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Nature Immunology 8, 1246–1254 (1 November 2007) | doi:10.1038/ni1515

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

Daniel E Kaufmann , Daniel G Kavanagh , Florencia Pereyra , John J Zaunders , Elizabeth W Mackey , Toshiyuki Miura , Sarah Palmer , Mark Brockman , Almas Rathod , Alicja Piechocka-Trocha , Brett Baker , Baogong Zhu , Sylvie Le Gall , Michael T Waring , Ryan Ahern , Kristin Moss , Anthony D Kelleher , John M Coffin , Gordon J Freeman , Eric S Rosenberg & Bruce D Walker

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.