FUNCTIONAL STUDIES OF HIV-TAT EFFECTS ON ENDOTHELIUM

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DESCRIPTION (Adapted from the applicant's description) The HIV-1 TAT protein is secreted from infected T-cells and monocyte-macrophages, and prior studies suggest it can potently alter endothelial growth, migration and adhesive interactions. The functional effects of TAT on endothelium appear to occur via its specific binding to the Flk-1/KDR receptor for vascular endothelial growth factor (VEGF) and to the alpha5 beta1, alphav beta3 and alphav beta5 surface integrins. This group recently have found that TAT can activate the FLT4 receptor for VEGF-C/VRP, as well as several Src kinase family members, the protein tyrosing phosphatase SHPTP-2, the focal adhesion kinases FAK and RAFTK/Pyk2 and the p44/42 MAP kinases Erk1 and 2. Moreover, TAT treatment of human umbilical vein endothelium cells (HUVEC) or bone marrow endothelium cells (BMEC) resulted in the release of nitric oxide (NO), increased protein levels of endothelial nitric oxide synthase (eNOS), and generation of the beta-chemokine monocyte chemotactic protein (MCP-1). NO is an important mediator of VEGF effects on vascular cell growth, chemotaxis and permeability. MCP-1 contributes to recruitment of monocyte-macrophages and T-cells and is believed to mediate transmigration of T-cells across an endothelial monolayer. The observations on TAT, coupled with previously reported work, suggest that it can subvert several vital endothelial functions by co-opting surface VEGF and integrin receptor triggered signal transduction pathways. This proposal seeks to systematically characterize the signaling pathways utilized by TAT in HUVEC and BMEC, and contrast them with those triggered by VEGF-A and VEGF-C/VRP, in order to determine the mechanisms of TAT-mediated mitogenesis, chemotaxis, adhesion molecule expression, and NO and MCP-1 release. The information obtained from these studies should help in defining how HIV-1 may cause endothelial dysfunction and injury, and assist in the creation of novel therapeutics to protect the HIV infected host.