IV drug use and HIV infections are two linked global health crises since needle sharing is a well-recognized mode of HIV transmission. While HIV-1 infection is the leading cause of death among Americans 25-44 years old, injection drug use now accounts for about one-third of all new US AIDS cases reported each year. Cocaine, often abused by HIV-infected patients, has been suggested to worsen HIV-associated dementia (HAD) via unknown mechanisms. The brain is a target organ for both, the recreational drugs and HIV-1. Disruption of the blood brain barrier (BBB) is the main route of HIV entry into the CNS. The mechanisms by which the monocytes and/or T cells cross the BBB into the CNS parenchyma still remain an enigma. BBB is critical for the maintenance of CNS homeostasis and for the regulation of the neural microenvironment. This proposal will investigate specific mechanisms by which cocaine and HIV co-operate to induce BBB disruption. We hypothesize that HIV proteins &cocaine can interact in an additive or synergistic manner to directly amplify cellular &molecular processes contributing to their toxic vascular effects such as, disruption of the BBB and increased transmigration of infected monocytes into the CNS. The rationale of this hypothesis is based on preliminary studies showing up-regulation of a vascular permeant PDGF-BB in the brains of macaques with Simian-human immunodeficiency virus encephalitis and in monocytes infected with HIV or exposed to cocaine. Reciprocally, our new findings also demonstrate that cocaine-mediated disruption of endothelial monolayer involves phosphorylation of the PDGF-beta receptor. This proposal will thus investigate a novel concept that PDGF/PDGF-R axis could be the missing link in cocaine/HIV-mediated disruption of BBB. Using a combination of in vitro and complementary murine models of HIV neurodegeneration, we will test the hypothesis in three specific aims: SA1 of the study will be focused on investigating the molecular mechanisms involved in upregulation of PDGF in monocytes exposed to HIV proteins and/or cocaine. SA2 will be focused on exploring the mechanisms involved in PDGF &cocaine-induced permeability changes in human brain microvascular endothelial cells. Finally, SA3 will use in vivo approach to test the hypothesis that inhibition of the PDGF/PDGF-R axis by the PDGF-beta receptor inhibitor gleevac, will result in abrogation of BBB disruption in HIV-transgenic rats and Tat transgenic mice exposed to cocaine.
Cocaine, a highly potent and addictive brain stimulant, often abused by HIV-infected patients, is known to exacerbate HIV-associated CNS disease. This proposal is aimed at understanding molecular mechanisms involved in the combined deleterious effects of HIV-1 and cocaine in the in the brain with the ultimate goal of testing novel therapeutics.
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