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

Nat Immunol. 2007 Nov;8(11):1246-54. doi: 10.1038/ni1515. Epub 2007 Sep 30.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


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