Harris Gelbard, M.D.,Ph.D.
Professor of Neurology, Pediatrics, Microbiology and Immunology
M.D. 1976, Northwestern University Medical School
Ph.D. 1983, Northwestern University

The Gelbard Lab – Understanding and Preventing the Molecular Consequences of Human Immunodeficiency Virus Type 1 Infection of the Central Nervous System

To use Al Gore’s words, NeuroAIDS remains “an inconvenient truth.”  Despite the fact that highly active antiretroviral therapy (HAART) has made AIDS a chronic treatable disease, it has proven considerably less effective as a therapy for the neurologic disease associated with HIV-1 infection of the central nervous system (CNS).  With over one million people infected with HIV-1 in the U.S. and well over 40,000,000 people infected worldwide, HIV-1’s ability to enter the CNS early in the course of infection, makes it a major source of neurologic morbidity, especially in a population that is aging and beginning to experience other neurodegenerative diseases, including Alzheimer’s disease.  Because HIV-1 infects cells of mononuclear lineage, but not post-mitotic neurons, it disrupts normal CNS functions by the production and secretion of pro-inflammatory cellular metabolites and viral gene products that act as neurotoxicants.  Our laboratory has investigated the effects of these neurotoxins on normal synaptic function.  In particular, we have focused on two enzyme targets, glycogen synthase kinase 3 beta (GSK-3b) in neurons, and mixed lineage kinase 3 (MLK3) in neurons and perivascular macrophage/microglia, in order to identify or design small molecule therapies to prevent their pathologic over-activation by inflammatory neurotoxins.  As part of this collaborative effort between several labs at our institution, we have utilized novel optical imaging techniques that involve photoconductive stimulation of neurons grown on silicon, as well as tip-enhanced near-field optical microscopy (TENOM, a technique to yield nano-scale optical and spectroscopic information) to better understand changes that occur to synaptic architecture during inflammation, as well as gain insight into how cells with immune effector functions can directly effect synaptic transmission.  We do this with the goal of determining what the bioenergetic consequences of synapse remodeling are in the face of immune activation, and whether inflammation inevitably leads to synaptic apoptosis.

Research Publications (2005-present)

1.         Perry, S.W., Litzburg, A., Bellizzi, M.J., and Gelbard, H.A.. HIV-1 transactivation of transcription protein induces mitochondrial hyperpolarization and synaptic stress leading to apoptosis.  J. Immunol. 2005; 174(7):4333-4344.

2.         Nelson J., Dou H., Ellison B., Uberti M., Xiong H., Anderson E., Mellon M., Gelbard H.A., Boska, M. and H.E. Gendelman.  Coregistration of quantitative proton magnetic resonance spectroscopic imaging with neuropathological and neurophysiological analyses defines the extent of neuronal impairments in murine HIV-1 encephalitis.   J. Neurosci. Res. 2005; 80(4):562-75.

3.         Dou, H., Ellison, B., Bradley, J., Kasiyanov, A., Xiong, H., Dewhurst, S., Gelbard, H.A., and H.E. Gendelman.  Neuroprotective activities of lithium in murine HIV-1 encephalitis.  J. Neurosci. 2005; 25(37):8375-85.

4.         Bellizzi, M.J., Lu, S.-M., Masliah, E. and Gelbard, H.A.. Synaptic activity becomes excitotoxic in neurons exposed to elevated levels of platelet-activating factor.  J. Clin. Inv., 115(11):3185-3192, 2005.

5.         Schifitto, G., Peterson, D.R., Zhong, J., Ni, H., Cruttenden,  K., Gaugh, M., Gendelman,  H.E., Boska,  M. and Gelbard, H.A..  Valproic acid adjunctive therapy for HIV-associated cognitive impairment. A first report.  Neurology. 2006, 66(6):919-21; [Epub 2006, Mar 1].

6.         Sui, Z., Fan, S., Sniderhan, L., Reisinger, E., Litzburg, A., Schifitto, G., Gelbard, H.A., Dewhurst, S., and S.B. Maggirwar. Inhibition of Mixed Lineage Kinase 3 Prevents HIV-1 Tat-Mediated Neurotoxicity and Monocyte Activation.  J Immunol. 2006 Jul 1;177(1):702-11.

7.         Sui, Z., Sniderhan, L.F., Fan, S., Kazmierczak, K., Reisinger, E., Kovacs, A.D., Potash, M.J., Dewhurst, S., Gelbard, H.A., and S.B. Maggirwar.  Human immunodeficiency virus-encoded Tat activates glycogen synthase kinase-3beta to antagonize nuclear factor-kappaB survival pathway in neurons.  Eur J Neurosci. 2006 May;23(10):2623-34.

8.         Norman, J.P., Perry, S.W., Kasischke, K.A., Volsky, D.J. and Gelbard, H.A. HIV-1 Tat Elicits Mitochondrial Hyperpolarization and Respiratory Deficit, with Dysregulation of Complex IV and NAD(P)H Homeostasis in Cortical Neurons.  J. Immunol. 2007, 178(2):869-76.

9.         Lu, S.-M. and Gelbard, H.A..  The phospholipid mediator platelet-activating factor mediates striatal synaptic facilitation. J. Neuroimmune Pharm. 2007, (in press).

10.       Sui, Z., Sniderhan, L.F., Schifitto, G., Phipps, R.P., Gelbard, H.A., Dewhurst, S. and S.B. Maggirwar.  Functional synergy between CD40 ligand and HIV-1 Tat contributes to inflammation: implications in HIV-1 dementia.  J. Immunol. 2007, 178(5):3226-3236