Infection with human immunodeficiency virus (HIV) is associated with the development of distinct neurological disorders, including dementia, myelopathy, and sensory neuropathy. Usually occurring in advanced HIV infection, the clinical features and temporal progression of these disorders remains incompletely characterized. Unanswered issues include the discordance between the clinical expression of dementia and the absence of HIV-related neuropathological changes; the timing of development of HIV-related neuropathological change with respect to systemic disease and immunodeficiency; the influence of antiretroviral therapy on neuropathological abnormalities; and the characterization of the sensory neuropathies in AIDS. The proposed studies will test four hypotheses: First, that quantitative differences in neuronal loss, astrocyte and microglial/macrophage proliferation, and expression of viral antigens in the brain determine the clinical course of HIV dementia. Second, despite entry of HIV into the brain relatively early in infection, the neuropathological changes associated with productive HIV infection develop only with advanced immune deficiency. Third, that specific antiretroviral therapies attenuate the neuropathological changes in dementia and myelopathy. Fourth, that the clinical expression of sensory neuropathy is related to changes in unmyelinated fiber densities and is provoked by certain antiretrovirals and nutritional deficiencies. By using well-characterized patients with advanced HIV infection, our studies will use state of the art stereological techniques to determine regional distribution of neuronal, astrocyte, and microglial numbers, and correlate these findings with patterns of neurocognitive decline, clinical features, and temporal progression of dementia and myelopathy. In patients with sensory neuropathy, the neuropathic pain will be characterized and related to changes in the structure and function of unmyelinated nerve fiber. Skin biopsy will be used to measure the degree of distal nerve fiber loss and will be validated by the study of nerve obtained by biopsy and autopsy. The studies will correlate the clinical expression of HIV-associated neurological disease with neuropathological abnormalities in brain, spinal cord, and peripheral nerve. The information from these projects will be applicable to the exploration of pathogenetic mechanisms and the rational design of therapies.