AIDS DEMENTIA: MOLECULAR AND CELLULAR MECHANISMS

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.