CAMPTOTHECIN INHIBITS TAT-MEDIATED TRANSACTIVATION OF TYPE-I HUMAN-IMMUNODEFICIENCY-VIRUS

Transcription of type I human immunodeficiency virus (HIV-I) is govern ed by the viral long terminal repeat (LTR). By using HTV-1 LTR-directe d reporter gene systems, we found that the DNA topoisomerase I inhibit or camptothecin inhibits Tat-mediated transactivation of HIV-1 LTR. Th e 293.27.2 cells that carry a stably transfected HIV-1 LTR-directed la cZ gene expression vector (pNAZ) were used. Inhibitions of LTR were ob served at camptothecin concentrations (IC50 about 0.03 mu m, which was an order of magnitude lower than for Ro 24-7429), which had minor eff ects on cell survival, expression of the cellular gene gro, or Rous sa rcoma virus-directed chloramphenicol acetyltransferase (CAT) gene expr ession. Inhibition was also seen with RPMI 8402, which is a human CD4- positive lymphocyte line transiently transfected with a HIV-1 LTR-dire cted (CAT) gene. Experiments with HIV-1 LTR mutants suggest that trans activation response sequence but not NF-kappa B is responsible for the inhibition by camptothecin. The target for camptothecin may be a cell ular factor that is important for the activation of HIV-1 LTR by Tat a nd thus may offer a potential target for therapy of HIV-1 infection.