title: Bis-anthracycline antibiotics inhibit human immunodeficiency virus type 1 transcription.
abstract: The increasing numbers of human immunodeficiency virus type 1 (HIV-1) strains that exhibit resistance to antiretroviral agents used at present require the development of new effective antiretroviral compounds. Tat transactivation was recognized early on as an attractive target for drug interference. To screen for and analyze the effects of compounds that interfere with Tat transactivation, we developed several cell-based reporter systems in which enhanced green fluorescence protein is a direct and quantitative marker of HIV-1 expression or Tat-dependent long terminal repeat activity. Using these reporter cell lines, we found that the bis-anthracycline WP631, a recently developed DNA intercalator, efficiently inhibits HIV-1 expression at subcytotoxic concentrations. WP631 also abrogated acute HIV-1 replication in peripheral blood mononuclear cells infected with various primary virus isolates. We demonstrate that WP631-mediated HIV-1 inhibition is caused by the inhibition of Tat transactivation. The data presented suggest that WP631 could serve as a lead compound for a new type of HIV-1 inhibitor.
authors.affiliation: Department of Cell Biology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA. okutsch@uab.edu
authors.forename: Olaf
authors.initials: O
authors.lastname: Kutsch
authors.forename: David N
authors.initials: DN
authors.lastname: Levy
authors.forename: Paula J
authors.initials: PJ
authors.lastname: Bates
authors.forename: Julie
authors.initials: J
authors.lastname: Decker
authors.forename: Barry R
authors.initials: BR
authors.lastname: Kosloff
authors.forename: George M
authors.initials: GM
authors.lastname: Shaw
authors.forename: W
authors.initials: W
authors.lastname: Priebe
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D018943:Anthracyclines / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004279:DNA, Viral / Q000187:drug effects; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D015696:Gene Products, tat / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D049452:Green Fluorescent Proteins; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008164:Luminescent Proteins / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D018943:Anthracyclines; D000900:Anti-Bacterial Agents; D019380:Anti-HIV Agents; D000970:Antineoplastic Agents; D004279:DNA, Viral; D015696:Gene Products, tat; D008164:Luminescent Proteins; D014157:Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D049452:Green Fluorescent Proteins