Prolonged Exposure to HIV Reinforces a Poised Epigenetic Program for PD-1 Expression in Virus-specific CD8 T Cells

Antigen-specific CD8 T cells play a critical role in controlling HIV infection but eventually lose antiviral functions in part because of expression and signaling through the inhibitory PD-1 receptor. To better understand the impact of prolonged TCR ligation on regulation of PD-1 expression in HIV-specific CD8 T cells we investigated the capacity of virus-specific CD8 T cells to modify the PD-1 epigenetic program following reduction in viral load. We observed that the transcriptional regulatory region was unmethylated in the PD-1 hi HIV-specific CD8 T cells while it remained methylated in donor matched naïve cells at acute and chronic stages of infection. Surprisingly, the PD-1 promoter remained unmethylated in HIV-specific CD8 T cells from subjects with a viral load controlled by antiviral therapy for greater than 2 years or from elite controllers. Together these data demonstrate that the epigenetic program at the PD-1 locus becomes fixed following prolonged exposure to HIV virus.