Multi-step co-evolution of HIV-1 and HLA-C-restricted HIV-1-specific CD8+ T cells and the association with disease progression

Disease progression during HIV-1 infection is proposed to correlate with the accumulation of virus variants that have evaded HIV-1-specific T cells; however, the multi-step co-evolution of HIV-1 with HIV-1-specific T cells has not been well investigated. Here, we analyzed the co-evolution of HIV-1 with HLA-C*14-restricted HIV-1-specific T cells in treatment-naïve HLA-C*14+ people living with HIV-1 (PLWH). The analyses of T cells specific for NefYT9-wild-type (WT) or escape mutant epitopes and HIV-1 sequences in HLA-C*14+ PLWH suggested that NefQ125H was first selected by NefYT9-WT-specific T cells, then NefQ125D was selected by NefYT9-6H-specific T cells. This co-evolution was confirmed by longitudinal analysis of HLA-C*14+ PLWH. The CD4 count in NefQ125D virus-infected HLA-C*14+ individuals was significantly lower than that in WT-virus-infected HLA-C*14+ individuals, suggesting that accumulation of the NefQ125D mutant epitope correlates with disease progression. Our findings demonstrate that the multi-step co-evolution of HIV-1 with HLA-C-restricted HIV-1-specific T cells is associated with disease progression in HIV-1 infection.