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 defects which are a consequences 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 take into account the possibility that a significant proportion of the virus in a patient may reside in mononuclear phagocytes. These agents must be able to penetrate into this cell and correct any functional defects induced by HIV. Therefore, we will attempt to determine the proportion of monocytes and tissue macrophages that are infected in patients infected 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) 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. We will also infect the monocyte cell line U-937 with HIV. We will then examine mo functions with knowledge of the proportion of cells that are infected with HIV. The functions to be studied include phagocytosis, killing of facultative intracellular bacteria and protozoa, oxidative burst, phagosomelysosome fusion, production of IL-1, and antigen processing. The effect of new agents developed by other members of this cooperative group, as well as 3'-Azido-3'-deoxythymidine (AZT) will be tested for their effect on HIV infection of mononuclear phagocytes and correction of functional defects induced by HIV.
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