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Journal of Virology, September 2008, p. 8548-8559, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00580-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Central Role of Reverting Mutations in HLA Associations with Human Immunodeficiency Virus Set Point{triangledown}

Philippa C. Matthews,1,{dagger}* Andrew Prendergast,1,{dagger} Alasdair Leslie,1 Hayley Crawford,1 Rebecca Payne,1 Christine Rousseau,2 Morgane Rolland,2 Isobella Honeyborne,1 Jonathan Carlson,3 Carl Kadie,3 Christian Brander,4 Karen Bishop,5 Nonkululeko Mlotshwa,5 James I. Mullins,2 Hoosen Coovadia,5 Thumbi Ndung'u,5 Bruce D. Walker,4,6 David Heckerman,3 and Philip J. R. Goulder1,4,5*

Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Rd., Oxford OX1 3SY, United Kingdom,1 Department of Microbiology, University of Washington School of Medicine, Seattle, Washington 98195-8070,2 Microsoft Research, One Microsoft Way, Redmond, Washington 98052,3 Partners AIDS Research Center, Massachusetts General Hospital, 13th St., Bldg. 149, Charlestown, Boston, Massachusetts 02129,4 HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa,5 Howard Hughes Medical Institute, Chevy Chase, Maryland6

Received 14 March 2008/ Accepted 10 June 2008

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 posttransmission. 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.

* Corresponding author. Mailing address for Philippa Matthews: Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Rd., Oxford OX1 3SY, United Kingdom. Phone: 44 1865 281883. Fax: 44 1865 281890. E-mail: p.matthews{at}doctors.org.uk. Mailing address for Philip Goulder: Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Rd., Oxford OX1 3SY, United Kingdom. Phone: 44 1865 281884. Fax: 44 1865 281890. E-mail: philip.goulder{at}paediatrics.ox.ac.uk

{triangledown} Published ahead of print on 2 July 2008.

{dagger} P.C.M. and A.P. contributed equally to this work.

Journal of Virology, September 2008, p. 8548-8559, Vol. 82, No. 17
0022-538X/08/$08.00+0     doi:10.1128/JVI.00580-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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