The pathogenesis of the immune deficiency associated with HIV infection is incompletely understood. Although HIV preferentially infects and kills lymphocytes bearing the CD-4 antigen, the lymphocyte subset which is most notably absent in AIDS, these phenomena alone cannot explain the profound immunodeficiency seen in these patients. Macrophages function in a pivotal role in the genesis of both humoral and cellular immune responses, as well as functioning as effector cells toward some intracellular pathogens and tumor cells, and in generalized inflammatory reactions. At least some macrophages have surface CD-4 antigen, the receptor for HIV, and recent studies have documented that at least a portion of human peripheral blood and alveolar macrophages can be infected with HIV. Our preliminary data show that HIV infected macrophages can serve as long-lived cellular reservoirs for HIV, which may directly deplete CD-4 bearing cells by fusion. In addition, abnormal function of HIV- infected macrophages may contribute to the immune dysfunction and increased susceptibility to infection characteristic of AIDS. The overall goal of this project is to define mechanisms by which HIV infects macrophages, and to determine the role that these cells may have in the pathogenesis of AIDS. To this end we have developed a unique system that permits long-term suspension culture of macrophages in which the functional and surface antigenic properties of individual cells can be quantitated. The specific goals of this project are: 1) to define mechanisms by which human macrophages can be infected by HIV; 2) to determine the antigenic and functional characteristics of HIV- infected macrophages; 3) to test whether HIV-infected macrophages can mediate killing of CD-4 bearing cells through fusion; 4) to determine how differences in virus strain or the physiologic state of the host cell affect the outcome of infection. These studies will provide definitive information about the role of macrophages in the pathogenesis of AIDS which will be of crucial importance to formulating treatment strategies.
