title: Compounds that target novel cellular components involved in HIV-1 transcription.
abstract: BACKGROUND
  Therapeutic intervention designed to block expression of human immunodeficiency virus (HIV) at a cellular level may slow the clinical progression of HIV-1 disease.
  
  
  METHODS
  Cellular models of latent (OM-10.1 and U1) and chronic (8E5) HIV infection were used to evaluate two benzothiophene derivatives, PD 121871 and PD 144795, for an ability to inhibit HIV activation and expression.
  
  
  RESULTS
  The benzothiophene derivatives were effective at micromolar concentrations in preventing tumor necrosis factor alpha (TNF alpha)-induced HIV-1 expression in OM 10.1 and U1 cultures. These compounds inhibited the activation of HIV-1 transcription; however, this inhibition was selective in that another TNF alpha-induced response, the transcription of autocrine TNF alpha, was unaffected. Constitutive HIV-1 expression by chronically infected 8E5 cells was also significantly reduced when treated with these experimental compounds. In TNF alpha-treated OM-10.1 cultures, the inhibition of HIV-1 transcription by these compounds was not due to a block of nuclear factor-kappa B induction. The benzothiophene derivatives also inhibited HIV-1 activation by phorbol ester treatment of OM-10.1 promyelocytes, although no inhibition of cellular differentiation toward a macrophage-like phenotype was observed. Furthermore, these experimental compounds induced a state of HIV-1 latency in cytokine-activated OM-10.1 cultures even when maintained under constant TNF alpha stimulation. The benzothiophene derivatives did not inhibit the activity of the HIV-1 trans-activator, Tat, when evaluated in transient transfection assays.
  
  
  CONCLUSIONS
  The benzothiophene derivatives appear to inhibit a critical cellular component, distinct from nuclear factor-kappa B, involved in HIV transcription and may serve to identify new therapeutic targets to restrict HIV expression.
authors.affiliation: Retrovirus Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Butera
authors.forename: B D
authors.initials: BD
authors.lastname: Roberts
authors.forename: J W
authors.initials: JW
authors.lastname: Critchfield
authors.forename: G
authors.initials: G
authors.lastname: Fang
authors.forename: T
authors.initials: T
authors.lastname: McQuade
authors.forename: S J
authors.initials: SJ
authors.lastname: Gracheck
authors.forename: T M
authors.initials: TM
authors.lastname: Folks
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism; D010703:Phorbol Esters / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D017735:Virus Latency
chemical_list: D000998:Antiviral Agents; D016328:NF-kappa B; C099152:PD 121871; D010703:Phorbol Esters; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; C095579:PD 144795