HIV envelope-directed signaling aberrancies and cell death of CD4+ T cells in the absence of TCR co-stimulation |
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Authors: | Tian Huan; Lempicki Richard; King Leslie; Donoghue Eileen; Samelson Lawrence E; Cohen David I |
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Institution: | Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health Bethesda, MD 20892, USA |
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Abstract: | HIV-1 infection in CD4+ T cells initiates a viral cytopathiceffect (CPE) that is dependent on the activation of intracellularprotein tyrosine kinases (PTK). PTK in T cells are also activatedduring the course of TCR or CD4 receptor engagement and themanner of receptor engagement may generate signals leading eitherto cell proliferation, tolerance induction (anergy) or programmedcell death (PCD). We have identified PTK triggered during theinteraction of cells stably expressing surface HIV envelope(gp120/gp41; HIVenv) and CD4+ T cells, which leads to extensiveand rapid individual cell death. We have found that this killingis accompanied by tyrosine phosphorylation and activation ofthe CD4-associated p56ick kinase, and by activation of a secondmember of the src family of PTK, p59fyn kinase, normally associatedwith T cell stimulation through the TCR. Interestingly, in contrastwith normal T cell signaling, the subunit of the TCR failsto become tyrosine-phosphorylated during signaling accompanyingHIV-directed cell killing. Downstream activation of the ZAP-70PTK also does not occur. Unlike T cell apoptosis triggered bysoluble HIVenv glycoproteins, which requires co-stimulationof CD4 and the antigen-specific TCR, T cell killing by membrane-associatedHIVenv does not require TCR co-stimulation, because aberrantsignaling and cell death are triggered by CD4+ but TCR–cell lines. These results are the first report where dual activationof the Lck and Fyn PTK does not result in normal downstreamsignaling through the ZAP PTK. We suggest by analogy to SCIDresulting from ZAP-70 mutations, that the dissociation of upstreamPTK activation from ZAP-70 signaling contributes to T cell depletionby HIV and to the development of AIDS. |
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Keywords: | cytopathic effect Fyn HIV-1 Lck protein tyrosine kinase |
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