We propose that astrocyte dysfunction in HIV-1-associated dementia (HAD) occurs through its Interactions with infected brain mononuclear phagocytes (MP; perivascular and parenchymal macrophages and microglia). We will study how this occurs taking advantage of a newly developed proteomics and imaging facllity within our center. Magnetic resonance imaging (1HMRI), 1HMRS spectroscopy and single proton emission computed tomography will access cell movement and functlon in a rodent animal model of human HAD and HIV encephalitis (HIVE). The work will investigate how MP Infection and/or activation affects astrocyte neuroregulatory functions as well as explore primary infection of astrocytes de novo. It is proposed that secretion of MP pro-inflammatory factors (for example, tumor necrosis factor, quinolinlc acid and platelet activating factor) attenuates astrocyte signaling pathways leading to the down regulation of glial trophins including brain derived neurotrophic factor, glial derived neurotrophic factor, nerve growth factor, and/or transforming growth factor beta as well as attenuating glutamate transporter function, HIV-infected macrophages secretions (cellular or viral products) may also inclte the production of neurotoxins from astrocytes (for example, nitric oxide), glutamate, interleukin-1beta, MP-astrocyte interactions will be investigated for their abilities to affect autocrine and/or paracrine amplification of glial neurotoxins and chemotactic function. The relative role of virus and astrocyte secretory responses will be studied for its influence in the neuropathogenesis of HIV infection in a severe combined immunodeficient (SCID) mouse model of human disease. SCID mice will be injected intracerebrally with productively infected human astrocytes with vesicular stomatitis virus expressing HIV-1, with lymphotropic (LAI) or macrophage tropic (DVJ, ADA or JR-FL) viruses. The generation of cytotoxlc T lymphocytes from reconstituted HIVE mice will be used to eliminate infected macrophages from the brain and permit the assessment and evaluation of astrocyte repair processes. Lastly, a novel, state-of-art proteomics facility that includes on-line protein sequencing, will establish a comprehensive database of global changes of protein expression in human primary astrocytes as it relates to cell functlon. Altogether, these works will permit the determination of astrocyte and neuronal functions evaluated as a consequence of HIV-1 infection, MP function and chemotaxis in laboratory and animal models of human HAD. Most importantly, the project has strong collaborative ties with each of the other projects focusing on a unique but as yet understudied part of NeuroAIDS, namely the role played by astrocytes in the disease process.
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