Camptothecin inhibits Tat-mediated transactivation of type 1 human immunodeficiency virus.
Transcription of type 1 human immunodeficiency virus (HIV-1) is governed by the viral long terminal repeat (LTR). By using HIV-1 LTR-directed reporter gene systems, we found that the DNA topoisomerase I inhibitor camptothecin inhibits Tat-mediated transactivation of HIV-1 LTR. The 293.27.2 cells that carry a stably transfected HIV-1 LTR-directed lacZ gene expression vector (pNAZ) were used. Inhibitions of LTR were observed at camptothecin concentrations (IC50 about 0.03 microM, which was an order of magnitude lower than for Ro 24-7429), which had minor effects on cell survival, expression of the cellular gene gro, or Rous sarcoma virus-directed chloramphenicol acetyltransferase (CAT) gene expression. Inhibition was also seen with RPMI 8402, which is a human CD4-positive lymphocyte line transiently transfected with a HIV-1 LTR-directed (CAT) gene. Experiments with HIV-1 LTR mutants suggest that transactivation response sequence but not NF-kappa B is responsible for the inhibition by camptothecin. The target for camptothecin may be a cellular factor that is important for the activation of HIV-1 LTR by Tat and thus may offer a potential target for therapy of HIV-1 infection.
Li
C J
CJ
Dana-Farber Cancer Institute, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115.
Wang
C
C
Pardee
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D001483:Base Sequence; D001569:Benzodiazepines / Q000494:pharmacology; D002166:Camptothecin / Q000494:pharmacology*; D002460:Cell Line; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000502:physiology; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D011758:Pyrroles; D012045:Regulatory Sequences, Nucleic Acid; D015533:Transcriptional Activation / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D011758:Pyrroles; D054322:tat Gene Products, Human Immunodeficiency Virus; D001569:Benzodiazepines; C070024:Ro 24-7429; D002166:Camptothecin