Mononuclear phagocytes (MP, microglia and perivascular macrophages) serve as targets for productive human immunodeficiency virus type-1 (HIV-1) infection within the central nervous system. Neuroimmune events leading to HIV-1-associated dementia (HAD) are associated with MP secretory products (cellular and viral toxins) produced during HIV-1 encephalitis (HIVE). Laboratory, animal model and postmortem brain tissue studies of HIVE uniformly demonstrate that microglial activation, not the absolute level of virus, is the best correlate for cognitive impairment during HAD. Based on these observations this project will investigate the role of microglial deactivation in pathogenesis of HAD in HIVE SCID model. The established infrastructure of our Center for Neurovirology and Neurodenegerative Disorders (CNND) will be utilized to explore the means to abrogate microglial activation in our experimental animal model of HIVE that reflects the biologic, immune and pathophysiologic effects of HIV-1 replication in brain MP. Specifically, we hypothesize that inhibition of kynurenine pathway in activated microglia leads to a reduction in the neurotoxic potential of these cells and results in cognitive improvement. To test this hypothesis, the following questions will be addressed: 1) What are the contributions of the kynurenine pathway in microglial activation and the consequential neurotoxic activities of immune activated and/or virus activated MP in HAD? 2) Is inhibition of kynurenine pathway in activated microglia a crucial link to improved clinical symptoms? & 3) Does inhibition of kynurenine pathway in activated microglia change neuronal function in the context of HAD neuropathogenesis? We will evaluate effects of MP deactivation via kynurenine pathway on neuro-inflammatory responses, neuronal dysfunction, and cognitive impairment in the HIVE SCID mouse model and correlate these observations with in vitro and ex vivo studies on MP. These works will allow us to investigate novel aspects of neuroimmunology and establish a link between immune and cognitive functions. The potential findings have broad relevance in pathogenesis of a wide range of neurodegenerative disorders beyond HAD. The integration between this project and the others is in serving to best understand the role of microglial immunity in the neuropathogenesis of HIV-1 disease.
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