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J. Virol. doi:10.1128/JVI.02455-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

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

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

^* To whom correspondence should be addressed. Email: cmr{at}u.washington.edu.

	Abstract

HIV-1 mutations that confer escape from 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 3 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 CTL. 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 7 susceptible residues, including 4 in Gag, were associated with lower plasma viral RNA loads (q < 0.2) 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 of Vpr>Gag>Rev>Pol>Nef>Vif>Tat>Env>Vpu (Fisher's exact p 0.0009 for each comparison), suggesting the same ranking of fitness costs by gene associated with CTL escape. Significantly more HLA-B (X² p = 3.59 x 10^-5) and HLA-C (X² 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 viral load.

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