The majority of infectious complications of AIDS result f rom the loss of mechanisms which hold in check opportunistic microorganisms present in the lung. The alveolar macrophage is thought to play a important role in this process, and it is known to be a target for HIV infection. We propose to directly study how HIV infection of alveolar macrophages (AM) and related phagocytic cells affects their capacity to phagocytose, inhibit and kill Cryptococcus neoformans, Mycobacterium avium-intracellulare and Mycobacterium tuberculosis. Experiments will be conducted with AMs recovered from the lungs of AIDS patients undergoing diagnostic bronchoscopy as well as normal AM and peripheral blood monocytes infected with HIV in vitro. The antimicrobicidal activity of these cells will be correlated with changes in specific functional parameters and cell surface antigens. The molecular mechanisms of virus-induced dysfunction will be determined by studying the effects of individual viral proteins (gp12O, gp4l, p24, tat, nef) added exogenously to AM cultures or expressed intracellularly from vectors transfected into monocytes and U937 cells. Conversely, we will evaluate how the binding of cryptococci and mycobacteria to HIV-infected phagocytic cells affects virus expression and cytopathicity in these cells. These studies are expected to provide fundamental insights into the mechanisms by which opportunistic infections arise in the lungs of HIV-infected persons, and may suggest new lines of investigation for the treatment of the pulmonary complications of AIDS.
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