Cutting Edge: Prolonged Exposure to HIV Reinforces a Poised Epigenetic Program for PD-1 Expression in Virus-Specific CD8 T Cells

• Published in: The Journal of immunology (1950) Vol. 191; no. 2; pp. 540 - 544
• Main Authors: Youngblood, Ben, Noto, Alessandra, Porichis, Filippos, Akondy, Rama S, Ndhlovu, Zaza M, Austin, James W, Bordi, Rebeka, Procopio, Francesco A, Miura, Toshiyuki, Allen, Todd M, Sidney, John, Sette, Alessandro, Walker, Bruce D, Ahmed, Rafi, Boss, Jeremy M, Sékaly, Rafick-Pierre, Kaufmann, Daniel E
• Format: Journal Article
• Language: English
• Published: United States 15.07.2013
• Subjects: Antiretroviral Therapy, Highly Active; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; DNA Methylation; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - virology; HIV-1 - immunology; Human immunodeficiency virus; Humans; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - metabolism; Promoter Regions, Genetic; Transcription, Genetic; Viral Load
• ISSN: 0022-1767; 1550-6606; 1550-6606
• DOI: 10.4049/jimmunol.1203161

Ag-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 programmed death-1 (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 after reduction in viral load. We observed that the transcriptional regulatory region was unmethylated in the PD-1hi HIV-specific CD8 T cells, whereas it remained methylated in donor-matched naive 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 >2 y or from elite controllers. Together, these data demonstrate that the epigenetic program at the PD-1 locus becomes fixed after prolonged exposure to HIV virus.