The research outlined in this proposal focuses on the interaction between the Human Immunodeficiency Virus (HIV) and hemopoietic progenitor cells ln the bone marrow of HIV-infected individuals. Cells of the granulocyte/macrophage (GM) lineage, specifically monocytes/macrophages in peripheral blood, brain, lung, and lymph nodes, as well as myeloid precursors in the bone marrow, have been shown to be infected in HIV seropositive individuals. The long term objectives of these studies are to determine the possible role that HIV-infected hemopoietic progenitors in the marrow play in (1) the persistence of HIV through latent infection, (2) the transmission of HIV to T4 lymphocytes and brain cells, (3) altered hematopoiesis, and (4) the defective immune function of infected monocytes/macrophages. In this particular study, the extent of HIV infection of hemopoietic precursors (CFU-GM, BFU-E, CFU-MIX) will be determined for patients at different stages of HIV-induced disease. This will be accomplished by plating bone marrow samples in hemopoietic colony assays and staining the resulting colonies in situ for the presence of HIV antigen. Attempts to correlate these findings with the expression and proviral DNA map of HIV in whole bone marrow and peripheral blood monocytes/macrophages will be performed. In order to determine whether GM stem cells or their progeny are a potential reservoir for latent HIV infection, individual hemopoietic colonies will be assayed for the presence of HIV proviral DNA, RNA, and antigen; furthermore, individual cell types within HIV infected colonies will be examined for HIV expression. Finally, it is critical to identify the exact factors responsible for the suppression of hemopoiesis observed in vitro and possibly operative in vivo. Experiments will be conducted to assess the role that monocytes/macrophages, T lymphocytes, patient's sera, and HIV-infected stem cells play in suppressing hemopoiesis, as well as to determine whether the therapeutic use of GM-CSF can detrimentally activate latent HIV infection.
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| Cen, D; Zauli, G; Szarnicki, R et al. (1993) Effect of different human immunodeficiency virus type-1 (HIV-1) isolates on long-term bone marrow haemopoiesis. Br J Haematol 85:596-602 |
