Infection with human immunodeficiency virus (HIV), the etiologic agent of the acquired immunodeficiency syndrome (AIDS), results in a specific depletion of helper/inducer T lymphocytes. However, the finding of neurological abnormalities in 60% of patients with AIDS is in sharp contrast to a strict tropism of virus for T- helper/inducer cells and macrophages. Recent evidence suggests that a tri-directional communication pathway between the immune, endocrine and central nervous systems may account for the neurological dysfunction associated with AIDS. The exact mechanism of communication remains unresolved, but peptide growth factors, hormones and their respective receptors appear to be the specific messengers in this network. The unexplored possibility that these pluripotent signaling agents may differentially regulated both the physiology of neuro-immuno-endocrine cells and he expression of HIV gene sequences, depending on the environmental context, will be examined in this proposal.
Specific aims of this proposal include: 1) characterizing the effects of classic immunomodulators on the growth and differentiation of glial cells, specifically oligodendrocyte progenitor cells and astrocyte type l cells; 2) defining the immunological properties of macaque endometrial cells; 3) characterizing the regulation of opiate gene expression in oligodendrocyte progenitor cells, astrocyte type l cells, and endometrial cells; and 4) determining the effects of selected signaling agents on regulation of HIV gene expression in these cell types.
These aims will be accomplished by using thymidine incorporation and expression of oligodendrocyte-specific and astrocyte-specific marker proteins to monitor the effects of T cell mitogens, HIV gp120, tumor necrosis factor, and protein kinase C on proliferation and differentiation of oligodendrocyte progenitor cells, both in the presence and absence of induced interleukin-2 receptors. Similar experiments will be performed on astrocyte type l cells. Northern blot analysis and nuclear run-on techniques will be used to monitor both the pattern and regulation of opiate gene expression in glial cells and in uterine endometrial cells. Agents which are shown to affect cell function in the proceeding experiments will be tested for their ability to modulate HIV gene expression, using transient transfection assays of each cell type with plasmid DNA containing eh HIV LTR linked to the bacterial reporter gene chloramphenicol acetyl transferase, in both the presence and absence of plasmids containing the HIV trans- activating gene tat. These experiments should provide specific insights into the pathological mechanisms underlying the neurological complications of AIDS, and should elucidate the role of communication between the immune system and neuro-endocrine systems in generating the systemic manifestations of AIDS.
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