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

Nature volume 443, pages 350–354 (2006)Cite this article

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 cells1,2,3,4, 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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Figure 1: PD-1 is upregulated on HIV-specific CD8 T cells.
Figure 2: PD-1 expression is associated with HIV disease progression.
Figure 3: Blockade of the PD-1/PD-L1 pathway significantly increases expansion of tetramer + cells and frequency of HIV-specific, IFN-γ-producing CD8 T cells.
Figure 4: Effect of PD-1 expression on CD4 T cells.

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Acknowledgements

This work was supported by a Royal Society postdoctoral fellowship (C.L.D.), the Harvard University Center for AIDS Research (D.E.K. and B.D.W.), grants from the Doris Duke Charitable Foundation (B.D.W.), the NIH (B.D.W., G.J.F., R.A., P.J.R.G.), the Howard Hughes Medical Institute (B.D.W.); a grant from the Foundation for the National Institutes of Health through the Grand Challenges in Global Health initiative (G.J.F. and R.A.), a contract from the NIH (B.D.W.), and the Mark and Lisa Schwartz Foundation. We thank S. Chetty, N. Ismail, N. Mkhwanazi, K. Nair, A. Piechocka-Trocha, A. Rathod and M. Vanderstock for technical assistance.

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  1. Cheryl L. Day and Daniel E. Kaufmann: *These authors contributed equally to this work

Authors and Affiliations

  1. HIV Pathogenesis Programme, Doris Duke Medical Research Institute, University of KwaZulu Natal, 4013, Durban, South Africa

    Cheryl L. Day, Photini Kiepiela, Eshia S. Moodley, Sharon Reddy, Chantal DePierres, Zenele Mncube, Hoosen M. Coovadia, Philip J. R. Goulder & Bruce D. Walker

  2. Partners AIDS Research Center, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Cheryl L. Day, Daniel E. Kaufmann, Elizabeth W. Mackey, Quentin Eichbaum, Marcus Altfeld, Philip J. R. Goulder & Bruce D. Walker

  3. Nuffield Department of Medicine, The Peter Medawar Building for Pathogen Research, Oxford University, OX1 3SY, Oxford, UK

    Cheryl L. Day, Alasdair J. Leslie, Philip J. R. Goulder & Paul Klenerman

  4. Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Julia A. Brown, Baogong Zhu & Gordon J. Freeman

  5. Emory Vaccine Center and Department of Microbiology & Immunology, Emory University School of Medicine, Atlanta, Georgia, 30322, USA

    Joseph D. Miller, Jaikumar Duraiswamy & Rafi Ahmed

  6. Immunology, Emory University School of Medicine,

    Joseph D. Miller, Jaikumar Duraiswamy & Rafi Ahmed

  7. Immunology Program, The Wistar Institute, Philadelphia, Pennsylvania, 19104, USA

    E. John Wherry

  8. Howard Hughes Medical Institute, Chevy Chase, Maryland, 20185, USA

    Bruce D. Walker

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Correspondence to Bruce D. Walker.

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Supplementary information

Supplementary Notes

This file contains Supplementary Figures 1–4 and Supplementary Table 1. These figures provide supporting data indicating that PD-1 expression is associated with functional impairment of HIV-specific CD8 T cells, and that PD-1 expression on HIV-specific CD8 T cells and total CD8 T cells is associated with viral load and absolute CD4 count. Supplementary Table 1 lists the MHC Class I tetramers used in this study. (PDF 1041 kb)

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Day, C., Kaufmann, D., Kiepiela, P. et al. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443, 350–354 (2006). https://doi.org/10.1038/nature05115

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