title: Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection.
abstract: OBJECTIVE
  Modulation of the host innate immune response is an attractive means of inhibiting hepatitis C virus (HCV) replication. Having previously determined that expression of the interferon-sensitive gene (ISG)15 protease USP18 is increased in the liver biopsy specimens of patients who do not respond to interferon (IFN)-alfa therapy, we hypothesized that USP18 might hinder the ability of IFN to inhibit HCV replication.
  
  
  METHODS
  The role of USP18 in IFN antiviral activity was examined using an in vitro model of HCV replication that reproduces the full viral life cycle. USP18 was silenced specifically using small inhibitory RNAs (siRNAs), and the dose response of HCV replication and infectious virus production to IFN-alfa was measured.
  
  
  RESULTS
  The siRNA knockdown of USP18 in human cells consistently potentiated the ability of IFN to inhibit HCV-RNA replication and infectious virus particle production by a factor of 1-2 log(10). USP18 knockdown also resulted in a number of cellular changes consistent with increased sensitivity to IFN. Decreasing USP18 expression led to increased cellular protein ISGylation in response to exogenous IFN-alfa, prolonged tyrosine phosphorylation of signal transducer and activation of transcription (STAT1), and a general enhancement of IFN-stimulated gene expression.
  
  
  CONCLUSIONS
  These data suggest that USP18 modulates the anti-HCV type I IFN response, and is a possible therapeutic target for the treatment of HCV infection.
authors.affiliation: Center for the Study of Hepatitis C, Rockefeller University, New York, New York, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Randall
authors.forename: Limin
authors.initials: L
authors.lastname: Chen
authors.forename: Maryline
authors.initials: M
authors.lastname: Panis
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Fischer
authors.forename: Brett D
authors.initials: BD
authors.lastname: Lindenbach
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.forename: Jenny
authors.initials: J
authors.lastname: Heathcote
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
authors.forename: Aled M
authors.initials: AM
authors.lastname: Edwards
authors.forename: Ian D
authors.initials: ID
authors.lastname: McGilvray
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D002460:Cell Line; D016207:Cytokines / Q000502:physiology; D010450:Endopeptidases / Q000235:genetics / Q000502:physiology*; D020868:Gene Silencing; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D053613:Janus Kinase 1 / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D043222:Ubiquitin Thiolesterase; D014452:Ubiquitins / Q000502:physiology
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D016898:Interferon-alpha; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014452:Ubiquitins; C074034:ISG15 protein, human; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D010450:Endopeptidases; C485560:USP18 protein, human; D043222:Ubiquitin Thiolesterase