title: Cell type-specific anti-human immunodeficiency virus type 1 activity of the transactivation inhibitor Ro5-3335.
abstract: The drug Ro5-3335 [7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2(H)-one] inhibits human immunodeficiency virus type 1 (HIV-1) gene expression at the transcriptional level through interference with Tat-mediated transactivation (M.-C. Hsu, A. D. Schutt, M. Holly, L. W. Slice, M. I. Sherman, D. D. Richman, M. J. Potash, and D. J. Volsky, Science 254:1799-1802, 1991). We confirmed this specific inhibitory effect in a quantitative bioassay based on transactivation of a chimeric gene comprising the HIV-1 long terminal repeat promoter fused to the lacZ gene of Escherichia coli and transfected in a HeLa cell line expressing Tat. Ro5-3335 was found to inhibit HIV-1 long terminal repeat-driven lacZ gene expression at a 50% inhibitory concentration of 0.5 microM. The in vitro anti-HIV-1 activity of Ro5-3335 was highly dependent on the nature of the host cells. The highest selectivity index, 50, was found in phytohemagglutinin-stimulated peripheral blood lymphocytes. The selectivity index was between 1 and 10 in the CD4+ T-cell lines CEM, MOLT-4 (clone 8), and HUT-78. In MT-4 and MT-2 cells, Ro5-3335 had no inhibitory effect on HIV-1 replication. The absence of anti-HIV-1 activity of Ro5-3335 in MT-4 cells was confirmed by using different parameters of virus replication and different multiplicities of infection. In persistently HIV-1-infected HUT-78/IIIB/LAI cells, Ro5-3335 failed to demonstrate any activity at subtoxic concentrations. The cytotoxicity of Ro5-3335 was significantly lower in peripheral blood lymphocytes than in the CD4+ T-cell lines.
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001570:Benzodiazepinones / Q000494:pharmacology*; D003588:Cytopathogenic Effect, Viral; D004247:DNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D011758:Pyrroles / Q000494:pharmacology*; D012313:RNA / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D001570:Benzodiazepinones; D011758:Pyrroles; C072173:Ro 5-3335; D012313:RNA; D004247:DNA