title: Novel type I interferon IL-28A suppresses hepatitis C viral RNA replication.
abstract: Interferon alpha (IFN-alpha)-based therapy is the currently approved treatment for chronic hepatitis C viral infection. The sustained antiviral response rate is approximately 50% for genotype-1 infection. The major challenge to the HCV community is to improve antiviral efficacy and to reduce the side effects typically seen in IFNalpha-based therapy. One of the strategies is to identify new interferons, which may have better efficacy and less undesirable side effects. In this report, we examined the role of IL-28A (IFN lambda2), a novel type I IFN, in suppression of human hepatitis C viral RNA replication. We have cloned both the human genomic DNA and cDNA of IL-28A, and evaluated their biological activity using HCV RNA replicon cell culture system. The results show that IL-28A effectively inhibits HCV subgenomic RNA replication in a dose-dependent manner. Treatment of human hepatoma cells with IL-28A activates the JAK-STAT signaling pathway and induces the expression of some interferon-stimulated genes (ISGs), such as 6-16 and 1-8U. We also demonstrate that IL-28A induces expression of HLA class I antigens in human hepatoma cells. Moreover, IL-28A appears to specifically suppress HCV IRES-mediated translation. Although IL-28A receptor shares one subunit with the IL-10 receptor, IL-10 treatment has no detectable effect on IL-28A-induced antiviral activity. Interestingly, IL-28A can synergistically enhance IFNalpha antiviral efficacy. Our results suggest that IL-28A antiviral activity is associated with the activation of the JAK-STAT signaling pathway and expression of ISGs. The effectiveness of IL-28A antiviral activity and its synergistic effect on IFN-alpha indicate that IL-28A may be potentially used to treat HCV chronic infection.
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, Florida 32610, USA. zhu@pathology.ufl.edu
authors.forename: Haizhen
authors.initials: H
authors.lastname: Zhu
authors.forename: Mike
authors.initials: M
authors.lastname: Butera
authors.forename: David R
authors.initials: DR
authors.lastname: Nelson
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D002460:Cell Line; D005805:Genes, MHC Class I / Q000235:genetics; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000276:immunology* / Q000628:therapy; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000378:metabolism; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D050832:Interferon-Stimulated Gene Factor 3 / Q000378:metabolism; D016898:Interferon-alpha / Q000627:therapeutic use; D016753:Interleukin-10 / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D053612:Janus Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D012367:RNA, Viral / Q000187:drug effects; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D014779:Virus Replication / Q000187:drug effects*; D000095022:Interferon Lambda
chemical_list: D000998:Antiviral Agents; D050856:Interferon Regulatory Factor-1; D007370:Interferon Type I; D050832:Interferon-Stimulated Gene Factor 3; D016898:Interferon-alpha; D016753:Interleukin-10; D007378:Interleukins; D053612:Janus Kinases; D012367:RNA, Viral; D050791:STAT Transcription Factors; C000624353:interferon-lambda, human; D000095022:Interferon Lambda