title: IL-28B (IFN-λ3) and IFN-α synergistically inhibit HCV replication.
abstract: Genetic variation in the IL-28B (interleukin-28B; interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C treated with peginterferon-α and ribavirin. However, the mechanisms by which polymorphisms in the IL-28B gene region affect host antiviral responses are not well understood. Using the HCV 1b and 2a replicon system, we compared the effects of IFN-λs and IFN-α on HCV RNA replication. The anti-HCV effect of IFN-λ3 and IFN-α in combination was also assessed. Changes in gene expression induced by IFN-λ3 and IFN-α were compared using cDNA microarray analysis. IFN-λs at concentrations of 1 ng/mL or more exhibited concentration- and time-dependent HCV inhibition. In combination, IFN-λ3 and IFN-α had a synergistic anti-HCV effect; however, no synergistic enhancement was observed for interferon-stimulated response element (ISRE) activity or upregulation of interferon-stimulated genes (ISGs). With respect to the time course of ISG upregulation, the peak of IFN-λ3-induced gene expression occurred later and lasted longer than that induced by IFN-α. In addition, although the genes upregulated by IFN-α and IFN-λ3 were similar to microarray analysis, interferon-stimulated gene expression appeared early and was prolonged by combined administration of these two IFNs. In conclusion, IFN-α and IFN-λ3 in combination showed synergistic anti-HCV activity in vitro. Differences in time-dependent upregulation of these genes might contribute to the synergistic antiviral activity.
authors.affiliation: First Department of Internal Medicine, University of Yamanashi, Yamanashi, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Shindo
authors.forename: S
authors.initials: S
authors.lastname: Maekawa
authors.forename: K
authors.initials: K
authors.lastname: Komase
authors.forename: M
authors.initials: M
authors.lastname: Miura
authors.forename: M
authors.initials: M
authors.lastname: Kadokura
authors.forename: R
authors.initials: R
authors.lastname: Sueki
authors.forename: N
authors.initials: N
authors.lastname: Komatsu
authors.forename: K
authors.initials: K
authors.lastname: Shindo
authors.forename: F
authors.initials: F
authors.lastname: Amemiya
authors.forename: Y
authors.initials: Y
authors.lastname: Nakayama
authors.forename: T
authors.initials: T
authors.lastname: Inoue
authors.forename: M
authors.initials: M
authors.lastname: Sakamoto
authors.forename: A
authors.initials: A
authors.lastname: Yamashita
authors.forename: K
authors.initials: K
authors.lastname: Moriishi
authors.forename: N
authors.initials: N
authors.lastname: Enomoto
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D001688:Biological Products / Q000494:pharmacology*; D002460:Cell Line; D004357:Drug Synergism; D020869:Gene Expression Profiling; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology*; D022781:Hepatocytes / Q000276:immunology / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007372:Interferons; D007378:Interleukins / Q000494:pharmacology*; D046228:Microarray Analysis; D014779:Virus Replication / Q000187:drug effects*; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D001688:Biological Products; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; C000624353:interferon-lambda, human; D000095022:Interferon Lambda