The prevalence of HIV infection in neonates, children, and adults in the US is such that the disability and morbidity caused by the AIDS Dementia Complex alone will have a significant clinical and social impact in the next decade. The occurrence of opportunistic infections, neoplasms, and HIV infection of cells in the brain are well documented. In contrast, little s known concerning the responses of brain cells (neurons and glia) to either the HIV infection or to the presence of factors secreted by lymphomyeloid cells infiltrating the brain. An understanding of these responses is crucial because treatment may be effective in eliminating the symptoms of AIDS peripheral to the brain may not deter the neurodegenerative processes that occur in the brain during AIDS. To develop this understanding, basic information about alterations in genetic expression in brain cells in response to AIDS must be collected, analyzed, and interpreted. The general hypothesis is that in AIDS brain there are alterations in the levels of specific glial and neuronal gene products that: i) stimulate gliosis; 2) are neurotrophic; and iii) result in suppression of immune responses. In analyzing these gene products, the focus will be on the most obvious brain cell response to AIDS, gliosis. Gliosis is a hallmark of neurodegeneration and is defined as the appearance of numerous astrocytes and microglia, both having reactive morphology. Reactive microglia are enlarged and have prominent processes. Reactive astrocytes are enlarged, have prominent processes, and are filled with glial fibrillary acidic protein, an astrocyte specific protein, and S100, a neurotrophic calcium binding protein. An increase in S100 has been suggested as a possible contributor to neuronal degenerating because of the neurotrophic effects of S100, i.e., neurons might be excessively stimulated by over production of a neurotrophic factor. It is proposed here that microglia-derived IL-1 stimulates astrogliosis in AIDS and that this stimulation includes elevated expression of S100, resulting in neuronal dysfunction and decreased synthesis of somatostatin and acetylcholine. In order to determine whether alterations in genetic expression in neurons parallels increased expression of S100, mRNA levels in two neuronal cell types that have been implicated in dementia, vis., those that synthesize somatostatin and acetylcholine, will be analyzed. In addition to its effects on astrocytes, microglia-derived IL-1 may, like macrophage-derived IL-1, induce release of adrenocorticotrophin that in turn causes release of adrenocorticosteroid (hydrocortisone), which is immunosuppressive. The increase in microglia-derived IL-1 in AIDS brain, reported here, may, therefore, exacerbate the immunodeficiency in AIDS as well as induce astrogliosis. To test the hypothesis, analysis will be done at the cellular level where specific cell types can be identified by immunohistochemistry and the levels of specific mRNAs relative to total polyadenylated mRNA levels assessed by the in situ hybridization in individual cells. Successful testing of the general hypothesis will provide basic information concerning the response of specific neuronal and glial cell populations known to be affected in dementing disorders. Such information is necessary for the development of effective strategies for treating the neurodegenerative processes in AIDS.
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