Multistep coevolution of HIV-1 and human leukocyte antigen-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 multistep coevolution of HIV-1 with HIV-1-specific T cells has not been well investigated. Here, we analyzed the coevolution of HIV-1 with human leukocyte antigen (HLA)-C*14-restricted HIV-1-specific T cells in treatment-naive 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 coevolution 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 multistep coevolution of HIV-1 with HLA-C-restricted HIV-1-specific T cells is associated with disease progression in HIV-1 infection.