Abstract:
The association between HLA-B*2705 and immune control of HIV-1 has previously been linked to targeting of the HLA-B*2705-restricted Gag epitope, KRWIILGLNK, by CD8+ T-cells. In order to better define the mechanisms of HLA-B*2705 immune control of HIV, we first characterized the CD8+ T-cell response in 9 HAART-naïve B*2705-positive subjects. Unexpectedly, we observed a strong response in 8/9 subjects to an HLA-B*2705-restricted Pol epitope, KRKGGIGGY (KY9). The magnitude of the KY9 response was only marginally lower than that of the KK10-specific response (median 695 vs 867 SFC/million PBMC; NS), and viral escape mutants were observed in both KY9 and KK10, resulting from selection pressure driven by the respective CD8+ T-cell response. Comparing inhibition of viral replication by CD8+ T-cells specific for the Gag-KK10, Pol-KY9 and Vpr-VL9 HLAB* 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 hrs of infection, by KK10- and KY9-specific CD8+ T-cells, but not until 18 hrs post-infection by VL9-specific CD8+ Tcells. There was no association between antiviral efficacy and proliferative capacity, cytotoxicity, polyfunctionality or TcR avidity. These data are consistent with previous studies indicating an important role for the B*2705-Gag-KK10 response in control of HIV, but also suggest a previously unrecognized role played by the subdominant Polspecific KY9 response in HLA-B*2705-mediated control of HIV; and that 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.
Authors: Payne RP, Kløverpris H, Sacha JB, Brumme Z, Brumme C, Buus S, Sims S, Hickling S, Riddell L, Chen F, Luzzi G, Edwards A, Phillips R, Prado JG, Goulder PJ.
