TY - JOUR
T1 - Efficacious early antiviral activity of HIV Gag- and Pol-specific HLA-B*2705-restricted CD8+ T cells
AU - Payne, Rebecca P.
AU - Kløverpris, Henrik
AU - Sacha, Jonah B.
AU - Brumme, Zabrina
AU - Brumme, Chanson
AU - Buus, Søren
AU - Sims, Stuart
AU - Hickling, Stephen
AU - Riddell, Lynn
AU - Chen, Fabian
AU - Luzzi, Graz
AU - Edwards, Anne
AU - Phillips, Rodney
AU - Prado, Julia G.
AU - Goulder, Philip J.R.
PY - 2010/10
Y1 - 2010/10
N2 - The association between HLA-B*2705 and the immune control of human immunodeficiency virus type 1 (HIV-1) has previously been linked to the targeting of the HLA-B*2705-restricted Gag epitope KRWIILGLNK (KK10) by CD8+ T cells. In order to better define the mechanisms of the HLA-B*2705 immune control of HIV, we first characterized the CD8 + T-cell responses of nine highly active antiretroviral therapy (HAART)-naïve B*2705-positive subjects. Unexpectedly, we observed a strong response to an HLA-B*2705-restricted Pol epitope, KRKGGIGGY (KY9), in 8/9 subjects. The magnitude of the KY9 response was only marginally lower than that of the KK10-specific response (median, 695 versus 867 spot-forming cells [SFC]/million peripheral blood mononuclear cells [PBMCs]; not significant [NS]), and viral escape mutants were observed in both KY9 and KK10, resulting from selection pressure driven by the respective CD8+ T-cell response. By comparing inhibitions of viral replication by CD8+ T cells specific for the Gag KK10, Pol KY9, and Vpr VL9 HLA-B*2705- restricted epitopes, we observed a consistent hierarchy of antiviral efficacy (Gag KK10 > Pol KY9 > Vpr VL9). This hierarchy was associated with early recognition of HIV-1-infected cells, within 6 h of infection, by KK10-and KY9-specific CD8+ T cells but not until 18 h postinfection by VL9-specific CD8+ T cells. There was no association between antiviral efficacy and proliferative capacity, cytotoxicity, polyfunctionality, or T-cell receptor (TCR) avidity. These data are consistent with previous studies indicating an important role for the B*2705-Gag KK10 response in the control of HIV but also suggest a previously unrecognized role played by the subdominant Pol-specific KY9 response in HLA-B*2705-mediated control of HIV and that the recognition of HIV-infected cells by CD8+ T cells early in the viral life cycle may be important for viral containment in HIV-infected individuals.
AB - The association between HLA-B*2705 and the immune control of human immunodeficiency virus type 1 (HIV-1) has previously been linked to the targeting of the HLA-B*2705-restricted Gag epitope KRWIILGLNK (KK10) by CD8+ T cells. In order to better define the mechanisms of the HLA-B*2705 immune control of HIV, we first characterized the CD8 + T-cell responses of nine highly active antiretroviral therapy (HAART)-naïve B*2705-positive subjects. Unexpectedly, we observed a strong response to an HLA-B*2705-restricted Pol epitope, KRKGGIGGY (KY9), in 8/9 subjects. The magnitude of the KY9 response was only marginally lower than that of the KK10-specific response (median, 695 versus 867 spot-forming cells [SFC]/million peripheral blood mononuclear cells [PBMCs]; not significant [NS]), and viral escape mutants were observed in both KY9 and KK10, resulting from selection pressure driven by the respective CD8+ T-cell response. By comparing inhibitions of viral replication by CD8+ T cells specific for the Gag KK10, Pol KY9, and Vpr VL9 HLA-B*2705- restricted epitopes, we observed a consistent hierarchy of antiviral efficacy (Gag KK10 > Pol KY9 > Vpr VL9). This hierarchy was associated with early recognition of HIV-1-infected cells, within 6 h of infection, by KK10-and KY9-specific CD8+ T cells but not until 18 h postinfection by VL9-specific CD8+ T cells. There was no association between antiviral efficacy and proliferative capacity, cytotoxicity, polyfunctionality, or T-cell receptor (TCR) avidity. These data are consistent with previous studies indicating an important role for the B*2705-Gag KK10 response in the control of HIV but also suggest a previously unrecognized role played by the subdominant Pol-specific KY9 response in HLA-B*2705-mediated control of HIV and that the recognition of HIV-infected cells by CD8+ T cells early in the viral life cycle may be important for viral containment in HIV-infected individuals.
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U2 - 10.1128/JVI.00793-10
DO - 10.1128/JVI.00793-10
M3 - Article
C2 - 20686036
AN - SCOPUS:77957195721
SN - 0022-538X
VL - 84
SP - 10543
EP - 10557
JO - Journal of virology
JF - Journal of virology
IS - 20
ER -