JVI Accepts, published online ahead of print on 29 August 2007
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J. Virol. doi:10.1128/JVI.01369-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Escape and compensation from early HLA-B57-mediated CTL pressure on HIV-1 Gag alters capsid interactions with cyclophilin A

Mark A. Brockman, Arne Schneidewind, Matthew Lahaie, Aaron Schmidt, Toshiyuki Miura, Ivna DeSouza, Faina Ryvkin, Cynthia A. Derdeyn, Susan Allen, Eric Hunter, Joseph Mulenga, Paul A. Goepfert, Bruce D. Walker, and Todd M. Allen*

Partners AIDS Research Center, Massachusetts General Hospital, Charlestown, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA; Emmanuel College, Departments of Biology and Chemistry, Boston, MA, USA; Emory Vaccine Center, Emory University, Atlanta, GA, USA; Zambia-Emory HIV Research Group (ZEHRG) and the Zambia Blood Transfusion Service, Lusaka, Zambia; University of Alabama at Birmingham, Birmingham, AL, USA

* To whom correspondence should be addressed. Email: tallen2{at}partners.org.


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Abstract

Certain histocompatibility leukocyte antigen (HLA) alleles are associated with improved clinical outcome in individuals infected with human immunodeficiency virus (HIV-1), but the mechanisms for their effects remain undefined. An early CD8+ T cell escape mutation in the dominant HLA-B57-restricted Gag epitope TW10 (TSTLQEQIGW) has been shown to impair HIV-1 replication capacity in vitro. We demonstrate here that this T242N substitution in the capsid protein is associated with upstream mutations at residues H219, I223, and M228 in the cyclophilin A (CypA)-binding loop in B57+ individuals with progressive disease. In an independent cohort of epidemiologically-linked transmission pairs, the presence of these substitutions in viruses encoding T242N was associated with significantly higher plasma viremia in donors, further suggesting that these secondary mutations compensated for the replication defect of T242N. Using NL4-3 constructs, we illustrate the ability of these CypA-loop changes to partially restore replication of the T242N variant in vitro. Notably, these mutations also enhanced viral resistance to the drug cyclosporine A, indicating a reduced dependence of the compensated virus on CypA that is normally essential for optimal infectivity. Therefore, mutations in TW10 allow HIV-1 to evade a dominant early CD8+ T cell response, but the benefits of escape are offset by a defect in capsid function. These data suggest that TW10 escape variants undergo a post-entry block that is partially overcome by changes in the CypA-binding loop and identify a mechanism for an HIV-1 fitness defect that may contribute to the slower disease progression associated with HLA-B57.




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