In response to NIMH announcements, we propose to create a multidisciplinary comprehensive Research Center for AIDS Dementia Complex Research. This Center will be based primarily within the Department of Neuropharmacology of the Research Institute of Scripps Clinic (RISC), with additional collaborating investigators based within the RISC Departments of Immunology and Molecular Biology, and the Department of Psychiatry, University California-San Diego. This Center will investigate the molecular and cellular mechanisms underlying the AIDS Dementia Complex by a highly focussed comparative evaluation of brain pathophysiology in selected AIDS patients with that found in 3 animal model systems suitable for invasive experimental investigation: Simian Immunodeficiency Virus (SIV), Feline Immunodeficiency Virus (FIV) and persistent selected neuronal infection with a murine neurotropic arenavirus, lymphocytic choriomeningitis virus (LCMV) capable of eluding immunodetection and clearance from host cells. With these animal models, the Center will correlate virus-dependent changes in immune system and nervous system function with the clinical profile of AIDS. In collaboration with the UCSD-based, NIMH-sponsored HIV Neurobehavioral Research Center and the US Naval Hospital, we will perform electrophysiological studies on HIV patients sampled throughout their clinical courses. These profiles will serve as a comparison for neuropsychological, macro-and microelectrode electrophysiological, and in vivo and in vitro evaluation of immune system and cytokine function in SIV and FIV. Murine studies will determine the functional alterations of persistent virus infections as expressed by neurobehavioral, electrophysiological, and molecular biological alterations within specific cell types of the cns (e.g., neuronal, glial, microglial, lymphocytic and vascular elements), and will evaluate the use of unique, genetically engineered anti-virus treatments as well as azidothymidine to reverse discrete cellular and behavioral sequelae of virus effects. These multidisciplinary studies will define the biological actions of persistent virus infections of the brain, the profiles of cell-cell signals activated by these infections, and the nature of the effects of these signals on neuronal function. In addition to their relevance tot he nature of AIDS Dementia Complex, these studies may illuminate other unexplained neuropsychiatric disorders for which infectious agent-caused immune dysfunction may be suspected.
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