Tat, Amyloid Beta and Brain Endothelial Barrier Function

One of the emerging problems in HIV/AIDS is an increase in an older population affected by HIV infection. This phenomenon is of significant concern, because aging is a predictor of rate of progression of HIV infection. Elderly patients develop AIDS more rapidly and have higher morbidity and mortality rates. Older patients are also more likely to develop AIDS-associated dementia. The present research application is focused on the mechanisms that may contribute to the development of dementia in elderly HIV -infected patients. Specifically, we propose to study the mechanisms related to the injury to the vascular endothelium and dysfunction of the blood brain barrier (BBB). Our research has concentrated on the hypothesis that the viral gene product, HIV Tat protein, can be responsible for brain microvascular endothelial cells (BMEC) injury and impaired normal function of the BBB. Furthermore, aging is associated with increased deposits of amyloid ~-peptide (A~) which also can induce dysfunction of BMEC. Therefore, it is striking to notice that A~ and HIV Tat protein may work in concert in older HIV patients to induce impaired function of the brain vascular endothelium and contribute to the development of neuroAIDS. In the present grant application, we hypothesize that A~ and Tat can crossamplify their cytotoxic effects and exacerbate the disruption of the BBB. Thus, a combined exposure to A~ and Tat can lead to accelerated entry of HIV-l into the CNS. To study these hypotheses, this research proposal is focused on the pathways related to A~ and/or Tat-induced cellular oxidative stress, monocyte transendothelial passage, disruption of expression of cell junction proteins, and decreased barrier function of the BBB. The main in vitro experimental system will consist of the unique and innovative co-cultures of human BMEC with astrocytes which endogenously produce and release Tat. Part of our studies will also employ an animal model of amyloid angiopathy exposed to Tat. The long term goals of the current proposal are to determine mechanisms which may prevent A~ and Tat-induced injury to BMEC. Data arising trom this proposal will be critical for a better understanding of mechanisms responsible for disruption of the BBB during HIV- I infection associated with aging. In a broader aspect, this proposal will contribute to better knowledge of how aging can contribute to the development of neurological complications of HIV/AIDS.