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.

1. Partners AIDS Research Center, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115, USA.
2. Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
3. Centre for Immunology, St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.
4. Howard Hughes Medical Institute, Chevy Chase, Maryland 20185, USA.
5. HIV Drug Resistance Program, National Cancer Institute, National Institutes of Health, Frederick, Maryland 21702, USA.
6. Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
7. These authors contributed equally to this work.

Correspondence to: Daniel E Kaufmann^1,7 e-mail: dkaufmann@partners.org

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