HIV- I infection of the central nervous system (CNS) has been demonstrated to be an early event after initial exposure, leading to common and serious brain dysfunction such as HIV- I encephalopathy. At present, the underlying pathogenesis of how HIV-1 enters the CNS and causes encephalopathy is not completely understood. The overall objective of this proposal is to determine whether HIV-1 or HIV-1 proteins can modulate brain endothelial cells and may enhance traversal of (HIV-1 infected) monocyte / macrophages into CNS, thereby perpetuating HIV-1 encephalopathy. HIV-1 may enter the brain by directly infecting brain endothelium, by crossing endothelium via absorbtive endocytosis, or via transcytosis of HIV-1 infected monocyte/ macrophages. Once HIV-1 is inside the CNS, it can trigger a cascade of events contributing to neurotoxicity and enhancing the immunopathological process. Since brain endothelium is a critical barrier to pathogens such as HIV- 1, it is critical to understand its role in HIV- I CNS infection. To this end, we have isolated and characterized human brain microvascular endothelial cells (HBMEC) and created an in vitro model of the (BBB) blood brain barrier by cultivating HBMEC on semipermeable tissue culture inserts. We showed that HIV- I envelope glycoprotein gpl2O, which is shed into the circulation of HIV- I infected patients is able to activate HBMEC, e.g., increase VCAM-1, ICAM-1 expression, PECAM-1 phosphorylation, monolayer permeability and monocyte transmigration. The proposed experiments are designed to further dissect the possible mechanisms of HIV-1 traversal across the blood brain barrier. This application is in response to RFA MH-00-010 to investigate mechanisms of HIV-1 trafficking in the CNS.
Specific aims are as follows: 1-To further assess in vitro models of the human blood brain barrier. 2-To characterize the in vitro human BBB model in response to HIV-1. 3-To examine whether HIV-1 enhances traversal of monocytes across in vitro model of the human BBB. By characterizing the individual steps involved in entry of monocytes into the brain, a better understanding of the pathogenesis of HIV-1-1 encephalopathy will be obtained and strategies may be developed to halt this process.
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