Application): The Nef proteins of the primate lentiviruses, human immunodeficiency virus types 1 and 2 (HIV-1 and HIV- 2), and the related simian immunodefiency virus (SIV), are reported to modulate transduction of T-cell activation signals emanating from the cell surface, and was shown to be necessary for maintaining high virus load and for inducing mechanism high load and for inducing AIDS in rhesus monkeys in the SIV model for Nef function. Presumably, the mechanism of the Nef-induced T-cell signaling defect involves physical interaction with one or more cellular factors involved in signal transduction. Previously, the investigators described physical interactions between the HIV-1 Nef protein and the c-Raf1 kinase in vitro, and have used deletion and site-specific mutagenesis techniques to map the site of the interaction to a well-conserved acidic sequence motif which is structurally similar to the Ha-Ras c-Raf1 binding site, at the carboxyl-terminal region of Nef. To identify which mechanism of the Nef-induced T-cell signaling defect in vivo, the wild-type T-cell lines with a retroviral expression vector. The nef-expressing T-cell lines will be stimulated with different mitogenic (Ionomycin, PHA, and PMA) and antigenic (anti-CD3 and anti-T-cell receptor antibodies) agents, and the response of the cell lines to T-cell activation will be monitored by measuring various T-cell activation markers. The results of this study should give us insights into the molecular mechanism of the Nef-induced T-cell signaling defect(s) in vivo and, in addition, significantly advance our understanding of the role of Nef in the pathogenesis of the virus.
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