JVI Accepts, published online ahead of print on 2 July 2008
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J. Virol. doi:10.1128/JVI.00580-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

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

* To whom correspondence should be addressed. Email: p.matthews{at}doctors.org.uk. philip.goulder{at}paediatrics.ox.ac.uk.


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Abstract

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.




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