The macrophage plays s central role in AIDS pathogenesis not only by being susceptible to HIV infection but also by serving as a major reservoir for the dissemination of virus in infected individuals. The alveolar macrophage is one of the principle cell types involved in the immune defense mechanisms of the lung. Based on our understanding of the macrophage as a critical cell in the induction of cellular immune responses, it is of great importance to study the nature of the interaction of the virus with human alveolar macrophages. The goal of this research proposal is the establishment of a system, utilizing primary human alveolar macrophages, for the analyses of macrophage function and gene expression following the introduction of HIV genes. This will involve the optimization of conditions for transfection of these cells and the transfection into alveolar macrophages of sub-genomic viral fragments as well as isolated HIV genes. Subsequently, the effect of specific viral gene expression on the expression of macrophage products and cell surface markers will be analyzed; specifically, the expression of major histocompatibility complex (MHC) class II antigens, tumor necrosis factor (TNF), interleukin- 1 (IL-1), the adherence molecules of LFA-1, Mac-1, and p150/95, FcRI and FcRII, and lysozyme. The mechanism of the modulation will be analyzed, the target of the effect will be defined, and the region(s) of functional importance in the viral gene will be determined. The activities of lymphocytotrophic and monocytotropic viruses will be compared in regard to their ability to perturb alveolar macrophage physiology. These studies will provide insight into mechaniss underlying the profound immunodeficiency which is central in AIDS pathogenesis.
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