Defective hematopoiesis is a major part of the clinical picture in patients infected with the AIDS virus, HIV, apparently independent of underlying secondary infections or chemotherapy. Among the mechanisms that could be responsible for these findings are: (1) infection of and direct damage to hemopoietic progenitor cells; and (2) infection of and damage to accessory cells, which produce a variety of hemopoietic growth factors (HGF) and extracellular matrix (ECM) macromolecules, which are necessary for supporting and promoting hemopoietic stem cell survival, proliferation, and differentiation within the bone marrow. The overall purpose of this proposal is to determine the effects of HIV infection on hemopoietic stromal cells. Since HIV can infect monocytes/macrophages in vivo and in vitro, probably can infect endothelial cells, and at least can replicate in transfected fibroblastic cells, these retroviruses may be capable of causing serious disruption of normal functions of these stromal cells and, hence, resulting in impairment of normal hemopoiesis. We will study stromal cells from HIV infected patients and will determine the effects of in vitro infection of normal and activated monocytes/macrophages, endothelial cells and marrow fibroblasts with recombinant laboratory constructs of viable HIV and isolates of HIV from infected patients on their hemopoietic supportive functions. Finally, we will use specific antibodies directed against HIV envelope glycoprotein or CD4, and site-directed muta- genesis of HIV envelope and trans-acting genes to alter the ability of HIV to infect, replicate in, and cause dysfunction of hemopoietic stromal and accessory cells in vitro.
| Emanuel, P D; Peiper, S C; Chen, Z et al. (1990) Specific inhibition of interleukin 3 bioactivity by a monoclonal antibody reactive with hematopoietic progenitor cells. Proc Natl Acad Sci U S A 87:4449-52 |
