Abstract
Progressive loss of T cell functionality is a hallmark of chronic infection with human immunodeficiency virus 1 (HIV-1). We have identified a novel population of dysfunctional T cells marked by surface expression of the glycoprotein Tim-3. The frequency of this population was increased in HIV-1-infected individuals to a mean of 49.4 +/- SD 12.9% of CD8(+) T cells expressing Tim-3 in HIV-1-infected chronic progressors versus 28.5 +/- 6.8% in HIV-1-uninfected individuals. Levels of Tim-3 expression on T cells from HIV-1-infected inviduals correlated positively with HIV-1 viral load and CD38 expression and inversely with CD4(+) T cell count. In progressive HIV-1 infection, Tim-3 expression was up-regulated on HIV-1-specific CD8(+) T cells. Tim-3-expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the Tim-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1-specific T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1-associated T cell dysfunction.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens, CD / genetics
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Antigens, CD / immunology
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Antiretroviral Therapy, Highly Active
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / immunology
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Disease Progression
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Extracellular Signal-Regulated MAP Kinases / genetics
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Extracellular Signal-Regulated MAP Kinases / immunology
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GATA3 Transcription Factor / genetics
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GATA3 Transcription Factor / immunology
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HIV Infections / drug therapy
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HIV Infections / immunology*
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HIV Infections / pathology
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HIV Infections / physiopathology
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HIV-1 / immunology*
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HIV-1 / pathogenicity
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HLA Antigens
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Hepatitis A Virus Cellular Receptor 2
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Humans
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Membrane Proteins / genetics
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Membrane Proteins / immunology*
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Phenotype
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Programmed Cell Death 1 Receptor
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / immunology
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Signal Transduction / immunology
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / immunology
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocytes / cytology
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T-Lymphocytes / immunology*
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / immunology
Substances
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Antigens, CD
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Apoptosis Regulatory Proteins
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GATA3 Transcription Factor
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HAVCR2 protein, human
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HLA Antigens
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Hepatitis A Virus Cellular Receptor 2
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Membrane Proteins
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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STAT5 Transcription Factor
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T-Box Domain Proteins
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T-box transcription factor TBX21
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Extracellular Signal-Regulated MAP Kinases
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p38 Mitogen-Activated Protein Kinases