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 by the investigators' laboratories has implicated indirect mechanisms as being responsible for the etiology of ADC, rather than direct infection of principal functional elements of the CNS, namely, the neurons, astrocytes, and oligodendrocytes. The PI presents evidence that neurons, astrocytes, and oligodendrocytes may be functionally compromised by exposure to viral components or cytokines released from HIV-1 infected macrophages/microglia. The proposed studies will examine the role of astrocytes and oligodendrocytes in the pathogenesis of ADC by employing complimentary expertise in HIV biology, neuroimmunology, and cell physiology. Using this multidisciplinary approach, the investigators will test the hypothesis that exposure to cytokines, individual viral gene products, HIV-1 virions, or other soluble products of infected macrophages/microglia, directly alters normal astrocyte and oligodendrocyte function, ultimately leading to neuronal cell injury and myelin damage. The three specific aims are: 1) to test the hypothesis that cytokine-induced astrocyte Na+/H+ exchanger and pH-sensitive K+ channel activities are mediated by novel isoforms of the amiloride-sensitive Na+/H+ exchanger apamin-sensitive K+ channel; 2) to test the hypothesis that alterations in normal astrocytic Na+/H+ exchange, glutamate transport, and K+ conductance produced by cytokines change the extracellular milieu of neurons in vivo, and thus contribute directly to Ca2+ induced neurotoxicity; and 3) to test the hypothesis that proinflammatory cytokine-induced ICAM-1 expression by oligodendrocytes contributes directly to changes in oligodendrocyte function. The emphasis of this project is to study these functions in human astrocytes and oligodendrocytes populations, using rat cells for comparison when appropriate. These studies thus represent a novel approach for evaluating the cellular and physiological basis of neuronal dysfunction in ADC by examining directly the effect of HIV-1 induced cytokines and HIV-1 itself on the function of the astrocyte, a critically important supporting cell within the CNS, and the oligodendrocyte, the myelin-producing cell of the CNS.
Showing the most recent 10 out of 19 publications
