Abstract
There is now considerable in vitro evidence that tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is involved in HIV-1 pathogenesis by inducing CD4+ T-cell death characteristic of AIDS. Therefore, we have tested levels of TRAIL in plasma samples from 107 HIV-1-infected and 53 uninfected controls as well as in longitudinal plasma samples from patients who started antiretroviral therapy (ART). TRAIL was elevated in plasma of HIV-1-infected patients compared with uninfected individuals, and patients receiving ART showed decreased plasma TRAIL levels that correlated with reduction in viral load. In vitro exposure to infectious and noninfectious HIV-1 induced TRAIL in monocytes and marginally in dendritic cells (DCs) but not in macrophages or T cells. Interestingly, the HIV-1 entry inhibitor, soluble CD4, blocked HIV-1-induced production of TRAIL. Furthermore, production and gene expression of TRAIL by monocytes were regulated by type I interferon via signal transducer and activator of transcription-1 (STAT1)/STAT2 signaling molecule. Ex vivo HIV-1 infection of human tonsil lymphoid tissue also resulted in increased TRAIL production. We demonstrate here that plasma TRAIL is elevated in HIV-1-infected patients and is decreased by ART therapy. The high production of TRAIL by antigen-presenting cells may contribute to the death of CD4+ T cells during progression to AIDS.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Acquired Immunodeficiency Syndrome / drug therapy
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Acquired Immunodeficiency Syndrome / immunology*
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Acquired Immunodeficiency Syndrome / metabolism
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Acquired Immunodeficiency Syndrome / pathology
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Apoptosis Regulatory Proteins / biosynthesis
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Apoptosis Regulatory Proteins / immunology*
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CD4 Antigens / immunology
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CD4 Antigens / pharmacology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / pathology
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CD4-Positive T-Lymphocytes / virology
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Cell Death / immunology
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Cells, Cultured
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism
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Dendritic Cells / pathology
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Dendritic Cells / virology
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Female
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / immunology*
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HIV-1 / immunology*
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Humans
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Interferon Type I / immunology
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Male
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / immunology*
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Monocytes / immunology*
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Monocytes / metabolism
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Monocytes / pathology
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Monocytes / virology
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STAT1 Transcription Factor / immunology
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STAT1 Transcription Factor / metabolism
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STAT2 Transcription Factor / immunology
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STAT2 Transcription Factor / metabolism
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Signal Transduction / immunology
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / immunology*
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Viral Load
Substances
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Apoptosis Regulatory Proteins
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CD4 Antigens
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Interferon Type I
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Membrane Glycoproteins
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STAT1 Transcription Factor
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STAT1 protein, human
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STAT2 Transcription Factor
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STAT2 protein, human
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tumor Necrosis Factor-alpha