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Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction

Nature Immunology volume 8, pages 1246–1254 (2007)Cite this article

Abstract

In progressive viral infection, antiviral T cell function is impaired by poorly understood mechanisms. Here we report that the inhibitory immunoregulatory receptor CTLA-4 was selectively upregulated in human immunodeficiency virus (HIV)–specific CD4+ T cells but not CD8+ T cells in all categories of HIV-infected subjects evaluated, with the exception of rare people able to control viremia in the absence of antiretroviral therapy. CTLA-4 expression correlated positively with disease progression and negatively with the capacity of CD4+ T cells to produce interleukin 2 in response to viral antigen. Most HIV-specific CD4+ T cells coexpressed CTLA-4 and another inhibitory immunoregulatory receptor, PD-1. In vitro blockade of CTLA-4 augmented HIV-specific CD4+ T cell function. These data, indicating a reversible immunoregulatory pathway selectively associated with CD4+ T cell dysfunction, provide a potential target for immunotherapy in HIV-infected patients.

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Figure 1: CTLA-4 is upregulated in HIV-specific CD4+ T cells.
Figure 2: Markers of disease progression are associated with CTLA-4 expression and failure to produce IL-2, but not with IFN-γ production, in HIV-specific CD4+ T cells.
Figure 3: Effect of viral load control by antiviral therapy on CTLA-4 expression in HIV-specific CD4+ T cells.
Figure 4: CTLA-4 blockade restores HIV-specific but not CMV-specific CD4+ T cell function.
Figure 5: Relationship between the expression of CTLA-4 and PD-1 by HIV-specific CD4+ T cells and a comparison of the functional effect of cosignaling blockade.

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Acknowledgements

We thank all study participants for their help, and J. Lieberman and C. Day for comments on the manuscript. Supported by the Harvard University Center for AIDS Research (D.E.K. and B.D.W.), Massachusetts General Hospital (Executive Committee on Research bridge funding grant to D.E.K.), the National Institutes of Health (B.D.W., E.S.R., D.G.K. and G.J.F.), the Foundation for the National Institutes of Health through the Grand Challenges in Global Health initiative (G.J.F.), the Howard Hughes Medical Institute (B.D.W.) and the Mark and Lisa Schwartz Foundation.

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  1. Daniel E Kaufmann and Daniel G Kavanagh: These authors contributed equally to this work.

Authors and Affiliations

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

    Daniel E Kaufmann, Daniel G Kavanagh, Florencia Pereyra, Elizabeth W Mackey, Toshiyuki Miura, Mark Brockman, Almas Rathod, Alicja Piechocka-Trocha, Brett Baker, Sylvie Le Gall, Michael T Waring, Ryan Ahern, Kristin Moss, Eric S Rosenberg & Bruce D Walker

  2. Division of Infectious Diseases, Brigham and Women's Hospital, Boston, 02115, Massachusetts, USA

    Florencia Pereyra

  3. Centre for Immunology, St Vincent's Hospital, Darlinghurst, 2010, New South Wales, Australia

    John J Zaunders & Anthony D Kelleher

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

    Toshiyuki Miura, Mark Brockman, Alicja Piechocka-Trocha, Michael T Waring & Bruce D Walker

  5. HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, 21702, Maryland, USA

    Sarah Palmer & John M Coffin

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

    Baogong Zhu & Gordon J Freeman

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Contributions

D.E.K. was responsible for the overall design and conduct; D.E.K., D.G.K., J.J.Z. and B.D.W. contributed to the experimental design; D.G.K., J.J.Z., M.B., J.M.C., A.D.K., G.J.F., E.S.R. and B.D.W. contributed intellectual input; D.E.K., D.G.K., F.P., E.W.M., T.M., S.P. and A.R. did experiments; F.P., A.P.-T., B.B., S.L.G., R.A., K.M. and E.S.R. provided clinical samples; B.Z. and G.J.F. provided monoclonal antibodies to PD-1 and PD-L1; M.T.W. provided technical assistance for flow cytometry; D.E.K., D.G.K. and B.D.W. wrote the paper; and B.D.W. provided supervision.

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Correspondence to Daniel E Kaufmann.

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Competing interests

G.J.F. has patents and patent application for CTLA-4, PD-1 and PD-1 ligands and their use to modulate immune responses.

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Kaufmann, D., Kavanagh, D., Pereyra, F. et al. Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction. Nat Immunol 8, 1246–1254 (2007). https://doi.org/10.1038/ni1515

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