The long term goals of this proposal are to elucidate the basic biology and pathogenesis of opportunistic fungal infections caused by Candida albicans and Cryptococcus neoformans in patients with AIDS. In order to accomplish this, we propose to first identify the molecular effectors of antifungal activity in normal human mononuclear cells from normal subjects, AIDS patients and appropriate controls. These studies will be pursued in conjunction with in vitro assessments of the fungicidal activities of such cells. The principal specific aims of this proposal are: 1) to identify, purify and characterize constitutive antifungal components (Con-AFC) of normal peripheral blood mononuclear cells by screening subcellular fractions of mononuclear cells for activity against Candida albicans and Cryptococcus neoformans in vitro. 2) to ascertain, by immunocytochemical means, which types of mononuclear cells contain these Con-AFC. 3) to identify the antifungal components in normal mononuclear phagocytes exposed to both crude lymphokine preparations and defined immunostimulants such as interferon-gamma, TNF, endotoxin and IL-1. Inducible antifungal components (Ind-AFC), if qualitatively different from con-AFC, will be purified and characterized. 4) to compare the ability of peripheral blood mononuclear cells from normal individuals, various HIV-seropositive subjects (including patients with AIDS and ARC) and appropriate other controls to inhibit and/or kill Cryptococcus neoformans, Candida albicans and selected other Candida spp. in vitro. 5) to ascertain the effects of in vivo administration of selected immunotherapeutic lymphokines on the in vitro activity of AIDS monocytes against Cryptococcus neoformans and Candida albicans. 6) to compare the content of constitutive and inducible AFC in peripheral blood mononuclear cells from normal and HIV-positive individuals, including patients with AIDS and ARC and appropriate controls. Accomplishing these goals will lead to improved understanding of the pathogenesis of opportunistic infections in AIDS patients and may identify novel approaches for their prevention and treatment.
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