OLTIPRAZ, AN INHIBITOR OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION

Glutathione depletion may play a pivotal role in the pathogenesis of h uman immunodeficiency virus type-1 (HIV-1) infection. Since certain co mpounds prevent experimental carcinogenesis by elevating the levels of glutathione and phase II detoxication enzymes, we compared the potenc ies of several inducers with their ability to inhibit basal levels of HIV-1 replication in H9 cutaneous T-cell lymphoma cells. All monofunct ional inducers tested elevated the levels of glutathione and quinone r eductase, a marker for phase II enzyme induction. However, only oltipr az [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione] was effective at i nhibiting HIV-1 replication (IC50 = 14.8 +/- 3.1 muM). The antiviral e ffect of oltipraz was potentiated by 3'-azido-3'-deoxythymidine. Thus, 1,2-dithiole-3-thiones represent a hitherto unrecognized class of ant i-HIV-1 agents. Oltipraz behaves kinetically as an irreversible inhibi tor of HIV-1 reverse transcriptase in the template-primer binding doma in. Oltipraz has been used to treat schistosomiasis in humans and is u ndergoing clinical evaluation as an anticarcinogen. Thus, oltipraz (an d other 1,2-dithiole-3-thiones) may have therapeutic utility in HIV-1- infected individuals, not only because of their antiretroviral activit y, but also by preventing the development of HIV-1-associated neoplasm s.