The aim of this proposal is to better understand the proportion of mononuclear phagocytes that are infected with Human Immunodeficiency Virus (HIV) in patients infected with HIV and the consequences of such infection on the function of this cell. The goal will be to provide information that will be useful for therapy directed at inhibiting HIV replication in macrophages and correcting immune defect which are a consequence of infection with HIV. There is increasing evidence that macrophages are infected with HIV, can be a reservoir for infection of other cells, and may be the cell which helps to transport HIV into the central nervous system. Hence, strategies to develop new agents active against HIV must consider that a significant proportion of HIV in a patient resides in mononuclear phagocytes. These agents must penetrate into this cell and correct any functional defects induced by HIV. Therefore, we will attempt to determine the proportion of infected monocytes and tissue macrophages in patients with HIV who have a spectrum of clinical illness ranging from asymptomatic to AIDS. Both immunofluorescent antibody and in situ techniques will be used. We will infect human monocyte derived macrophages (mo), pulmonary mo and the monocyte line U-937 with strains of HIV isolated from peripheral blood mononuclear cells, brain tissue and pulmonary mo. The latter two sources may yield HIV isolates which will more efficiently infect mo. Mo of varying time in culture will be infected and the susceptibility to infection will be correlated with mo expression of CD4. We will measure mo functions with knowledge of the proportion of mo that are infected with HIV. The functions to be studied are: spontaneous and stimulated IL-1 production, antigen processing, expression of receptors for HLA- DR and gamma interferon, phagocytosis and intracellular killing of facultative intracellular bacteria and proptozoa, oxidative burst, phagosome-lysosome fusion and, in collaboration with S. Morrison, D. Phil., mo protease secretion and procoagulant activity. The effect of 3'-azido-3' deoxythymidine (AZT) and subsequently developed agents will be evaluated for their in vitro effect on HIV replication in mo and their ability to correct HIV induced mo dysfunction.
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