title: 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.
abstract: 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 retrovirally 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-alpha 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-alpha 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-alpha production.
authors.affiliation: Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: S V
authors.initials: SV
authors.lastname: Yurasov
authors.forename: M
authors.initials: M
authors.lastname: Pettoello-Mantovani
authors.forename: C A
authors.initials: CA
authors.lastname: Raker
authors.forename: H
authors.initials: H
authors.lastname: Goldstein
mesh_terms: D000818:Animals; D017209:Apoptosis; D001853:Bone Marrow / Q000196:embryology*; D002454:Cell Differentiation; D019070:Cell Lineage; D016332:Fetal Tissue Transplantation; D006085:Graft Survival; D015497:HIV-1 / Q000502:physiology*; D006410:Hematopoiesis; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000821:virology*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D011828:Radiation Chimera; D013950:Thymus Gland / Q000637:transplantation; D014183:Transplantation, Heterologous; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016298:Hematopoietic Cell Growth Factors; D014409:Tumor Necrosis Factor-alpha