Role of cellular communication through gap junctions, tunneling nanotubes, hemichannels and ATP receptors during the pathogenesis of NeuroAIDS.

HIV infection of the central nervous system (CNS) can result in neurologic dysfunction with devastating consequences in a significant number of individuals with AIDS. The major CNS complications in individuals with HIV are encephalitis, dementia and/or cognitive impairment that are characterized by leukocyte infiltration into the CNS, microglia activation, aberrant chemokine expression, blood brain barrier (BBB) disruption, and eventual damage and/or loss of neurons. As the HIV-infected population lives longer, an understanding of the impact of the virus on chronic disease processes such as NeuroAIDS becomes increasingly relevant. NeuroAIDS has been associated with the presence of elevated CNS inflammatory factors, such as cytokines, PAF, excitatory aminoacids (especially glutamate) and their receptors, soluble viral proteins, and chemokines, as determined in post-mortem examination of tissue. These observations in vivo have been correlated with in vitro findings that support the participation of these factors as mediators of neurodegeneration. The mechanism that triggers these abnormalities are not always associated with high viral replication but rather with inflammation. To study the development of NeuroAIDS we examine two different, but interrelated, potential mechanisms of pathogenesis.

Our focus is to examine the role of HIV infection of astrocytes in the pathogenesis of NeuroAIDS as well as in immune cells, macrophages and T cells, with special emphasis in the role of gap junction channels, hemichannels of pannexins and connexin, ATP receptors and a new system of communication named TNT. We examined how these systems amplify inflammation and toxicity and how these communication systems are altered by HIV infection in vitro and in vivo. 

These studies are essential to understand the mechanism by which HIV remains in the brain, as a reservoir of the virus, and to explorer the question of how HIV changes the phenotype of HIV-infected cells to its advantage. Experimental approach: We use cellular and molecular biological techniques to study the expression, post-transcriptional modifications and intercellular trafficking of neurotransmitters and their receptors, chemokines/cytokines as well as electrophysiology. Our approach involves the use of primary immune and CNS cells and tissues and samples obtained from individuals with NeuroAIDS.

Selected Publications. Eugenin E. Ph.D

1. Eugenin E. A., Gonzalez H., Sáez C. G. and Sáez J. C. (1998) Gap junctional communication coordinates the vasopressin-induced glycogenolisis in rat hepatocytes. Am. J. Physiol 274 (6); G 1109-1116.

2. Eugenin E.A., Eckcart D., Theis M., Willecke K., Bennett M.V. and Sáez J.C. (2001) Microglia at brain stab wounds express connexin43 and in vitro form functional gap junctions after treatment with interferon-g and tumor necrosis factor-a. Proc. Natl. Acad. Sci. USA 98 (7), 4190-4195.

3. Eugenin E.A., Branes M.C., Berman J.W. and Saez J.C. (2003) TNF-a plus IFN-g induce connexin43 expression and formation of gap junctions between human monocytes/macrophages that enhance physiological responses.J Immunology. 170: 1320-1328.

4. Eugenin E.A. and Berman J.W. (2003) Chemokine dependent mechanisms of leukocyte trafficking across a model of the blood-brain barrier. Methods. 29, 351-361.

5. Eugenin E.A., D’Aversa T., Lopez L., Calderon T. and Berman J.W. (2003) MCP-1 (CCL2) protects human neurons and astrocytes from NMDA or HIV-tat-induced apoptosis. Journal of Neurochemistry. 85: 1299-1311.

6. Eugenin E.A, Dyer G., Calderon T.M. and berman J.W. (2005) HIV-1 tat protein induces migration of human fetal microglia by a mechanism CCL2 (MCP-1) dependent. Possible role of microglial axis CCL2-CCR2 in NeuroAIDS. Glia. 49: 501-510.

7. D’Averza T.G., Eugenin E.A., Berman J.W. (2005) NeuroAIDS: Contributions of HIV-1 proteins tat and gp120, and CD40 to microglial activation. J. Neuroscience Res. 81: 436-46.

8. Eugenin E.A., Gamss R., Buckner C., Buono D., Klein R., Schoenbaum E.E., Calderon T.M. and Berman J.W. (2006) Shedding of PECAM-1 during HIV-infection: A role for sPECAM-1 in NeuroAIDS and in the pathogenesis of dementia. J Leukocyte Biology. 79: 444-452.

9. King J.E., Eugenin E.A., Buckner C. and Berman J.W. (2006) New insights in HIV-tat induced neurotoxicity. Microbes and Immunity. 8: 1347-1357.

10. Eugenin E.A., Osiecki K., Lopez L., Goldstein H., Calderon T.M. and Berman J.W. (2006) CCL2/MCP-1 mediates enhanced transmigration of HIV-infected leukocytes across the blood brain barrier: a potential mechanism of HIV-CNS invasion and NeuroAIDS. J. Neuroscience. 26:1098-106

11. Buckner C., Luers A., Calderon T., Eugenin E.A. and Berman J.W. (2006) 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 Pharmacol.1 (2) 160-181.

12. Calderon T.M., Eugenin E.A., Lopez L., Hesselgesser J., Raine C.S. and Berman J.W. (2006) Upregulation of SDF-1a by astrocytes and endothelial cells in multiple sclerosis lesions: Mechanism of induction by myelin basic protein. J. Neuroimmunology. 177(1-2): 27-39.

13. Eugenin E. A., King J.E., Nath A., Calderon T. M., Zukin S.R., Bennett M.V.L, and Berman J. W. (2007) HIV-tat induces the formation of an LRP-PSD95-NMDAR-nNOS complex necessary for neuronal apoptosis. PNAS, 104 (9)3438-3443.

    14. Eugenin E.A., Morgello S., Klotman M.E., Mosoian A., Lento P.A., Berman J.W., and Schecter A.D. (2008) HIV infects human arterial smooth muscle cells in vivo and in vitro: Implications for the pathogenesis of HIV-mediated vascular disease. American Journal of Pathology.172 (4), 1100-11.

    15. Rao V.R., Eugenin E.A., Berman J.W. and Prasad V.R. (2009) Methods to study monocyte migration induced by HIV-infected cells.  Prasad and Kalpana Editors, in HIV protocols by Humana Press. 485:295-309.

    16. Opazo C., Gianini A., Pancetti F., Azkcona G., Noches V., Gonzalez P., Porto M., Rosenthal D., Eugenin E., Kalergis A., and Riedel C.A. (2008) Maternal Hypothyroxinemia impairs Spatial Learning and Synaptic nature and function in the Offspring. Endocrinology. 149(10):5097-106.

    17. Rao V.R., Sas A., Eugenin E., Siddappa N.B., Bimonte-Nelson H., Berman J.W. Ranga U., Tyor W.R. and Prasad V.R. (2008) HIV-1 clade-specific differences in the induction of neuropathogenesis. J Neuroscience. 28 (40), 10010-10016.

    18. Eugenin E.A., Gaskill P.J., and Berman J.W. (2009) Tunneling nanotubes (TNT) are induced by HIV-infection of macrophages: a potential mechanims for intercellular HIV trafficking. Cellular Immunology.254 (2);142-148. 

    19. Bueno S., Gonzalez P., Cautivo K., Mora J., Leiva E., Tobar H., Fennelly G., Eugenin E.A., Jacobs W., Riedel C., Kalergis A. (2009) Protective T cell immunity against respiratory syncytial virus is efficiently induced by recombinant BCG. Proc. Natl. Acad. Sci. USA. 105(52):20822-7

    20. Eugenin E.A., Gaskill P.J., and Berman J.W. (2009) Tunneling nanotubes (TNT): a potential mechanism for intercellular trafficking. Communicative & Integrative Biology. 2(3): 243-4.

    21. Gaskill P.J., Calderon T.M., Luers A.J., Eugenin E.A., Javitch J.A., and Berman J.W. (2009) HIV infection of human macrophages is increased by dopamine; a bridge between HIV associated neurologic disorders and drug abuse. Am J. Pathology. 175(3)1148-59.

    22. Agiostratidou G., Suyama K.,Badano I., Keren R., Chung S., Anzovino A., Hulit J., Qian B., Bouzahzah B., Eugenin E., Loudig O., Phillip G.R., Locker J. and Hazan R.B. (2009) Loss of retinal cadherin facilitates mammary tumor progression and metastasis. Cancer Res. 69(12): 5030-8.

    23. Hazleton J.E., Berman J.W., and Eugenin E.A. (2010) Novel mechanism of central nervous system damage in HIV infection. HIV/AIDS-Research and Palliative Care. 2, 39-49.

    24. 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.

    25. Roberts T.K., Eugenin E.A., Morgello S., Clements J.E, Zink M.C., and Berman J.W. (2010) PrP^C, the Cellular Isoform of the Human Prion Protein, is a Novel Marker of HIV-Associated Neurocognitive Impairment and Modulates Neuroinflammation. American J. Pathology. 177(4) 1848-60.

    26. Eugenin E.A., King J.E., Hazleton J.E., Major E.O., Bennett M.V.L., Zukin R.S. and Berman J.W. (2011) Differences in NMDA receptor expression during development determine the response of neurons to HIV-tat mediated neurotoxicity. Neurotoxicity Research. 19 (1) 138-48.

    27. 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.