Inhibition of purified CD34+ hematopoietic progenitor cells by human immunodeficiency virus 1 or gp120 mediated by endogenous transforming growth factor β1

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) β1 neutralizing serum or TGF-β1 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-β1 produced by purified hematopoietic progenitors. Moreover, by using a sensitive assay on the CCL64 cell line, increased levels of bioactive TGF-β1 were recovered in the culture supernatant of HIV-1/gp120-treated CD34⁺ cells. Anti-TGF-β1 neutralizing serum or TGF-β1 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.