HIV type 1 infection of human fetal bone marrow cells induces apoptotic changes in hematopoietic precursor cells and suppresses their in vitro differentiation and capacity to engraft SCID mice

To investigate the mechanism of HIV-1-induced hematopoietic abnormalities, we examined the effect of HIV-1 infection on the in vitro and in vivo behavior of precursor cells obtained from human fetal bone marrow (HFBM). After infection with the monocyte-tropic isolate HIV-1(ADA), HFBM cells displayed a significant decrease in their subsequent in vitro production of precursor cell colonies and a marked impairment in their engraftment of the bone marrow of irradiated SCID mice. By injecting retrovitally tagged, purified human CD34⁺ cells into HIV-1(ADA)-infected or uninfected human thymic tissue implanted in SCID mice, we demonstrated that HIV-1 infection also inhibited the in vivo differentiation of CD34⁺ cells into T cells. To determine the mechanism by which HIV-1 suppressed hematopoietic activity, we investigated whether HIV-1 infection induced apoptotic cell death in hematopoietic cells. Multiparameter flow cytometry with FITC-labeled annexin V and propidium iodide demonstrated that infection of the HFBM with monocyte-tropic, but not T cell line-tropic HIV-1, stimulated apoptosis in the CD34⁺ hematopoietic precursor population. The presence of a TNF-α inhibitor during exposure of the HFBM cells to HIV-1 substantially reduced the level of apoptosis of CD34⁺ cells and significantly decreased the repression of in vitro colony formation induced by HIV-1. However, inhibition of TNF-α during HFBM cell culture with HIV-1 did not restore their capacity to engraft SCID mice. Taken together, these results indicated that HIV-1 suppression of human hematopoietic cell maturation is a multifactoral phenomenon, a crucial element of which may be HIV-1-induced apoptosis of precursor cells mediated by TNF-α production.