This is a competing continuation proposal that will look at the dissemination of HIV into central nervous system tissue using a model of the blood/brain barrier which depends on the culture of endothelial cells and astrocytes. This model allows the analysis of binding and transmigration of leukocytes and monocytes. The principal hypothesis underlying this proposal is that the HIV-1 protein will alter adhesion molecules and chemokine expression of endothelial cells such that transmigration will be altered, probably enhanced. In addition, the principal investigator proposes that the binding and migration of infected cells across the blood/brain barrier, as well as exposure to tat, will have an impact on the structural integrity and permeability of that barrier. The PI and collaborators will test these hypothesis with the following specific aims: (1) to determine the effect of tat on monocyte and lymphocyte transmigration across a co-culture of human brain microvascular endothelial cells and astrocytes; (2) to characterize second messenger and signal transduction pathways involved in tat-induced adhesion molecule and monocyte chemoattractant protein 1 (MCP-1) expression by brain microvascular endothelial cells; (3) to examine the effect of tat on the structure of endothelial cells in culture. In addition, the principal investigators will (4) assess chemokine and chemokine receptor and adhesion molecular expression in pediatrics AIDS encephalitis, and (5) they will analyze the effect of tat on chemokine and chemokine receptor expression by human microglia. In addition, they will analyze the auto-regulation of chemokine and chemokine receptor expression by chemokines added exogenously.
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