Central nervous system involvement often occurs in individuals infected with human immunodeficiency virus type I (HIV-1). The most common clinical syndrome, characterized by cognitive, motor, and behavioral disturbances, is the acquired immunodeficiency syndrome (AIDS) Dementia Complex (ADC), and is unique to HIV-1 infection. However, the pathogenesis of this syndrome is poorly understood. The long-range goal of this project is to elucidate the molecular and cellular processes responsible for ADC. Previous work from our laboratories focused directly on virological aspects of ADC, reporting for the first time (i) the complete nucleotide sequence, genome organization, and biological phenotype of virus cloned directly from uncultured human brain, (ii) the identification of the HIV- 1 envelope glycoprotein as a critical determinant for macrophage tropism (and consequently """"""""neurotropism""""""""), (iii) a limited degree of viral genome heterogeneity and defectiveness within the CNS compartment, and (iv) a significant correlation between HIV-1 viral load, gene expression, localization within the CNS, and clinical severity of ADC. The results of these studies thus implicated macrophage-tropic strains of HIV-1 in the pathogenesis of ADC, and strongly suggested indirect mechanisms not involving direct infection of principal functional elements of the CNS, namely, the neurons, oligodendrocytes and astrocytes. Evidence is now accumulating that neurons and astrocytes may be functionally compromised by exposure to viral components or cellular factors released from HIV-1 infected macrophages/microglia. In this project, we are proposing to examine the role of astrocytes in the pathogenesis of ADC by employing complementary expertises in HIV biology, neuroimmunology, and cell physiology. Using this multidisciplinary approach, we will test the hypothesis that exposure to HIV-1 virions,individual viral gene products, cytokines, or other soluble products of infected macrophages/microglia directly alters normal astrocyte function ultimately leading to neuronal cell injury.
The specific aims are: 1) to determine if virions, HIV-1 envelope glycoproteins (gp160, 41), or HIV-1 regulatory proteins (tat) alter astrocyte cytokine expression, in particular that of TNF-alpha, IL-1, and IL-6; and 2) to determine if these viral products, cytokines, or other products released from infected macrophages/microglia alter human astrocyte exchange (antiport) system, Na+-glutamate cotransport system, and/or ion channels, specifically K+ channels. The emphasis of this project is to study these functions in human astrocyte populations using rat astrocytes for comparison when appropriate, and to use biologically relevant and molecularly well characterized HIV-1 viral strains known to be associated with ADC. These studies thus represent a novel approach for evaluating the cellular and physiological basis of neuronal dysfunction in ADC by examining directly, in well-defined biological assays, the effect of HIV-1 and HIV-1 induced- cytokines on the function of the astrocyte, a critically important supporting cell within the CNS.
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