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

• Type of Material: Article
• Authors: Benjamin Youngblood, Emory University; Alessandra Noto, Vaccine and Gene Therapy Institute of Florida; Filippos Porichis, Harvard University; Rama Akondy, Emory University; Zaza M. Ndhlovu, Harvard University; James W. Austin, Emory University; Rebeka Bordi, Vaccine and Gene Therapy Institute of Florida; Francesco A. Procopio, Vaccine and Gene Therapy Institute of Florida; Toshiyuki Miura, Nagasaki University; Todd M. Allen, Harvard University; John Sidney, La Jolla Institute for Allergy and Immunology; Alessandro Sette, La Jolla Institute for Allergy and Immunology; Bruce D. Walker, Harvard University; Rafi Ahmed, Emory University; Jeremy Boss, Emory University; Rafick-Pierre Sekaly, Vaccine and Gene Therapy Institute of Florida; Daniel E. Kaufmann, Harvard University
• Language: English
• Date: 2013-07-15
• Publisher: American Association of Immunologists
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2013 by The American Association of Immunologists, Inc.
• Final Published Version (URL): http://dx.doi.org/10.4049/jimmunol.1203161
• Title of Journal or Parent Work: Journal of Immunology
• ISSN: 0022-1767
• Volume: 191
• Issue: 2
• Start Page: 540
• End Page: 544
• Grant/Funding Information: This work was supported by National Institutes of Health (NIH) grants P01 AI080192-04 (to R.A., J.M.B, R.P.S, D.E.K.), R37 AI30048-17 (to R.A.), American Cancer Society (A.C.S) postdoctoral fellowship PF-09-134-01-MPC (to B.A.Y.), and NIH R01 HL092565 (to D.E.K)
• Keywords: COMMITMENT; REPLICATION; LIGANDS; Life Sciences & Biomedicine; EXHAUSTION; MEMORY; CHRONIC VIRAL-INFECTION; PERSISTENCE; Immunology; TISSUE; DEMETHYLATION; Science & Technology; ANTIRETROVIRAL THERAPY
• Research Categories: Health Sciences, Immunology

Abstract

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.