EFFECTS OF ZIDOVUDINE ON CLONAL PROLIFERATION OF HEMATOPOIETIC PROGENITORS OF THE HUMAN FETUS. • 1791

Abstract

The Pediatric AIDS Clinical Trials Group recently reported that perinatal Zidovudine (AZT) reduces maternal-fetal transmission of human immunodeficiency virus, type 1, but results in lower hematocrits in the neonates. Although the benefits of this treatment are obvious, the Group cautioned that adverse effects of AZT on the fetus and neonate require more definition. With this in mind, we compared the effects of AZT on clonal maturation of hematopoietic progenitors obtained from the bone marrow of women of child-bearing age (n=7) with its effects on progenitors from the marrow, liver, and blood of human fetuses (n=5-7). We also sought to determine whether the adverse effects of AZT on fetal hematopoiesis resulted exclusively from an action on progenitors, or also involved inhibiting production of granulocyte colony-stimulating factor (G-CSF) or erythropoietin (Epo). Using AZT concentrations measured in the blood of women and their fetuses receiving perinatal AZT (0.1-10 μM), we observed that mature erythroid progenitors (CFU-E) were consistently the most sensitive to the adverse effects of AZT and that multipotent progenitors(CFU-MIX) were consistently the most resistant. Erythroid and granulocyte progenitors from fetal and neonatal sources were more sensitive to AZT than were those from the marrow of adult women. AZT inhibited not only the growth of progenitors, but resulted in fewer erythrocytes per erythroid progenitor and fewer neutrophils per granulocytic progenitor. The inhibitory effects of AZT were explained by an action on CD34+ cells. No effect was observed on production of G-CSF protein or mRNA by monocytes of either fetal or adult origin, or on production of Epo protein or mRNA by HEP3B cells (as a model of cells producing Epo). We speculate that the low hematocrits of neonates delivered after antenatal AZT treatment are the result of reduced clonal maturation of fetal CD34+ erythroid progenitors, and that fetal progenitors are inhibited to a greater extent than are maternal progenitors.