Neurological involvement is common in acquired immunodeficiency syndrome (AIDS). A subacute encephalitis now termed the """"""""AIDS dementia complex"""""""" (ADC) may afflict up to 80% of adult AIDS patients. ADC is characterized clinically by cognitive, motor and behavioral dysfunction. ADC occurs in the absence of recognized opportunistic pathogens, and there is strong indication that direct infection of the nervous system by human immunodeficiency virus type-1 (HIV-1) is responsible for the ADC. This application is based on the hypothesis that HIV-1 infection of astrocytes, the major glial cell of the central nervous system (CNS), contributes to the pathophysiology of ADC. There is both in vivo and in vitro evidence that astrocytes can be infected with HIV-1, and that astrocytes express the CD4 molecule, which is the receptor for HIV-1. Astrocytes perform a wide range of critical functions in the CNS, among them, maintaining a balanced microenvironment for neurons, responding to CNS infection/trauma, and functioning as an endogenous antigen- presenting cell in the CNS. Alterations in astrocyte function, either by direct infection with HIV-1 or by soluble factors from other HIV-1 infected cells direct will influence the overall functioning and integrity of the brain. We propose to investigate the effect of HIV-1 infection of human astrocytes with respect to 1) gene expression of astrocyte antigens, 2) cytokine production by HIV-1 infected astrocytes, 3) biological response of infected astrocytes to cytokines, 4) cytokine regulation of HIV-1 infection in astrocytes and 5) proteinase production/activity by infected astrocytes. These studies will provide functional information on how HIV-1 alters gene expression in astrocytes at both the transcriptional and translational level, how HIV-1 infected astrocytes respond to cytokines, and how cytokines that have biological effects on astrocytes may modulate HIV-1 activity in these cells. A consequence of HIV-1 of astrocytes may be an indirect effect on neuronal activity, thereby resulting in some of the neurological symptoms of ADC. Understanding how HIV-1 perturbs the biological activity of the astrocytes will provide insights into the pathogenesis of ADC.
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