This research center will investigate the clinical features, cellular pathology, and pathogenetic mechanisms of the neurological complications of HIV infection in humans. The primary HIV related neurological disorders - dementia, myelopathy, and sensory neuropathy - will be studied prospectively in individuals with advanced HIV infection to characterize the clinical features of neurological disease, their temporal progression, and relationship to antiretroviral therapy. This systematic clinical characterization will provide the basis for detailed clinicopathological correlation with biopsy and autopsy tissue. Cellular pathology will be defined using a variety of morphological methods, including assessment of neuronal and astrocyte densities, viral burden, and localization of viral genome. The phenotype of inflammatory cells, their state of activation, and the presence and localization of cytokines in nervous system tissue will be correlated with clinical features of neurological disease and the localization of viral antigens, DNA, and RNA. The regulation of cytokine production by HIV-infected brain microglia in vitro will be examined. Complementary techniques for assessing viral burden in nervous system tissue will be utilized and correlated with clinical features of neurological disease. The role of sequence differences in neurotropism and neurovirulence will be examined by sequence analysis of the V3 region and the long terminal repeat (LTR) in paired samples from brain and spleen obtained directly from clinical specimens by polymerase chain reaction. Finally, perturbations in the blood-brain barrier will be examined by studying the state of activation of perivascular macrophages and the quantity and distribution of nitric oxide in brain tissues. These studies will lead to improved understanding of the neuropathological substrate of the primary HIV-related neurological disorders. The pathogenetic mechanisms underlying these syndromes will be explored and will provide a direction to future in vitro studies and to more rational development of therapeutic agents.
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