Alcohol abuse is considered to be a ma or risk factor in the development of HIV-associated dementia. In addition, impaired function of the brain vasculature and disruption of the blood-brain barrier (BBB) might be critical factors in mechanisms of HIV-1 virus trafficking in the central nervous system (CNS). Evidence indicates that both alcohol and the viral gene product, the protein Tat, can induce injury or dysfunction of brain microvascular endothelial cells (BMEC), which can lead to the breakdown of the BBB. In the present grant application, we hypothesize that ethanol and Tat can cross-amplify their cytotoxic effects and exacerbate the disruption of the BBB. Thus, combined exposure to ethanol and Tat can lead to accelerated entry of the HIV-1 into the CNS. This hypothesis is strongly supported by our preliminary data, which suggest that exposure to both Tat and ethanol can markedly induce oxidative stress in BMEC. In addition, we demonstrated that induction of cellular oxidative stress can lead to decreased expression of specific transmembrane proteins, such as occludin, which build intercellular junctions, i.e., the structures responsible for the integrity of the brain endothelium and functional BBB. Based on these facts, we developed the leading hypothesis of the current proposal that combined exposure to ethanol and Tat can exacerbate the disruption of the integrity of the cerebral vascular endothelium through the induction of cellular oxidative stress and the subsequent alterations of junctional protein expression. This hypothesis will be studied using in vitro and in vivo experimental settings. In our animal studies, we will employ both acute and chronic models of alcohol exposure, combined with Tat treatment. The long term goals of the current proposal are to determine mechanisms which may prevent ethanol and Tat-induced injury to BMEC. Thus, data arising from this proposal will be critical for a better understanding of mechanisms responsible for disruption of the BBB during HIV-1 infection associated with alcohol abuse. We believe that a better knowledge of these processes will contribute to the possible development of therapeutic interventions to prevent IFIV- I entry into the CNS.
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