene-wide map of HLA class I-associated substitutions in HIV-1 subtype B Gag. This features 111 HLA-associated substitutions occurring at 51 of 500 Gag codons, more than 50% of which occur within published and/or putative HLA-restricted CTL epitopes. A modest inverse correlation was observed between the total number of HLA-associated Gag polymorphic sites within each individual and plasma viral load in chronic untreated infection (R = -0.17, P < 0.0001), supporting the hypothesis that a broad ability to target Gag in vivo contributes to viral control. A modest positive correlation was observed between the proportion of these sites exhibiting HLA-associated substitutions and plasma viral load (R = 0.09, P = 0.03), consistent with a loss of viremia control with the accumulation of CTL escape mutations.
Conclusion: Results contribute to our understanding of immune-driven viral adaptation and suggest that the accumulation of CTL escape mutations in Gag results in clinically detectable consequences at the population level. These data have implications for HIV vaccines.
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