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.
|Crowe, S M; Mills, J; Elbeik, T et al. (1992) Human immunodeficiency virus-infected monocyte-derived macrophages express surface gp120 and fuse with CD4 lymphoid cells in vitro: a possible mechanism of T lymphocyte depletion in vivo. Clin Immunol Immunopathol 65:143-51|
|Crowe, S M; Elbeik, T; Ulrich, P P et al. (1991) Lack of evidence of occult human immunodeficiency virus in seronegative individuals at very high risk of infection. J Med Virol 35:160-4|
|Gilbert, M; Kirihara, J; Mills, J (1991) Enzyme-linked immunoassay for human immunodeficiency virus type 1 envelope glycoprotein 120. J Clin Microbiol 29:142-7|
|Crowe, S M; Mills, J; Kirihara, J et al. (1990) Full-length recombinant CD4 and recombinant gp120 inhibit fusion between HIV infected macrophages and uninfected CD4-expressing T-lymphoblastoid cells. AIDS Res Hum Retroviruses 6:1031-7|
|Crowe, S M; McGrath, M S; Elbeik, T et al. (1989) Comparative assessment of antiretrovirals in human monocyte-macrophages and lymphoid cell lines acutely and chronically infected with the human immunodeficiency virus. J Med Virol 29:176-80|
|Locksley, R M; Crowe, S; Sadick, M D et al. (1988) Release of interleukin 1 inhibitory activity (contra-IL-1) by human monocyte-derived macrophages infected with human immunodeficiency virus in vitro and in vivo. J Clin Invest 82:2097-105|