Inhibition of purified CD34+ hematopoietic progenitor cells by human immunodeficiency virus 1 or gp120 mediated by endogenous transforming growth factor beta 1.
Human CD34+ hematopoietic progenitor cells, stringently purified from the peripheral blood of 20 normal donors, showed an impaired survival and clonogenic capacity after exposure to either heat-inactivated human immunodeficiency virus (HIV) 1 (strain IIIB) or cross-linked envelope gp120. Cell cycle analysis, performed at different times in serum-free liquid culture, showed an accumulation in G0/G1 in HIV-1- or gp120-treated cells and a progressive increase of cells with subdiploid DNA content, characteristic of apoptosis. In blocking experiments with anti-transforming growth factor (TGF) beta 1 neutralizing serum or TGF-beta 1 oligonucleotides, we demonstrated that the HIV-1- or gp120-mediated suppression of CD34+ cell growth was almost entirely due to an upregulation of endogenous TGF-beta 1 produced by purified hematopoietic progenitors. Moreover, by using a sensitive assay on the CCL64 cell line, increased levels of bioactive TGF-beta 1 were recovered in the culture supernatant of HIV-1/gp120-treated CD34+ cells. Anti-TGF-beta 1 neutralizing serum or TGF-beta 1 oligonucleotides were also effective in inducing a significant increase of the plating efficiency of CD34+ cells, purified from the peripheral blood of three HIV-1-seropositive individuals, suggesting that a similar mechanism may be also operative in vivo. The relevance of these findings to a better understanding of the pathogenesis of HIV-1-related cytopenias is discussed.
Zauli
G
G
Institute of Human Anatomy, University of Ferrara, Italy.
Vitale
M
M
Gibellini
D
D
Capitani
S
S
D018952:Antigens, CD34; D001483:Base Sequence; D002453:Cell Cycle; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D006679:HIV Seropositivity / Q000473:pathology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000502:physiology* / Q000821:virology; D006801:Humans; D007970:Leukopenia / Q000209:etiology; D008297:Male; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation
D018952:Antigens, CD34; D016895:Culture Media, Serum-Free; D015699:HIV Envelope Protein gp120; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta