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Journal of Virology, April 2005, p. 5000-5005, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.5000-5005.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Majority of Currently Circulating Human Immunodeficiency Virus Type 1 Clade B Viruses Fail To Prime Cytotoxic T-Lymphocyte Responses against an Otherwise Immunodominant HLA-A2-Restricted Epitope: Implications for Vaccine Design

Marcus Altfeld,1* Todd M. Allen,1 Elizabeth T. Kalife,1 Nicole Frahm,1 Marylyn M. Addo,1 Bianca R. Mothe,2 Almas Rathod,1 Laura L. Reyor,1 Jason Harlow,1 Xu G. Yu,1 Beth Perkins,1 Loren K. Robinson,1 John Sidney,3 Galit Alter,1 Mathias Lichterfeld,1 Alessandro Sette,3 Eric S. Rosenberg,1 Philip J. R. Goulder,1,4 Christian Brander,1 and Bruce D. Walker1,5

Partners AIDS Research Center, Massachusetts General Hospital, and Division of AIDS, Harvard Medical School, Boston, Massachusetts,1 Howard Hughes Medical Institute,5 La Jolla Institute for Allergy and Immunology, San Diego,3 Department of Biological Sciences, California State University; San Marcos, California,2 Department of Pediatrics, Nuffield Department of Medicine, Oxford, United Kingdom4

Received 1 October 2004/ Accepted 2 December 2004

Human immunodeficiency virus type 1 (HIV-1) mutates to escape immune selection pressure, but there is little evidence of selection mediated through HLA-A2, the dominant class I allele in persons infected with clade B virus. Moreover, HLA-A2-restricted responses are largely absent in the acute phase of infection as the viral load is being reduced, suggesting that circulating viruses may lack immunodominant epitopes targeted through HLA-A2. Here we demonstrate an A2-restricted epitope within Vpr (Vpr59-67) that is targeted by acute-phase HIV-1-specific CD8+ T cells, but only in a subset of persons expressing HLA-A2. Individuals in the acute stage of infection with viruses containing the most common current sequence within this epitope (consensus sequence) were unable to mount epitope-specific T-cell responses, whereas subjects infected with the less frequent I60L variant all developed these responses. The I60L variant epitope was a stronger binder to HLA-A2 and was recognized by epitope-specific T cells at lower peptide concentrations than the consensus sequence epitope. These data demonstrate that HLA-A2 is capable of contributing to the acute-phase cytotoxic T-lymphocyte response in infected subjects, but that most currently circulating viruses lack a dominant immunogenic epitope presented by this allele, and suggest that immunodominant epitopes restricted by common HLA alleles may be lost as the epidemic matures.

* Corresponding author. Mailing address: Partners AIDS Research Center, Massachusetts General Hospital, 149 13th St., Boston, MA 02129. Phone: (617) 724-2461. Fax: (617) 724-8586. E-mail: maltfeld{at}partners.org.

Journal of Virology, April 2005, p. 5000-5005, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.5000-5005.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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