title: Novel alpha interferon (IFN-alpha) variant with improved inhibitory activity against hepatitis C virus genotype 1 replication compared to IFN-alpha2b therapy in a subgenomic replicon system.
abstract: Hepatitis C virus (HCV) treatment is based on the association of pegylated alpha interferon (IFN-alpha) and ribavirin. To improve the level of sustained virological response to treatment, especially in patients infected with HCV genotype 1, new IFNs with improved efficacy and toxicity profiles may be developed. In this report, we show that, in the BM4-5 cell line harboring an HCV subgenomic replicon, a novel and naturally occurring human IFN-alpha17 variant, GEA007.1, which was discovered by using an original population genetics-based drug discovery approach, inhibits HCV genotype 1 RNA replication more efficiently than does IFN-alpha2b. Moreover, we show that complete viral clearance is obtained in BM4-5 cells after long-term treatment with GEA007.1, while HCV subgenomic RNA is still detected in cells treated with other IFN-alpha variants or with standard IFN-alpha2b. Eventually, we demonstrate that the better inhibitory activity of GEA007.1 compared to that of standard IFN-alpha is likely to be due to stronger and faster activation of the JAK-STAT signaling pathway and to broader expression of IFN-alpha-responsive genes in cells. Our results demonstrate a superior inhibitory activity of GEA007.1 over that of IFN-alpha2b in the HCV replicon system. Clinical trials are required to determine whether GEA007.1 could be a potent "next generation" IFN for the treatment of HCV infection, especially in nonresponders or relapsing patients infected with HCV genotype 1 who currently represent a clinical unmet need.
authors.affiliation: INSERM, U271, Laboratoire des virus hépatiques et pathologies associées, 151 cours Albert Thomas, Lyon, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Escuret
authors.forename: Amaury
authors.initials: A
authors.lastname: Martin
authors.forename: David
authors.initials: D
authors.lastname: Durantel
authors.forename: Romain
authors.initials: R
authors.lastname: Parent
authors.forename: Olivier
authors.initials: O
authors.lastname: Hantz
authors.forename: Christian
authors.initials: C
authors.lastname: Trépo
authors.forename: Thierry
authors.initials: T
authors.lastname: Menguy
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bottius
authors.forename: Jerome
authors.initials: J
authors.lastname: Dardy
authors.forename: Jean
authors.initials: J
authors.lastname: Maral
authors.forename: Jean Louis
authors.initials: JL
authors.lastname: Escary
authors.forename: Fabien
authors.initials: F
authors.lastname: Zoulim
mesh_terms: D000998:Antiviral Agents / Q000627:therapeutic use*; D002460:Cell Line; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000235:genetics / Q000627:therapeutic use*; D008156:Luciferases / Q000378:metabolism; D012367:RNA, Viral / Q000032:analysis / Q000378:metabolism; D011994:Recombinant Proteins; D012093:Replicon; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D008156:Luciferases