title: Isolation and characterization of interferon lambda-resistant hepatitis C virus replicon cell lines.
abstract: Pegylated interferon lambda-1a (Lambda) is currently in clinical development for the treatment of chronic hepatitis C virus (HCV) infection. To gain insight into the potential mechanisms of non-responsiveness that may occur in patients treated with Lambda, HCV subgenomic replicon cell-lines with impaired susceptibility to the unpegylated recombinant (r) form of interferon (IFN) lambda-1 (rIFNλ) were isolated and characterized. The selected replicon cell populations showed a defect in the activation of the IFN-dependent JAK-STAT signaling pathway. Reduced phosphorylation of STAT proteins and lower expression levels of the cellular janus kinases Jak1 and Tyk2 were observed in these cell populations, which may account for the impaired JAK-STAT signaling and reduced antiviral responses to rIFNλ. Overall, this in vitro study provides molecular insights into the possible mechanism of viral evasion to rIFNλ in the HCV replicon cell system.
authors.affiliation: Discovery Virology, Bristol-Myers Squibb Research and Development, Wallingford, CT 06492, USA. jacques.friborg@bms.com
authors.forename: Jacques
authors.initials: J
authors.lastname: Friborg
authors.forename: Baiqing
authors.initials: B
authors.lastname: Lin
authors.forename: Chaoqun
authors.initials: C
authors.lastname: Chen
authors.forename: Fiona
authors.initials: F
authors.lastname: McPhee
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral; D016174:Hepacivirus / Q000187:drug effects / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000821:virology; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007372:Interferons; D007378:Interleukins / Q000276:immunology* / Q000494:pharmacology; D015398:Signal Transduction; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D007155:Immunologic Factors; D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda
keywords: HCV; Interferon; Lambda; Resistance