PATHOGENESIS AND CYTOKINES IN HIV SENSORY NEUROPATHY

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The central and peripheral nervous system and the immune system are primary targets for human immunodeficiency virus type 1 (HIV-1) infection in individuals with acquired immunodeficiency syndrome (AIDS). The pathogenesis of the peripheral neuropathy has not been elucidated. The structural features of the peripheral sensory system offers the possibility to determine the exact mechanism by which neuronal damage is produced by HIV-1, dissecting out the relevant roles of macrophage/monocytes, HIV-1 infection-of macrophage/monocytes, cytokines production, and opportunistic viral infections. We will test the hypotheses that the distal progressive sensory neuropathy of AIDS is 1) A dying back disorder and 2) that humoral factors or cytokines secreted by macrophages are the likely cause. We will use immunohistochemistry, PCR techniques and in situ hybridization to identify cytokine-producing cells in peripheral nervous tissue from AIDS patients to confirm the identity of the HIV-1 infected cells, and the presence of opportunistic viruses. Cytokine production will be correlated with inflammation, neuronal loss, and replication of HIV-1. Biopsied sural nerve and post-mortem tissues of patients dying with AIDS and acute death controls will include the sural, tibial and sciatic nerves, the corresponding L5 and Sl dorsal root ganglia, and the whole spinal cord. Morphometric analyses will be performed to decide if this is a true dying back neuropathy or due to the cumulative effects of multiple peripheral nerve lesions. This proposal capitalizes on the high incidence of neuropathy among subjects dying with AIDS and will result in determination whether the incidence and progression of neuropathy among the AIDS subjects may result from cytokine production by macrophage/monocytes in situ in DRGs.