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, methyl-6,8-bis(methylthio)pyrrolo[1,2-a]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 vi ral genome into host DNA. We report that MIII (but not OLT) is a nonto xic 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 (ED(50) = 14 +/- 1 and 41 +/- 4 mu M, resp ectively). Electrophoretic mobility-shift assays (EMSA) reveal that MI II does not significantly reduce the PMA-induced DNA binding activitie s 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. Whe ther this translates into antiviral synergy in vivo is being examined by comparing OLT and MIII pharmacokinetics to the pharmacodynamic effe cts of orally-administered OLT in patients with p24 antigenemia. (C) 1 996 Academic Press, Inc.