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Programmed death-1 expression on CD4+ and CD8+ T cells in treated and untreated HIV disease

Cockerham, Leslie R.a; Jain, Viveka; Sinclair, Elizabethb; Glidden, David V.c; Hartogenesis, Wendya; Hatano, Hiroyua; Hunt, Peter W.a; Martin, Jeffrey N.c; Pilcher, Christopher D.a; Sekaly, Rafickd; McCune, Joseph M.b; Hecht, Frederick M.a; Deeks, Steven G.a

doi: 10.1097/QAD.0000000000000314
Clinical Science

Background: There is intense interest in the role of programmed death 1 (PD-1) in causing persistent T-cell dysfunction in HIV infection. However, the impact of HIV infection and antiretroviral treatment (ART) on the expression of PD-1 on T cells is still poorly defined.

Methods: PD-1 was measured longitudinally in a cohort of recently HIV-infected individuals (n = 121) who started ART early (<6 months after infection) vs. later (≥2 years after infection). PD-1 was also measured cross-sectionally in a diverse cohort of chronically HIV-infected adults (n = 206).

Results: PD-1 expression levels were high on CD8+ T cells during early HIV infection. PD-1 levels increased on both CD4+ and CD8+ T cells populations in those who delayed therapy (11 and 10%/year, respectively). PD-1 levels declined and were similar in those treated early vs. late after 1 year of ART. In both cohorts, PD-1 expression on CD4+ T cells was associated with CD4+ T-cell activation (CD38+HLA-DR+) and inversely with CD4+ cell count. In contrast, PD-1 expression on CD8+ T cells was most strongly associated with CD8+ T-cell activation and with plasma viral load in viremic individuals.

Conclusion: Across two large cohorts of untreated and treated individuals, we found consistent associations between HIV RNA levels, CD8+ T-cell activation and PD-1 expression on CD8+ T cells. In contrast, CD4+ T-cell counts and CD4+ T-cell activation were more consistent correlates of PD-1 expression on CD4+ T cells. PD-1 expression appears to be driven by both direct antigen and homeostatic pathways.

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aHIV/AIDS Division, San Francisco General Hospital

bDivision of Experimental Medicine

cDepartment Epidemiology and Biostatistics, UCSF, San Francisco, California

dVaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, USA.

Correspondence to Leslie Cockerham, MD, HIV/AIDS Division, San Francisco General Hospital, University of California, San Francisco, Box 0874, San Francisco, CA 94143-0874, USA. Tel: +1 415 476 4082 x334; fax: +1 415 476 6953; e-mail:

Received 10 March, 2014

Revised 16 April, 2014

Accepted 16 April, 2014

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website (

© 2014 Lippincott Williams & Wilkins, Inc.