THE HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 TAT PROTEIN POTENTIATES ZIDOVUDINE-INDUCED CELLULAR TOXICITY IN TRANSGENIC MICE

3'-Azido-2',3'-dideoxythymidine (AZT, zidovudine) is the principal ant iretroviral agent in the treatment of AIDS. Although beneficial, AZT r emains restricted for human usage because of its severe toxic effects. We examined the AZT sensitivity in transgenic mice expressing HIV-1 o ne-exon-encoded 72 amino acid Tat (Tat(72)) and full-length 86 amino a cid Tat (Tat(86)) proteins. Administration of AZT (1 mg/ml) in drinkin g water for 1 week resulted in a three- to fourfold decrease in hemato poietic progenitors from bone marrow in Tat mice compared to AZT-treat ed nontransgenic controls as determined by erythroid and granulocyte/m acrophage colony-forming unit assays, In liver and thymus, two of the tissues examined, AZT treatment of Tat mice resulted in as much as 80- 90% suppression of Mn-superoxide dismutase (Mn-SOD) activity. Other pa rameters associated with loss of Mn-SOD such as increase in carbonyl p roteins and decrease of sulfhydryl content were also significantly enh anced by AZT in Tat mice, Our in vivo study suggests that AZT therapy is associated with oxidative damage affecting cellular functions in se veral tissues and that Tat is one of the contributory factors in AZT-i nduced toxicities, The findings of AZT-induced oxidative damage may he lp to improve the therapeutic index of AZT and other related drugs in AIDS patients. (C) 1997 Academic Press.