HTLV-III/LAV is currently recognized as the etiologic agent of AIDS. Although the primary target cell of infection appears to be the T4 lymphocyte, the potential role of other cell types in the pathogenesis of this syndrome has not been fully explored. The integral association of the monocyte/macrophage system with T cells and the known importance of these cells in other lentivirus infections, makes this an important cell population to study with regard to HTLV-III/LAV interactions. Specifically, macrophage immune defects may be defined and these cells might represent sites of viral persistence in vivo. As an approach to these questions, two in vitro systems have been established: In the first, normal human alveolar macrophages (AM's) obtained by broncholavage have been shown to be infectible with HTLV-III/LAV in vitro. The infection of these cells is nonproductive as measured by supernatant RT activity, with virus replication demonstrable after addition of stimulated allogeneic peripheral blood mononuclear leukocytes. In the second, a persistent and productive HTLV-III/LAV infection of the macrophage-like cell line, U-937, has been established and maintained for over 70 days.
The specific aims of this proposal are: (1) To characterize the nature of the nonproductive in vitro HTLV-III/LAV infection of AM's. Attempts to activate virus expression will be made and the presence and state of the viral nucleic acid will be determined. (2) To attempt to modify the in vitro HTLV-III/LAV infection of AM's by treatments with cytokines or antiviral agents. Possible prevention of AM infection or abrogation of activation/transfer to target lymphocytes will be studied. (3) To determine the functional consequences of in vitro HTLV-III/LAV infection of AM's by examining these cells' ability to restrict the replication of intracellular organisms. (4) To utilize the persistent HTLV-III/LAV infection of U-937 cells to examine the long-term effects of treatment with cytokines or antiviral agents and to determine if non-productive cell lines can be derived. (5) To determine if AM's harvested from individuals with AIDS harbor HTLV-III/LAV. Attempts to activate virus expression in vitro and nucleic acid hybridization studies will be performed. Through pursuit of these studies, it should be determined if AM's are important targets and reservoirs of HTLV-III/LAV infection and if functional correlates of infection can be defined. This may provide a better understanding of retrovirus infection in humans and provide a framework for devising clinical interventions.
