High-functional-avidity cytotoxic T lymphocyte responses to HLA-B-restricted gag-derived epitopes associated with relative HIV control

Christoph T. Berger, Nicole Frahm, David A. Price, Beatriz Mothe, Musie Ghebremichael, Kari L. Hartman, Leah M. Henry, Jason M. Brenchley, Laura E. Ruff, Vanessa Venturi, Florencia Pereyra, John Sidney, Alessandro Sette, Daniel C. Douek, Bruce D. Walker, Daniel E. Kaufmann, Christian Brander

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    95 Citations (Scopus)

    Abstract

    Virus-specific cytotoxic T lymphocytes (CTL) with high levels of functional avidity have been associated with viral clearance in hepatitis C virus infection and with enhanced antiviral protective immunity in animal models. However, the role of functional avidity as a determinant of HIV-specific CTL efficacy remains to be assessed. Here we measured the functional avidities of HIV-specific CTL responses targeting 20 different, optimally defined CTL epitopes restricted by 13 different HLA class I alleles in a cohort comprising 44 HIV controllers and 68 HIV noncontrollers. Responses restricted by HLA-B alleles and responses targeting epitopes located in HIV Gag exhibited significantly higher functional avidities than responses restricted by HLA-A or HLA-C molecules (P = 0.0003) or responses targeting epitopes outside Gag (P < 0.0001). The functional avidities of Gag-specific and HLA-B-restricted responses were higher in HIV controllers than in noncontrollers (P = 0.014 and P = 0.018) and were not restored in HIV noncontrollers initiating antiretroviral therapy. T-cell receptor (TCR) analyses revealed narrower TCR repertoires in higher-avidity CTL populations, which were dominated by public TCR sequences in HIV controllers. Together, these data link the presence of high-avidity Gag-specific and HLA-B-restricted CTL responses with viral suppression in vivo and provide new insights into the immune parameters that mediate spontaneous control of HIV infection. © 2011, American Society for Microbiology.
    Original languageEnglish
    Pages (from-to)9334-9345
    JournalJournal of Virology
    Volume85
    Issue number18
    DOIs
    Publication statusPublished - 1 Sep 2011

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