OLTIPRAZ, A NOVEL INHIBITOR OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1) REPLICATION

Glutathione (GSH) levels are markedly depleted in patients infected wi th human immunodeficiency virus type 1 (HIV-I) and supplementation of media with high concentrations (5-20 mM) of low-molecular weight thiol s prevents HIV-1 replication in cultured cells. We were intrigued whet her chemopreventive enzyme inducers might represent a more pharmacolog ically feasible method to inhibit HIV-1 replication since these compou nds elevate intracellular concentrations of GSH at nontoxic doses in v ivo. After establishing that all inducers surveyed were able to elevat e GSH levels in human T-cell and monocytoid cell lines, we were surpri sed to find that oltipraz (5-pyrazinyl-4-methyl-1,2-dithiole-3-thione) was uniquely able to inhibit HIV-1 replication (IC50 = 5-15 mu M) Olt ipraz and other antiviral 1,2-dithiole-3-thiones (DTTs) appear to inhi bit acute HIV-I replication by inactivating reverse transcriptase (RT) . However, among DTTs that inhibit HIV-I replication in acutely infect ed cells, only oltipraz was able to inhibit HIV-I replication in a chr onic infection model. Thus, in addition to inactivating RT, oltipraz a ppears to have an additional antiviral mechanism distal to viral integ ration. Our laboratories are attempting to determine the mechanism by which oltipraz inhibits HIV-I replication in chronically infected cell s; we are also attempting to determine the bioorganic mechanism for th e inactivation of RT. Since the covalent modification of schistosomal proteins and transcription factor(s) are thought to be responsible for the antiparasitic and chemopreventive activities of DTTs, respectivel y, our studies should be relevant to understanding the diverse medicin al properties of DTTs. Oltipraz, an antischistosomal drug undergoing c linical evaluation as an anticarcinogen, inhibits HIV-1 replication at concentrations achievable in human serum. It is intriguing to conside r oltipraz as a therapeutic agent not only for its antiretroviral acti vity, but also for the prevention of HIV-1 associated neoplasms. (C) 1 995 Wiley-Liss, Inc.