Abstract
Activation through the TCR and the costimulatory molecule CD28 influences the susceptibility of T cells to HIV-1 infection and regulates proviral gene expression. Signaling events initiated by CD28 that directly impact HIV-1 transcription have not been fully characterized. T cell lines expressing CD8alpha/28 chimeric receptors containing a mutation in tyrosine 173 to phenylalanine, which inhibits the recruitment of phosphatidylinositol 3-kinase (PI3K) to CD28, expressed higher levels of HIV-1 following T cell activation. Whereas constitutively active PI3K decreased provirus transcription, inhibiting endogenous PI3K with specific inhibitors or by overexpressing PTEN phosphatase enhanced HIV-1 expression. PI3K-dependent inhibition required the viral Tat protein and a trans activation response region element. Tat pull-down and coimmunoprecipitation experiments indicate that PI3K affects the formation of the Tat-associated kinase trans-activating complex. These studies demonstrate that PI3K negatively impacts HIV-1 transcription and that Tat activity is sensitive to T cell signaling events.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antiviral Agents / genetics
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Antiviral Agents / physiology*
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CD28 Antigens / genetics
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CD28 Antigens / immunology
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CD28 Antigens / metabolism
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CD28 Antigens / physiology*
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CHO Cells
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Cell Line
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Cricetinae
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Down-Regulation / genetics
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Down-Regulation / immunology
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Enzyme Activation / genetics
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Enzyme Inhibitors / pharmacology
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Gene Products, tat / antagonists & inhibitors*
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Gene Products, tat / physiology*
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HIV-1 / genetics*
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Humans
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Jurkat Cells
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Mutagenesis, Site-Directed
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphatidylinositol 3-Kinases / physiology*
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Phosphoinositide-3 Kinase Inhibitors
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Proviruses / genetics
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Proviruses / metabolism
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Transcription, Genetic / immunology*
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Up-Regulation / genetics
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Up-Regulation / immunology
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tat Gene Products, Human Immunodeficiency Virus
Substances
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Antiviral Agents
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CD28 Antigens
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Enzyme Inhibitors
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Gene Products, tat
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Phosphoinositide-3 Kinase Inhibitors
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tat Gene Products, Human Immunodeficiency Virus