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Journal of Virology, November 2007, p. 12608-12618, Vol. 81, No. 22
0022-538X/07/$08.00+0     doi:10.1128/JVI.01369-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Escape and Compensation from Early HLA-B57-Mediated Cytotoxic T-Lymphocyte Pressure on Human Immunodeficiency Virus Type 1 Gag Alter Capsid Interactions with Cyclophilin A

Partners AIDS Research Center, Massachusetts General Hospital, Charlestown, Massachusetts,¹ Howard Hughes Medical Institute, Chevy Chase, Maryland,² Emmanuel College, Departments of Biology and Chemistry, Boston, Massachusetts,³ Emory Vaccine Center, Emory University, Atlanta, Georgia,⁴ Zambia-Emory HIV Research Group and the Zambia Blood Transfusion Service, Lusaka, Zambia,⁵ University of Alabama at Birmingham, Birmingham, Alabama⁶

Received 22 June 2007/ Accepted 20 August 2007

Certain histocompatibility leukocyte antigen (HLA) alleles are associated with improved clinical outcomes for individuals infected with human immunodeficiency virus type 1 (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 postentry 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.

Published ahead of print on 29 August 2007.

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