Selective Upregulation of CTLA-4 on CD8+ T Cells Restricted by HLA-B*35Px Renders them to an Exhausted Phenotype in HIV-1 infection.

HLA-B35Px is associated with HIV-1 disease rapid progression to AIDS. However, the mechanism(s) underlying this deleterious effect of this HLA allele on HIV-1 infection outcome has not fully understood. CD8+ T cells play a crucial role to control the viral replication but impaired CD8+ T cells represent a major hallmark of HIV-1 infection. Here, we examined the effector functions of CD8+ T cells restricted by HLA-B35Px (HLA-B35:03 and HLA-B35:02), HLA-B27/B57 and non-HLA-B27/B57 (e.g. HLA-A01, A02, A03, A11, A24, A26, B40, B08, B38, B44). CD8+ T cells restricted by HLA-B35Px exhibited an impaired phenotype compared with those restricted by HLA-B27/B57 and even non-HLA-B27/B57. CD8+ T cells restricted by non-HLA-B27/B57 when encountered their cognate epitopes upregulated TIM-3 and thus became suppressed by regulatory T cells (Tregs) via TIM-3: Galectin-9 (Gal-9). Strikingly, CD8+ T cells restricted by HLA-B35Px expressed fewer TIM-3 and therefore did not get suppressed by Tregs, which was similar to CD8+ T cells restricted by HLA-B27/B57. Instead, CD8+ T cells restricted by HLA-B35Px upon recognition of their cognate epitopes upregulated CTLA-4. The transcriptional and impaired phenotype (e.g. poor effector functions) of HIV-specific CD8+ T cells restricted by HLA-B35 was related to persistent CTLA-4, elevated Eomes and blimp-1 but poor T-bet expression. As such, anti-CTLA-4 antibody, Ipilimumab, reversed the impaired proliferative capacity of antigen-specific CD8+ T cells restricted by HLA-B35Px but not others. This study supports the concept that CD8+ T resistance to Tregs-mediated suppression is related to allele restriction rather than the epitope specificity. Our results aid to explain a novel mechanism for the inability of HIV-specific CD8+ T cells restricted by HLA-B35Px to control viral replication.