title: Antiviral potency analysis and functional comparison of consensus interferon, interferon-alpha2a and pegylated interferon-alpha2b against hepatitis C virus infection.
abstract: BACKGROUND
  Current treatments for chronic hepatitis C virus (HCV) employing pegylated interferon (PEG-IFN) plus ribavirin are successful in approximately 50% of patients. Consensus IFN (CIFN) is a recombinant type I IFN that has demonstrated efficacy where conventional therapy has failed. We evaluated the host cell antiviral response and anti-HCV actions induced by IFN-alpha2a, PEG-IFN-alpha2b or CIFN on cultured immortalized human hepatocytes, Huh7 human hepatoma cells and Huh7 cells that harboured genetically distinct HCV RNA replicons or were infected with HCV 2a.
  
  
  METHODS
  Cultured cells were treated with each IFN at relevant dosing based upon the pharmacological attainable in vivo serum maximum IFN concentrations. Gene expression and antiviral properties were measured using protein, RNA and virus quantification assays.
  
  
  RESULTS
  CIFN treatment maximally triggered Janus kinase signal transducer and activator of transcription signalling in association with enhanced IFN-stimulated gene (ISG) expression. Increased antiviral potency of CIFN was associated with enhancement of IFN-induced blockade upon viral protein synthesis, protection of the cellular IFN promoter stimulator-1 (IPS-1) protein from HCV proteolysis and reduced replication of an IFN-resistant HCV replicon variant. Microarray analyses revealed that CIFN treatment induced a distinct pattern of ISG expression in cultured hepatocytes compared with other IFNs.
  
  
  CONCLUSIONS
  CIFN exhibits increased anti-HCV potency over IFN-alpha2a and PEG-IFN through maximal and distinct induction of ISG expression and enhanced intracellular innate antiviral response, while protecting IPS-1 from HCV proteolysis. CIFN might offer a treatment regimen imparting translational control programmes and restoration of the retinoic acid-inducible gene-1/IPS-1 pathway and could be considered for previous treatment failures.
authors.affiliation: Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Erickson
authors.forename: Scott
authors.initials: S
authors.lastname: Seiwert
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000187:drug effects* / Q000472:pathogenicity; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D020411:Oligonucleotide Array Sequence Analysis; D011092:Polyethylene Glycols; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D007370:Interferon Type I; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011506:Proteins; D011994:Recombinant Proteins; D014764:Viral Proteins; D011092:Polyethylene Glycols; C417083:peginterferon alfa-2b