HIV-1 gp120-induced Endothelial Cell Dysfunction

Project: Research project

Description

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.
StatusFinished
Effective start/end date4/1/033/31/08

Funding

  • National Institutes of Health: $104,865.00
  • National Institutes of Health: $103,383.00
  • National Institutes of Health: $100,548.00
  • National Institutes of Health: $55,397.00
  • National Institutes of Health: $106,390.00
  • National Institutes of Health: $46,547.00

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HIV-1
Endothelial Cells
Blood-Brain Barrier
HIV
Brain
AIDS Dementia Complex
Endothelium
Virus Diseases
Dementia
Human Immunodeficiency Virus env Gene Products
Occludin
Human Immunodeficiency Virus Proteins
Tight Junction Proteins
Central Nervous System Infections
Tight Junctions
Chemokine Receptors
Poisons
Encephalitis
Atrophy
Fluorescent Antibody Technique

ASJC

  • Medicine(all)