This clinical and laboratory program on AIDS and tuberculosis will attack the challenges posed by these diseases in pathogenesis and therapy. We intend to uncover fundamental aspects of the cell-mediated immune response in man, to emerge with better ways to monitor the immune system in disease, and to improve host resistance. We will consider cell-mediated resistance at three levels. The first is the patient and centers on several ongoing protocols in subproject A. We will evaluate the effects of individual cytokines [IL-2, IFN-gamma] administered intradermally, particularly on responses to HIV-1 antigens, and we will assess the possible role of endogenous cytokine production, e.g., TNFalpha, to explain symptomatology such as fever, wasting, and disease progression. The second level entails cellular interaction systems in culture. In subproject B, the afferent limb of the immune response to HIV-1 and to TB will be studied with a concerted evaluation of dendritic cells, monocytes, helper and killer T cells. Our goal is to define protective T cells against M.Tub. and HIV-1, by generating such cells de novo from select, patient populations. In subproject C we examine the efferent limb of immunity using a model of transendothelial leukocyte migration. We will define the lymphocyte and endothelial stimuli that lead to emigration, and we will recreate the in vivo responses that occur during skin tests for delayed type hypersensitivity and following intradermal injection of recombinant IL-2. The third level of analysis is within cells in subproject D. Can intracellular mediators be identified that reflect stimulation with cytokines like IL-2 and IFN-gamma, both in tissue culture and in patients with AIDS and TB? What intracellular targeting pathways can be defined that might explain the distinct life cycle of HIV-1 in macrophages and T cells? What signalling occurs in monocytes exposed to M.Tub. and do any of these signals lead to enhanced expression of HIV-1? At all levels of this program, we emphasize molecular criteria in primary cell and patient populations. The research plan derives from published and preliminary data in the current funding period.
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