Despite effectiveness of HAART, prevalence of cognitive abnormalities has increased as HIV infected individuals live longer. Large numbers of HIV infected people exhibit some form of cognitive impairment, termed HAND. Monocytes/macrophages in the CNS are the best indicator of neurocognitive dysfunction, suggesting that monocyte transmigration across the blood brain barrier (BBS) is important in neuropathogenesis of AIDS. HIV infected opiate abusers have exacerbated CNS disease with increased inflammation and neuron injury that contribute to neurologic impairment.Opiate drug abuse augments NeuroAIDS. A new therapy for those addicted to opioids is buprenorphine, whose effects on immune cells and CNS vasculature have not been well characterized. How this drug impacts HIV-mediated neuropathological processes is unknown.Transmigration of monocytes across the BBB results in accumulation of monocytes/macrophages within the CNS, a hallmark of NeuroAIDS and its associated cognitive impairments. This inflammatory process is enhanced by opioid abuse. The chemokine CCL2 is highly elevated in the CNS of HIV infected people and mediates the enhanced transmigration of HIV-infected monocytes across the BBB. It is critical to evaluate the impact of buprenorphine as it may affect the transmigration of HIV infected monocytes and consequent neuroinflammation, as well as BBB function. Monocytes and brain microvascular endothelial cells (BMVEC) elaborate factors that enhance CNS damage. This proposal examines how buprenorphine alters HIV infected monocytes and the BBB to assess its impact on NeuroAIDS in the drug abusing population.
Specific aims :1. Examine membrane proteins on HIV infected monocytes that mediate their transmigration across the BBB to CCL2 and how they are altered by buprenorphine. Examine effects of buprenorphine on inflammatory mediators produced by monocytes and BMVEC. 2. Determine effects of buprenorphine on surface proteins and phosphorylation of signaling proteins in BMVEC that facilitate diapedesis of HIV infected monocytes to CCL2 and that maintain BBB integrity. 3. Determine changes in transmigration of HIV infected cells treated with buprenorphine in response to CCL2.
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