Although highly active antiretroviral therapy (HAART) has proven effective in treating individuals infected with human immunodeficiency virus 1 (HIV), neuropsychological abnormalities are still major clinical problems of infection. In addition, there are significant numbers of drug abusers in the HIV infected population and many of these individuals have accelerated and more severe neurocognitive dysfunctions when compared to non-drug users infected with HIV. The mechanisms by which drugs of abuse exacerbate neuronal damage in the HIV infected population have not been completely characterized. Some studies have found that drug abuse increases the number of T lymphocytes and monocytes that enter the brain during HIV infection when compared to infected individuals without a history of drug abuse or to non-HIV infected drug abusers. Monocyte entry into the central nervous system (CNS) has been shown to play an important role in the neuropathogenesis of HIV infection. Monocyte, as well as T lymphocyte, influx into the CNS contributes to neuronal damage and the subsequent development of neurocognitive deficits in HIV infected individuals. Thus, characterization of the mechanisms of monocyte and T lymphocyte influx into the CNS would be beneficial in the design of clinical strategies to limit the neurocognitive dysfunctions that occur in HIV infected drug abusers. Many drugs of abuse, including cocaine and methamphetamine, elevate extracellular dopamine levels in the CNS. We have the novel finding that dopamine synergizes with the chemokine CXCL12 (SDF-1) in inducing uninfected human T lymphocyte and monocyte transmigration across an in vitro model of the human blood brain barrier (BBB). In addition, dopamine decreases the expression of the tight junction protein claudin 5 in BBB endothelial cells, a mechanism by which dopamine may decrease the impermeability of the BBB and promote leukocyte transmigration. It is therefore our hypothesis that elevated CNS levels of extracellular dopamine in HIV infected drug abusers exacerbates the infiltration of monocytes and T lymphocytes, both uninfected and HIV infected, into the CNS in response to CXCL12. This leukocyte influx may contribute to enhanced CNS inflammation, BBB disruption, HIV entry and infection of parenchymal cells, and neuronal damage. To address this hypothesis we will;1) characterize dopamine modulation of CXCL12 induced uninfected and HIV infected T lymphocyte and monocyte transmigration across the BBB and identify the dopamine receptor(s) whose activation contributes to enhanced leukocyte chemotaxis to CXCL12, 2) determine how dopamine receptor(s) activation modulates the chemotactic response of T lymphocytes and monocytes to CXCL12 and how these processes are altered by HIV infection, and 3) analyze the effects of dopamine on the cells of the BBB that may affect CXCL12 induced uninfected and HIV infected T lymphocyte and monocyte transmigration.

Public Health Relevance

Neurological problems in HIV infected individuals are increasing in severity, especially if these individuals are also drug abusers. We propose to study how damage to the brain is increased in HIV infected drug abusers. The results of these studies will provide information that would be useful in the development of therapies to treat the neurologic dysfunctions that are major clinical problems in HIV infected drug abusers.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-AARR-D (05))
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Avila, Albert
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Albert Einstein College of Medicine
Schools of Medicine
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McFarren, Alicia; Lopez, Lillie; Williams, Dionna W et al. (2016) A fully human antibody to gp41 selectively eliminates HIV-infected cells that transmigrated across a model human blood brain barrier. AIDS 30:563-72
Coley, Jacqueline S; Calderon, Tina M; Gaskill, Peter J et al. (2015) Dopamine increases CD14+CD16+ monocyte migration and adhesion in the context of substance abuse and HIV neuropathogenesis. PLoS One 10:e0117450
Williams, Dionna W; Tesfa, Lydia; Berman, Joan W (2015) Novel flow cytometric analysis of the blood-brain barrier. Cytometry A 87:897-907
Williams, Dionna W; Anastos, Kathryn; Morgello, Susan et al. (2015) JAM-A and ALCAM are therapeutic targets to inhibit diapedesis across the BBB of CD14+CD16+ monocytes in HIV-infected individuals. J Leukoc Biol 97:401-12
Carvallo, Loreto; Lopez, Lillie; Che, Fa-Yun et al. (2015) Buprenorphine decreases the CCL2-mediated chemotactic response of monocytes. J Immunol 194:3246-58
Williams, Dionna W; Veenstra, Mike; Gaskill, Peter J et al. (2014) Monocytes mediate HIV neuropathogenesis: mechanisms that contribute to HIV associated neurocognitive disorders. Curr HIV Res 12:85-96
Eugenin, Eliseo A; Berman, Joan W (2013) Cytochrome C dysregulation induced by HIV infection of astrocytes results in bystander apoptosis of uninfected astrocytes by an IP3 and calcium-dependent mechanism. J Neurochem 127:644-51
Megra, Bezawit; Eugenin, Eliseo; Roberts, Toni et al. (2013) Protease resistant protein cellular isoform (PrP(c)) as a biomarker: clues into the pathogenesis of HAND. J Neuroimmune Pharmacol 8:1159-66
Orellana, J A; Velasquez, S; Williams, D W et al. (2013) Pannexin1 hemichannels are critical for HIV infection of human primary CD4+ T lymphocytes. J Leukoc Biol 94:399-407
Gaskill, Peter J; Calderon, Tina M; Coley, Jacqueline S et al. (2013) Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND. J Neuroimmune Pharmacol 8:621-42

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