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Journal of Virology, June 2007, p. 6742-6751, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.00022-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Effective T-Cell Responses Select Human Immunodeficiency Virus Mutants and Slow Disease Progression{triangledown} ,{dagger}

A. J. Frater,1,2 H. Brown,1,2 A. Oxenius,3 H. F. Günthard,4 B. Hirschel,5 N. Robinson,1,2 A. J. Leslie,6 R. Payne,6 H. Crawford,6 A. Prendergast,6 C. Brander,7 P. Kiepiela,8 B. D. Walker,7,8 P. J. R. Goulder,6,7,8 A. McLean,9 R. E. Phillips,1,2* and the Swiss HIV-Cohort Study

Nuffield Department of Clinical Medicine, John Radcliffe Hospital and Peter Medawar Building for Pathogen Research, Oxford University, Oxford OX1 3SY, United Kingdom,1 Institute of Emergent Infections of Humans, The James Martin 21st Century School, at The Peter Medawar Building for Pathogen Research, South Parks Road, Oxford, OX1 3SY, United Kindgom,2 Institute for Microbiology, Eidgenössische Technische Hochschule, CH-8092 Zürich, Switzerland,3 Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zürich, CH-8091 Zürich, Switzerland,4 Division of Infectious Diseases, University Hospital, CH-1211 Geneva, Switzerland,5 Department of Paediatrics, Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, Oxford OX1 3SY, United Kingdom,6 Partners AIDS Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129,7 HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZuluNatal, Durban, South Africa,8 Institute of Emergent Infections of Humans, The James Martin 21st Century School, at Zoology Department,Oxford University, South Parks Road, Oxford OX1 3PS, United Kingdom9

Received 4 January 2007/ Accepted 25 March 2007

The possession of some HLA class I molecules is associated with delayed progression to AIDS. The mechanism behind this beneficial effect is unclear. We tested the idea that cytotoxic T-cell responses restricted by advantageous HLA class I molecules impose stronger selection pressures than those restricted by other HLA class I alleles. As a measure of the selection pressure imposed by HLA class I alleles, we determined the extent of HLA class I-associated epitope variation in a cohort of European human immunodeficiency virus (HIV)-positive individuals (n = 84). We validated our findings in a second, distinct cohort of African patients (n = 516). We found that key HIV epitopes restricted by advantageous HLA molecules (B27, B57, and B51 in European patients and B5703, B5801, and B8101 in African patients) were more frequently mutated in individuals bearing the restricting HLA than in those who lacked the restricting HLA class I molecule. HLA alleles associated with clinical benefit restricted certain epitopes for which the consensus peptides were frequently recognized by the immune response despite the circulating virus's being highly polymorphic. We found a significant inverse correlation between the HLA-associated hazard of disease progression and the mean HLA-associated prevalence of mutations within epitopes (P = 0.028; R2 = 0.34). We conclude that beneficial HLA class I alleles impose strong selection at key epitopes. This is revealed by the frequent association between effective T-cell responses and circulating viral escape mutants and the rarity of these variants in patients who lack these favorable HLA class I molecules, suggesting a significant pressure to revert.

* Corresponding author. Mailing address: Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, United Kingdom. Phone: 44 1865 281230. Fax: 44 1865 281890. E-mail: Rodney.Phillips{at}ndm.ox.ac.uk

{triangledown} Published ahead of print on 4 April 2007.

{dagger} Supplemental material for this article is available at http://jvi.asm.org/.

Journal of Virology, June 2007, p. 6742-6751, Vol. 81, No. 12
0022-538X/07/$08.00+0     doi:10.1128/JVI.00022-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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