HIV-1 suppression of hematopoiesis in vitro mediated by envelope glycoprotein and TNF-alpha.
Dysmorphic marrow morphology and bone marrow failure are common in AIDS patients, but the mechanism of HIV-1 effects on blood cell production is unclear. Experiments to test the susceptibility of hematopoietic progenitor cells to HIV-1 infection have led to conflicting results. We found that hematopoietic colony formation by burst-forming units-erythroid and CFU-GM was equivalently inhibited by both active and heat-inactivated, noninfectious virus. Inhibition was dependent on the presence of macrophages and was not observed in cultures derived from highly enriched CD34+ cells. We hypothesized that TNF-alpha, produced by mononuclear phagocytes after contact with HIV-1 or gp120 and itself a potent suppressor of hematopoiesis, might mediate this effect. The addition of anti-TNF-alpha neutralizing Abs to marrow cultures abrogated inhibition by gp120 or virus. In contrast, neutralizing Abs to Il-4, IFN-alpha, and TGF-beta failed to improve colony formation. TNF-alpha was released from blood monocytes and marrow mononuclear cells stimulated by gp120. TNF-alpha is increased in the blood of patients with late stage AIDS and may mediate many of the symptoms of the disease. Our data do not support a requirement of direct infection of hematopoietic progenitor cells by HIV-1 for the inhibition of hematopoiesis in vitro. We propose instead an indirect mechanism of viral suppression of hematopoiesis as a result of TNF-alpha induction by virus or viral envelope glycoprotein. The importance of local TNF-alpha production in patients' marrow is amenable to clinical testing.
Maciejewski
J P
JP
Hematology Branch, National Heart, Lung and Blood Institute, National Cancer Institute, Bethesda, MD. 20892.
Weichold
F F
FF
Young
N S
NS
D015703:Antigens, CD / Q000276:immunology; D018952:Antigens, CD34; D015152:Blotting, Northern; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D017077:Culture Media, Conditioned; D015686:Gene Products, env / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D019302:HIV Envelope Protein gp160; D015497:HIV-1 / Q000502:physiology*; D006410:Hematopoiesis / Q000502:physiology*; D006801:Humans; D009000:Monocytes / Q000502:physiology; D011498:Protein Precursors / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D015703:Antigens, CD; D018952:Antigens, CD34; D017077:Culture Media, Conditioned; D015686:Gene Products, env; D015699:HIV Envelope Protein gp120; D019302:HIV Envelope Protein gp160; D011498:Protein Precursors; D014409:Tumor Necrosis Factor-alpha