Negative regulators may mediate some of the inhibitory effects of HIV-1 infected stromal cell layers on erythropoiesis and myelopoiesis in human bone marrow long term cultures.
This report presents results concerning the potential role of negative regulators in hematopoietic suppression observed in human immunodeficiency virus (HIV)-infected long-term cultures (LTC) of human bone marrow cells. Confluent stromal cell layers established from human bone marrow cells were exposed to HIV-1ADA, a monocytotropic strain of HIV-1. A progressive increase in the concentration of HIV-1 p24 antigen in cultures exposed to HIV-1ADA demonstrated that there was a productive infection. Cells from both noninfected and HIV-infected stromal cell layers produced factors that stimulated the proliferation of colony-forming units for granulocytes and macrophages (CFU-GM) from non-infected CD34+ cells. In contrast, when noninfected CD34+ cells were directly cocultured on intact stromal cell layers fewer CFU-GM and burst-forming units for erythroid cells (BFU-E) were detected in HIV-infected LTC than in noninfected LTC. One week after the addition of CD34+ cells, the number of CFU-GM in HIV-infected LTC in six of nine experiments was reduced compared to noninfected control LTC. In those six experiments, the number of CFU-GM was only 53 +/- 5% (SEM) of the number in noninfected LTC. The number of BFU-E in HIV-1-infected LTC was only 46 +/- 5% of the number in noninfected LTC (n = 5). There were fewer BFU-E in HIV-1-infected LTC, whether or not there was a reduced number of CFU-GM. Neutralizing antibody to tumor necrosis factor alpha (TNF-alpha) had no effect on the number of BFU-E in HIV-infected LTC. The number of BFU-E, however, was 2.1 +/- 0.2-fold greater (n = 3) in HIV-infected LTC incubated with neutralizing antibody to interferon-alpha. In HIV-infected LTC with decreased numbers of CFU-GM, the number of CFU-GM was approximately 2-fold greater after incubation of HIV-infected LTC with anti-interleukin-4 (IL-4). The effect of anti-TNF-alpha was variable, and anti-transforming growth factor-beta had no effect on the number of CFU-GM in HIV-infected LTC. After 2 weeks, the number of CFU-GM in HIV-infected LTC incubated with anti-IL-4 and anti-TNF-alpha was 2- to 4-fold greater than in untreated HIV-infected LTC. Antibody treatment did not promote an increase in the number of CFU-GM in noninfected LTC or in LTC in which CFU-GM numbers were not reduced after HIV infection.(ABSTRACT TRUNCATED AT 400 WORDS)
Schwartz
G N
GN
Transplantation Therapy Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Kessler
S W
SW
Szabo
J M
JM
Burrell
L M
LM
Francis
M L
ML
D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34; D001853:Bone Marrow / Q000821:virology; D001854:Bone Marrow Cells; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D004920:Erythropoiesis; D015497:HIV-1 / Q000502:physiology*; D006410:Hematopoiesis; D006801:Humans; D016898:Interferon-alpha / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D017154:Stromal Cells / Q000821:virology; D016212:Transforming Growth Factor beta / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D015703:Antigens, CD; D018952:Antigens, CD34; D016207:Cytokines; D016898:Interferon-alpha; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4