Inhibition of human immunodeficiency virus type 1 long terminal repeat-driven transcription by an in vivo metabolite of oltipraz: implications for antiretroviral therapy.

Metabolite III (MIII, 7-methyl-6,8-bis(methylthio)pyrrolo[1,2-alpha]pyrazine), a major in vivo metabolite of oltipraz (OLT, 5-pyrazinyl-4-methyl-1,2-dithiole-3-thione), appears to disrupt human immunodeficiency virus type 1 (HIV-1) replication at a point distal to integration of the viral genome into host DNA. We report that MIII (but not OLT) is a nontoxic inhibitor of long terminal repeat (LTR)-driven expression of beta-galactosidase in phorbol-12-myristate-13-acetate (PMA)-stimulated and unstimulated 293.27.2 cells (ED50 = 14 +/- 1 and 41 +/- 4 microM, respectively). Electrophoretic mobility-shift assays (EMSA) reveal that MIII does not significantly reduce the PMA-induced DNA binding activities of NF-kappa B or AP-1. Although the mechanism by which MIII inhibits LTR-driven transcription remains unclear, the antiviral synergism of OLT and MIII in vitro are likely due their independent activities. Whether this translates into antiviral synergy in vivo is being examined by comparing OLT and MIII pharmacokinetics to the pharmacodynamic effects of orally-administered OLT in patients with p24 antigenemia.