title: Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. Current therapy with pegylated interferon alpha (IFN-alpha) in combination with ribavirin is associated with adverse effects and often fails to induce a sustained response. IFN-lambdas, recently discovered IFN gene family members, exhibit antiviral and cell stimulatory activities similar to IFN-alpha. We aimed to determine whether IFN-lambda exhibits antiviral activity toward HCV and to compare the signal transduction and effector gene pathways with those of IFN-alpha.
  
  
  METHODS
  Using the HCV replicon system and cell culture infectious reporter virus, we compared IFN-alpha and IFN-lambda effects on HCV RNA replication and protein expression, as measured by quantitative reverse-transcriptase polymerase chain reaction, luciferase expression, and Western blot. Receptor expression and signaling pathways were explored using flow cytometry and Western blot. IFN-alpha- and IFN-lambda-mediated gene expression changes were compared using microarray analyses.
  
  
  RESULTS
  IFN-lambda exhibited dose- and time-dependent HCV inhibition, independent of types I and II IFN receptors. The kinetics of IFN-lambda-mediated signal transducers and activators of transcription (STAT) activation and induction of potential effector genes were distinct from those of IFN-alpha. IFN-lambda induced steady increases in levels of known interferon stimulated genes (ISGs), whereas IFN-alpha ISGs peaked early and declined rapidly. IFN-lambda inhibited replication of HCV genotypes 1 and 2 and enhanced the antiviral efficacy of subsaturating levels of IFN-alpha.
  
  
  CONCLUSIONS
  These results demonstrate distinct differences in IFN-lambda- and IFN-alpha-induced antiviral states. Understanding these differences may prove useful for developing new HCV treatment strategies.
authors.affiliation: Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 10021, USA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Marcello
authors.forename: Arash
authors.initials: A
authors.lastname: Grakoui
authors.forename: Giovanna
authors.initials: G
authors.lastname: Barba-Spaeth
authors.forename: Erica S
authors.initials: ES
authors.lastname: Machlin
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Kotenko
authors.forename: Margaret R
authors.initials: MR
authors.lastname: MacDonald
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rice
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000821:virology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D016174:Hepacivirus / Q000235:genetics*; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007372:Interferons; D007378:Interleukins / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000473:pathology / Q000821:virology; D020411:Oligonucleotide Array Sequence Analysis; D012367:RNA, Viral / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D012367:RNA, Viral; C000624353:interferon-lambda, human; D000095022:Interferon Lambda