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Journal of Virology, July 2008, p. 6434-6446, Vol. 82, No. 13
0022-538X/08/$08.00+0     doi:10.1128/JVI.02455-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

HLA Class I-Driven Evolution of Human Immunodeficiency Virus Type 1 Subtype C Proteome: Immune Escape and Viral Load {triangledown}

Christine M. Rousseau,1* Marcus G. Daniels,2 Jonathan M. Carlson,3,4 Carl Kadie,4 Hayley Crawford,5 Andrew Prendergast,5 Philippa Matthews,5 Rebecca Payne,5 Morgane Rolland,1 Dana N. Raugi,1 Brandon S. Maust,1 Gerald H. Learn,1 David C. Nickle,1 Hoosen Coovadia,6 Thumbi Ndung'u,6 Nicole Frahm,7 Christian Brander,7 Bruce D. Walker,7,8 Philip J. R. Goulder,5,6,7 Tanmoy Bhattacharya,2,9 David E. Heckerman,1,4 Bette T. Korber,2,9 and James I. Mullins1,10

Department of Microbiology, University of Washington, Seattle, Washington,1 Los Alamos National Laboratory, Los Alamos, New Mexico,2 Department of Computer Science and Engineering, University of Washington, Seattle, Washington,3 Machine Learning and Applied Statistics Group, Microsoft Research, Redmond, Washington,4 Department of Pediatrics, Nuffield Department of Medicine, Oxford, England,5 HIV Pathogenesis Program, Nelson Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa,6 Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts,7 Howard Hughes Medical Institute, Chevy Chase, Maryland,8 Santa Fe Institute, Santa Fe, New Mexico,9 Department of Medicine, University of Washington, Seattle, Washington,10

Received 14 November 2007/ Accepted 11 April 2008

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 ≤ 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.

* Corresponding author. Mailing address: Department of Microbiology, University of Washington, 1959 NE Pacific Street, Box 358070, Seattle, WA 98195-8070. Phone: (206) 732-6102. Fax: (206) 732-6167. E-mail: cmr{at}u.washington.edu

{triangledown} Published ahead of print on 23 April 2008.

Journal of Virology, July 2008, p. 6434-6446, Vol. 82, No. 13
0022-538X/08/$08.00+0     doi:10.1128/JVI.02455-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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