title: Inhibition of HIV replication in acute and chronic infections in vitro by a Tat antagonist.
abstract: The human immunodeficiency virus-1 (HIV-1) trans-activator Tat is an attractive target for the development of antiviral drugs because inhibition of Tat would arrest the virus at an early stage. The drug Ro 5-3335 [7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepine-2(H)-one], inhibited gene expression by HIV-1 at the level of transcriptional trans-activation by Tat. The compound did not inhibit the basal activity of the promoter. Both Tat and its target sequence TAR were required for the observed inhibitory activity. Ro 5-3335 reduced the amount of cell-associated viral RNA and antigen in acutely, as well as in chronically infected cells in vitro (median inhibition concentration 0.1 to 1 micromolar). Effective inhibition of viral replication was also observed 24 hours after cells were transfected with infectious recombinant HIV-1 DNA. The compound was active against both HIV-1 and HIV-2 and against 3'-azido-3'-deoxythymidine (AZT)-resistant clinical isolates.
authors.affiliation: Department of Virology, Hoffmann-La Roche, Nutley, NJ 07110.
authors.forename: M C
authors.initials: MC
authors.lastname: Hsu
authors.forename: A D
authors.initials: AD
authors.lastname: Schutt
authors.forename: M
authors.initials: M
authors.lastname: Holly
authors.forename: L W
authors.initials: LW
authors.lastname: Slice
authors.forename: M I
authors.initials: MI
authors.lastname: Sherman
authors.forename: D D
authors.initials: DD
authors.lastname: Richman
authors.forename: M J
authors.initials: MJ
authors.lastname: Potash
authors.forename: D J
authors.initials: DJ
authors.lastname: Volsky
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology*; D002460:Cell Line; D015696:Gene Products, tat / Q000037:antagonists & inhibitors*; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015498:HIV-2 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D000998:Antiviral Agents; D001570:Benzodiazepinones; D015696:Gene Products, tat; D011758:Pyrroles; D054322:tat Gene Products, Human Immunodeficiency Virus; C072173:Ro 5-3335; D015215:Zidovudine