This is a competitive renewal request for our NIMH Center Grant (MH 47690_ """"""""AIDS Dementia: Molecular and Cellular Mechanisms:. This currently funded multidisciplinary Research Center has since its inception actively pursued the molecular and cellular mechanisms underlying the CNS manifestations of lentivirus infection by a highly focused comparative evaluation of HIV brain pathophysiology as defined by neuropsychological and sleep disruption with neurobehavioral, electrophysiological, virological and immunological manifestations of infection with Simian Immunodeficiency Virus (SIV), and Feline Immunodeficiency Virus (FIV) as well as transgenic mice over- expressing either the cytokines mediating inflammatory and immune responses, or selected glycoproteins of the lentivirus envelope in neurons, astrocytes or other CNS cells. Based on progress within this Center, and on research developments within the overall AIDS research effort, research to be conducted over the next 5 year period will focus on determination of the molecular and cellular mechanisms of early CNS changes, to refine and compare these animal models with HIV for convergent manifestations of pathophysiological mechanisms, and to evaluate potential drug treatments for the reversal or attenuation of the early CNS manifestation of lentivirus infection. Accordingly, funding is now requested for 6 Core projects and 12 individual, but highly collaborative research components. Two components will extend recent progress in HIV-associated CNS dysfunctions, comparing conventional neuropsychological test batteries with CANTAB, an automated neuropsychological assessment battery developed within this Center for SUV CNS studies, and examining the disruption of sleep in early HIV sero-converting patients, its role in neuropsychological performance, and its short term treatment, as well as a recently discovered plasma cytokine correlation with CNS EEG activity. Two highly interactive components will focus on SIV infection of rhesus macaque. A recently developed, micro-glia derived neuroinvasive, neurovirulent SIV stock will be evaluated in a neurobehavioral and physiological animal model with quantitative monitoring to characterize the time course of the CNS manifestations of FIV. Functionally modified FIV mutants will be studied for patterns of brain cellular infectivity and neurovirulence as assessed by clinical and neurologic progress, sleep disruption, EEG and event related potentials; an FIV microglia study will attempt to replicate the enhanced neurovirulence obtained in the SIV Model, and anti TNFalpha or NMDA receptor antagonists, alone or in combination on FIV-induced neurologic disease will be studied. Five projects in rodents will examine specific molecular mediators within defined cell classes. Three projects will employ transgenic mouse mutants to overexpress specific cytokines, natural proteins or viral proteins (IFNgamma expression in rods and cones; astrocytic expression of HIV gp120, IL6 or IFNalpha or either human CD4 on brain microglia/macrophages or human amyloid precursor protein in neurons) either singly or in combination to identify the mechanisms underlying neuropathophysiology int he absence of direct lentivirus infection of neurons. A fourth project will examine the cytokines IL1-beta, TNFalpha, and IL6, as well as HIV glycoproteins on cerebellar neuronal development in vitro. The fifth will utilize newly developed molecular discovery techniques to identify mRNAs expressed by activated microglia, determine their relationships to other cells of the monocyte/macrophage lineage, and changes in their gene expression patterns during cytokine exposure or virus infection. Together, this focused array of highly interactive research studies will further clarify the nature of AIDS-associated neurocognitive and motor dysfunctions, and provide animal models in which specific early reversible pathological processes common to HIV, SIV and FIV may be slowed or reversed. In addition, these studies may illuminate other unexplained aspects of fundamental neuronal-glial-immune system interaction, the nature of brain resident microglia, and the basis for neuropsychiatric disorders of unknown origin.
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