Protective HLA class I alleles drive the differences in HIV-1–specific CD8 T-cell proliferative capacity between controllers and ART-treated or untreated progressors. (A) Flow cytometry of CFSE-labeled CD8 T cells from 3 representative HLA-B*2705 subjects incubated with no antigen, the B*2705-restricted HIV-1 optimal epitope B*2705-KK10, or the HIV-1 optimal epitope B*2705-GY10. Numbers in top left quadrants indicate percent CD3⁺CD8⁺CFSE^low cells. Whereas robust proliferative responses were observed in the HIV-1 controller subject (i), no significant responses were present in the progressor (ii) or ART-treated (iii) subjects. Responses to both epitopes were detected by IFN-γ Luminex assay in all 3 subjects studied. (B) Hierarchical representation of HIV-1–infected subjects based on their mean proliferative response to panels of HLA-class I matched HIV-1 epitopes. Bars represent data for individual subjects. (C) Statistical analysis of mean proliferative responses among the 3 groups of HIV-1–infected subjects in the discovery cohort (n = 64). HC indicates HIV-1 controllers; CP, chronic progressors; and ARTC, ART-treated subject. (D) Statistical comparison of mean proliferative responses to epitopes restricted by protective versus nonprotective HLA-I alleles in all subjects. (E) Representative single-donor HIV-specific cytotoxic T-lymphocyte (CTL) proliferative responses stratified by protective and nonprotective restricting alleles. (F) Statistical analysis of intraindividual proliferative responses stratified by protective versus nonprotective HLA-I alleles in controllers, progressors, and ART-treated subjects. Throughout the figure, HC data are represented in blue; CP in red; and ARTC in green; protective HLA class I alleles (B*5701/03, B*2705 and B*5801) are shown in purple; and nonprotective HLA I alleles in orange. All comparisons of adjusted means were performed using generalized linear models controlling for clustering within subjects. Comparison of mean proliferative responses among the 3 groups were done by ANOVA, followed by posttest comparisons with Tukey. Comparisons of protective versus nonprotective alleles were performed with Student t test. Vertical interval bars correspond to the SEM.