MUTAGENICITY OF AZT IN CHILDREN OF HIV-INFECTED WOMEN

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Zidovudine (AZT or ZDV) therapy has been shown to reduce the rate of maternal transmission of the human immunodeficiency virus (HIV) during pregnancy and delivery, but the long-term effects of perinatal treatment of infants is currently unknown. Because AZT produces DNA damage in several biological systems and is carcinogenic in rodents, long-term follow-up and assessment of the benefits and risks of therapy in infants should include an evaluation of the genotoxic potential of ZAT in these patients. In this study the researchers will use a set of molecular dose and effect biomarkers to determine the potential of AZT to act as a transplacental clastogen or mutagen in pregnant women at therapeutic doses, and to produce biological data that will improve the assessment of the long-term genetic risks of AZT therapy in children and adults. The genotoxic potential of in utero AZT therapy will be valuated by scoring chromosome aberrations (CAS) in lymphocytes and measuring the frequency of somatic mutations (Mfs) at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) locus in T-cells and the glycophorin A (GPA) locus in erythrocytes of cord blood specimens from newborn children of: (I) HIV-infected women treated with AZT during pregnancy and delivery (AZT-treated group); (ii) HIV-infected women not given AZT (AZT- control group); and (iii) uninfected women (control-control group), with n+50/group. These date will be correlated with the plasma concentrations of AZT and the levels of AZT incorporation in cord WBC DNA, and in T-cells from AZT-exposed rodents, quantified by RIA. The potential confounding effects of substance use by the mothers will be assessed by way of interview information, medical histories, and screening for cotinine in cord blood plasma. In children with evidence of AZT-induced genotoxicity at birth, the persistence of these effects will be assessed by measuring CAs and HPRT and GPA Mfs in peripheral blood samples collected 12 months postpartum. Concurrent with these pediatric studies, the HPRT assay will also be used to examine mutations (I) in human lymphoblastoid cells exposed to AZT in vitro and (ii) in mice and rats receiving AZT doses ranging from therapeutic (in Humans) to carcinogenic (in rodents). Finally molecular methods (e.g., Southern blot and mismatch amplification mutation assays) will be developed to detect specific, frequently occurring mutations (i.e., "hotspots") found in AZT-treated human cells and then used to screen for these characteristic mutations in AZT-exposed rodents and children.