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-B*35Px 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-B*35Px (HLA-B*35:03 and HLA-B*35:02), HLA-B*27/B57 and non-HLA-B*27/B57 (e.g. HLA-A*01, A*02, A*03, A*11, A*24, A*26, B*40, B*08, B*38, B*44). CD8(+)T cells restricted by HLA-B*35Px exhibited an impaired phenotype compared with those restricted by HLA-B*27/B57 and even non-HLA-B*27/B57. CD8(+)T cells restricted by non-HLA-B*27/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-B*35Px expressed fewer TIM-3 and therefore did not get suppressed by Tregs, which was similar to CD8(+)T cells restricted by HLA-B*27/B57. Instead, CD8(+)T cells restricted by HLA-B*35Px 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-B*35 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-B*35Px 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-B*35Px to control viral replication. Author summary A rare group of HIV-infected individuals with HLA-B*35Px rapidly progress to AIDS but those with HLA-B*27 and HLA-B*57 spare disease progression. Previous studies have suggested that viral mutation may prevent a robust immune response against the virus in these with HLA-B*35Px. However, the functionality of HIV-specific CD8(+)T cells restricted by HLA-B*35Px remains unclear. In this study, we demonstrate that HIV-specific CD8(+)T cells restricted by HLA-B*35Px (HLA-B*35:03 and HLA-B*35:02) exhibit an impaired phenotype (e.g. low proliferative capacity, poor cytotoxic molecules expression and, poor cytokine production ability). Interestingly, CD8(+)T cells restricted by HLA-B*27/B*57 evade regulatory T cells (Tregs) suppression but not those restricted by non-HLA-B*27/B*57. CD8(+)T cells restricted by non-HLA-B*27/B*57 when encountering their epitopes upregulate TIM-3 but not those restricted by HLA-B*27/B*57 and HLA-B*35Px. As a result, CD8(+)T cells restricted by non-HLA-B*27/B*57 become suppressed by Tregs via TIM-3: Galectin-9 interactions. Strikingly, CD8(+)T cells restricted by HLA-B*35Px upregulate CTLA-4 when encountering their epitopes, which render them to an exhausted phenotype. This differential response is linked to the up-regulation of Eomes, Blimp-1 but low T-bet expression in CD8(+)T cells restricted by HLA-B*35Px. These results implicate that reinvigoration of these cells might be feasible using an anti-CTLA-4 antibody.