HIV-1 gp120-induced Endothelial Cell Dysfunction

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DESCRIPTION (provided by applicant): The human immunodeficiency virus (HIV) invades the brain in the early stages of infection For patients in the advanced stage of infection, dysfunction of the central nervous system (CNS) is a common cause of morbidity and often leads to progressive dementia, cerebral atrophy and death. Evidence suggest that HIV and /or HIV-associated proteins are critical to the pathogenesis of the HIV-associated dementia (HAD)complex .To elucidate the pathogenesis of HAD, it is important to understand by what mechanisms HIV invades the brain. Breakdown of the blood-brain barrier is commonly seen in patients with HAD, despite the lack of productive HIV-infection of the brain endothelium. The HIV-1 envelope protein gp120 is present in the brain of patients with HIV encephalitis, and is neurotoxic Recent evidence from our laboratory, and by others, suggests a direct effect of gp120 on the brain endothelium. It is our hypothesis that gp120 directly causes blood-brain barrier dysfunction and plays a major role in viral invasion of the brain To test this hypothesis, we plan the following aims. Aim 1: To test the hypothesis that HIV-1 gp120 proteins are toxic to human brain microvascular endothelial cells and directly induce a disruption and/or damage of the blood-brain barrier we will measure endothelial cell permeability and apoptosis. Aim 2 To test the hypothesis that exposure of gp120 proteins to human brain microvascular endothelial cells result in the loss of tight junction proteins we will assess the expression of occludin, claudia-5 and zonula occludens-1 using western blotting and immunofluorescence. Aim 3: To determine if chemokine receptors are involved in gp120-induced blood-brain barrier disruption and/or damage Aim 4: To determine the signal transduction pathways involved in gp120-induced blood-brain barrier dysfunction. Data from these experiments will help determine the role that gp120 plays in the breach of blood-brain barrier integrity and HIV invasion of the brain, and will suggest therapeutic approaches to preventing gp120-mediated dysfunction of the brain endothelium during HIV infection.