It is generally agreed that the blood-brain barrier (BBB) is impaired in HIV-1 associated dementia (HAD). However, the mechanism for BBB dysfunction is not well understood. Post-mortem examination of brain tissue from subjects with HIV-1 encephalitis (HIVE) revealed that brain microvascular endothelial cell (BMVEC) tight junction (TJ) integrity is diminished and can be correlated with macrophage egress and HAD. How immune competent HIV-1 -infected macrophages influence BMVEC TJ expression and function resulting in BBB compromise is the focus of the proposal. To address this, we asked the following questions: 1) Do immune- activated and/or virus-infected monocytes affect BMVEC TJ assembly? 2) Can modulation of key signaling pathways (such as Rho) for regulation of cytoskeletal organization in BMVEC alter TJ function? 3) Can inhibition of Rho prevent monocyte migration into brain during HIVE? We will employ (a) primary cell models, (b) a functional BBB model consisting of BMVEC and astrocytes seeded on opposing sides of a porous membrane, and (c) a novel xenograft system for HIVE in which peripheral human peripheral blood lymphocytes and monocytes have been shown to migrate into brain parenchyma. These will provide clues about how TJ integrity may be manipulated pharmacologically. Such studies should have broad relevance in the pathogenesis of a wide range of neurodegenerative disorders.
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