Studies of neurologic disease associated with late stages of HIV infection, particularly dementia, vacuolar myelopathy and painful sensory neuropathy suggest an important role for macrophages and microglia in disease pathogenesis. Numbers of macrophages are increased in the spinal cord and nerves of affected individuals and show signs of activation. There is ample evidence of systemic T cell activation and increased entry of activated CD8 T cells into the CNS, especially early in infection. However, analysis of CSF late in infection in patients with AIDS dementia has most consistently shown elevated levels of beta2 microglobulin, quinolinic acid and neopterin, all products of macrophage lineage cells. Immunocytochemical staining of CNS tissue and assessment of brain mRNA show increases in TNF-alpha associated with microglia. In contrast, IL- 1beta is associated primarily with perivascular macrophages and mRNA is decreased in the brains of demented patients. In all of these lesions, T cells are infrequent and T cell cytokine mRNA decreased compared to control CNS tissue. Although dementia is a common problem in the late stages of HIV infection, it is not universal. In order to further clarify the role of altered production of cytokines, the entry of mononuclear cells into the CNS, and the susceptibility of certain patients to dementia and myelopathy the following aims are proposed: 1) To determine whether abnormalities in cytokine expression associated with AIDS dementia accompany other HIV-associated neurologic diseases such as vacuolar myelopathy, opportunistic infections, and neoplasia, using semiquantitative PCR, immunocytochemistry and enzyme immunoassays. 2) To extend studies on TNF-alpha by identifying the cells producing mRNA, measuring protein, and assessing the predicted effects of local production in the brains of demented persons using in situ PCR and immunologic assays. 3) To characterize more completely the state of macrophage activation in the nervous system in HIV-associated neurologic disease by assessing expression of other cytokines and arachidonic acid metabolites. 4) To determine the reasons for increased expression of TNF-alpha in the CNS of AIDS patients with neurologic disease by assessing the role of genetic factors, HIV infection, and local production of other cytokines. 5) To determine the factors associated with mononuclear cell entry into the CNS and functional activation of entering cells by assessing soluble adhesion molecules in CSF and blood and surface adhesion molecules on peripheral blood mononuclear cells and CSF cells.
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