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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA025567-05
Application #
8263978
Study Section
Special Emphasis Panel (ZRG1-AARR-D (05))
Program Officer
Purohit, Vishnudutt
Project Start
2008-07-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$338,746
Indirect Cost
$134,682
Name
Albert Einstein College of Medicine
Department
Pathology
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
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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
Williams, Dionna W; Calderon, Tina M; Lopez, Lillie et al. (2013) Mechanisms of HIV entry into the CNS: increased sensitivity of HIV infected CD14+CD16+ monocytes to CCL2 and key roles of CCR2, JAM-A, and ALCAM in diapedesis. PLoS One 8:e69270
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Williams, Dionna W; Eugenin, Eliseo A; Calderon, Tina M et al. (2012) Monocyte maturation, HIV susceptibility, and transmigration across the blood brain barrier are critical in HIV neuropathogenesis. J Leukoc Biol 91:401-15
Roberts, Toni Kay; Buckner, Clarisa Michelle; Berman, Joan W (2010) Leukocyte transmigration across the blood-brain barrier: perspectives on neuroAIDS. Front Biosci (Landmark Ed) 15:478-536
Gaskill, Peter J; Calderon, Tina M; Luers, Aimee J et al. (2009) Human immunodeficiency virus (HIV) infection of human macrophages is increased by dopamine: a bridge between HIV-associated neurologic disorders and drug abuse. Am J Pathol 175:1148-59