1. HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu Natal, Durban 4013, South Africa
2. Partners AIDS Research Center, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115, USA
3. Nuffield Department of Medicine, The Peter Medawar Building for Pathogen Research, Oxford University, Oxford OX1 3SY, UK
4. Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
5. Emory Vaccine Center and Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA
6. Immunology Program, The Wistar Institute, Philadelphia, Pennsylvania 19104, USA
7. Howard Hughes Medical Institute, Chevy Chase, Maryland 20185, USA
8. *These authors contributed equally to this work

Correspondence to: Bruce D. Walker^1,2,7 Correspondence and requests for materials should be addressed to B.D.W. (Email: bwalker@partners.org).

Abstract

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^{1, 2, 3, 4}, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice⁵. 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 load⁵. 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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