Dr. Berman's laboratory examines the mechanisms that mediate HIV entry into the CNS and how viral and inflammatory mediators damage neurons and other CNS cells. More than 40 million people worldwide are HIV infected. As a result of antiretroviral therapies, HIV infected people are living longer. HIV enters the CNS early after infection and despite therapy, persists within the CNS. Prevalence of NeuroAIDS and its associated cognitive impairment is increasing. An understanding of mechanisms that mediate these effects are critical to the development of therapeutic strategies.

HIV infection of the CNS can have devastating consequences, often resulting in cognitive impairment and severe neurological complications. The basis of this impairment is poorly understood. Although its development is associated with early viral infiltration of the CNS, the number of activated monocytes/macrophages within the CNS appears to be a better indicator of neurologic compromise than viral load, suggesting that leukocyte infiltration and cognitive impairment are tightly correlated. How infected monocytes cross the blood brain barrier (BBB) and infiltrate the CNS is not well understood. This process is critical to the development of NeuroAIDS as it brings leukocytes into the brain where they activate and infect microglia, and effect damage to the BBB and other CNS cells. The mechanisms of HIV-infected monocyte transmigration across the BBB have only been minimally characterized. We are characterizing several of the steps in this transmigration process using a tissue culture model of the human BBB. We analyze the mechanisms that mediate attachment and diapedesis of HIV-infected monocytes across the BBB to identify markers that contribute to brain infection and BBB disruption, such as adhesion molecules, tight junction and adherens proteins, chemokines and their receptors. The lab has a major translational component, examining sera and CSF from HIV infected individuals for predictors of cognitive impairment, as well as patient cells for unique markers of this impairment and for their ability to transmigrate across the blood brain barrier. We examine tissue from HIV-infected individuals for altered proteins. The overall goal is to identify targets for therapeutic intervention to limit the entry of HIV into the CNS.

Many HIV-infected people who abuse drugs have more extensive CNS damage associated with significant cognitive impairment. As many drugs of abuse cause an increase in extracellular dopamine, we examine the effects of dopamine on HIV infection of macrophages. We demonstrated that dopamine increases HIV infection of human macrophages and are addressing the mechanisms by which dopamine causes this increase as well as alterations in macrophage function. We also study the impact of buprenorphine and methadone, therapies for Opiate abuse, in the context of NeuroAIDS.

1. Eugenin EA, D’Aversa T, Lopez L, Calderon T, Berman JW:  MCP-1 (CCL2) protects human neurons and astrocytes from NMDA or HIV-tat-induced apoptosis. J Neurochem 85(5):1299-3111, 2003.
2. Eugenin EA, Dyer G, Calderon T, Berman JW: HIV-1 tat protein induces a migratory phenotype in human fetal microglia by a CCL2 (MCP-1)-dependent mechanism: possible role in NeuroAIDS. Glia 49(4): 501-10, 2005.
3. Eugenin EA, Gamss R, Buckner C, Buono D, Klein RS, Schoenbaum EE, Calderon TM, Berman JW: Shedding of PECAM-1 during HIV infection: a potential role for soluble PECAM-1 in the pathogenesis of NeuroAIDS.  J Leukoc Biol 76:444-452, 2006.
4. Eugenin EA, Osieki K, Lopez L, Goldstein H, Calderon TM, Berman JW:  CCL2/Monocyte chemoattractant protein-1 mediates enhanced transmigration of human immunodeficiency virus (HIV)-infected leukocytes across the blood-brain barrier: a potential mechanisms of HIV-CNS invasion and NeuroAIDS.  J Neurosci 26(4):1098-1106, 2006.
5. Buckner, C.M., Luers, A.J., Calderon, T.M., Eugenin, E.A. and Berman J.W.:  Neuroimmunity and the blood brain barrier:  the molecular regulation of leukocyte transmigration and viral entry into the nervous system with a focus on NeuroAIDS.  J. Neuroimmune Pharm 1(1-2):160-181, 2006
6. Eugenin, E.A., King, J.E., Nath, A., Calderon, T.M., Zukin, R.S, Bennett, M.V. and Berman, J.W.: HIV-tat induces formation of an LRP-PSD-95-NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes.  Proc Natl Acad Sci 104(9):3438-3443, 2007.
7. Eugenin E., Gaskill P.J., and Berman J.W. (2009) Tunneling nanotubes (TNT) are induced by HIV-infection of macrophages: a potential mechanism for intercellular HIV trafficking. Cell Immunol. 254(2):142-8, 2009.
8. Gaskill PJ, Calderon TM, Luers AJ, Eugenin EA, Javitch JA, Berman JW. (2009) Human immunodeficiency virus (HIV) of human macrophages is increased by dopamine: a bridge between HIV-associated neurologic disorders and drug abuse. Am J. Pathology, 175(3):1148-59, 2009. King J.E., Eugenin E.A., Hazleton J.E., Morgello S. and Berman J.W.(2010) Mechanisms of HIV-Tat Induced phosphorylation of NMDA Receptor Subunit 2A in Human Primary Neurons:  Implications for NeuroAIDS Pathogenesis. Am. J Pathology, 176 (6): 2819-30.
9. Roberts T.K, Eugenin EA, Morgello S, Clements JE, Zink MC, Berman JW, PrPC, the cellular isoform of the human prion protein, is a novel biomarker of HIV-associated neurocognitive impairment and mediates neuroinflammation. Am J Pathol. 2010 Oct;177(4):1848-60.
10. Eugenin E.A., Clements J.E, Zink M.C., and Berman J.W. (2011) HIV infection of human astrocytes disrupts blood brain barrier integrity by a gap junction dependent mechanism. The Journal of Neuroscience. 31(26):9456-65.
11. Buckner, C.M. Calderon, T.M., Williams, D.W., Belbin, T.J., Berman, J.W. (2011) Characterization of monocyte maturation/differentiation that facilitates their transmigration across the blood-brain barrier and infection by HIV: implications for NeuroAIDS. Cell Immunol. 267(2): 109-23.
12. Williams, DW, Eugenin, EA, Calderon, TM, Berman, JW. (2012) Monocyte Maturation, HIV Susceptibility, and Transmigration Across the Blood Brain Barrier are Critical in HIV Neuropathogenesis.  Journal of Leukocyte Biology, Mar;91(3):401-15.
13. Gaskill P.J., Carvallo L., Eugenin E.A., Berman J.W. (2013) Characterization and function of the human macrophage dopaminergic system: implications for CNS disease and drug abuse. J Neuroinflammation. 18; 9(1):203.
14. Gaskill PJ, Calderon TM, Coley JS and Berman JW (2013) Drug Induced Increases in CNS Dopamine Alter Monocyte, Macrophage and T cell Functions: Implications for HAND. Journal of Neuroimmune Pharmacology, March 2013.
15. Williams, DW, Calderon, TM, Lopez, L, Carvallo, L, Gaskill, PJ, Eugenin, EA, Moregllo, S, Berman, JW. (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.  Jul 26;8(7):e69270