JOURNAL ARTICLE

PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression

Cheryl L Day, Daniel E Kaufmann, Photini Kiepiela, Julia A Brown, Eshia S Moodley, Sharon Reddy, Elizabeth W Mackey, Joseph D Miller, Alasdair J Leslie, Chantal DePierres, Zenele Mncube, Jaikumar Duraiswamy, Baogong Zhu, Quentin Eichbaum, Marcus Altfeld, E John Wherry, Hoosen M Coovadia, Philip J R Goulder, Paul Klenerman, Rafi Ahmed, Gordon J Freeman, Bruce D Walker
Nature 2006 September 21, 443 (7109): 350-4
16921384
Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.

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