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

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.

• Authors: 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
• Journal: Nature immunology (Nat Immunol) Vol. 8 Issue 11 Pg. 1246-54 (Nov 2007) ISSN: 1529-2908 [Print] United States
• PMID: 17906628 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• Antigens, Differentiation
• Apoptosis Regulatory Proteins
• CTLA-4 Antigen
• CTLA4 protein, human
• Cytokines
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor

Topics

• Antigens, CD (immunology, metabolism)
• Antigens, Differentiation (metabolism)
• Apoptosis Regulatory Proteins (immunology, metabolism)
• CD4-Positive T-Lymphocytes (immunology, metabolism, virology)
• CD8-Positive T-Lymphocytes (immunology, metabolism, virology)
• CTLA-4 Antigen
• Cytokines (metabolism)
• Disease Progression
• HIV Infections (immunology, metabolism)
• Humans
• Polymerase Chain Reaction
• Programmed Cell Death 1 Receptor
• Up-Regulation
• Viral Load