title: Ribavirin enhances IFN-α signalling and MxA expression: a novel immune modulation mechanism during treatment of HCV.
abstract: The nucleoside analogue Ribavirin significantly increases patient response to IFN-α treatment of HCV, by directly inhibiting viral replication. Recent studies indicate that Ribavirin also regulates immunity and we propose that Ribavirin enhances specific interferon sensitive gene (ISG) expression by amplifying the IFN-α-JAK/STAT pathway. We found that IFN-α-induced STAT1 and STAT3 phosphorylation was increased in hepatocytes co-treated with Ribavirin and IFN-α, compared to IFN-α alone. Ribavirin specifically enhanced IFN-α induced mRNA and protein of the anti-viral mediator MxA, which co-localised with HCV core protein. These novel findings indicate for the first time that Ribavirin, in addition to its viral incorporation, also enhances IFN-α-JAK/STAT signalling, leading to a novel MxA-mediated immuno-modulatory mechanism that may enhance IFN-α anti-viral activity against HCV.
authors: School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland. N.Stevenson@tcd.ie
authors: Nigel J
authors: NJ
authors: Stevenson
authors: Alison G
authors: AG
authors: Murphy
authors: Nollaig M
authors: NM
authors: Bourke
authors: Catherine A
authors: CA
authors: Keogh
authors: John E
authors: JE
authors: Hegarty
authors: Cliona
authors: C
authors: O'Farrelly
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016174:Hepacivirus / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006526:Hepatitis C / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D022781:Hepatocytes / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D016898:Interferon-alpha / Q000494:pharmacology*; D064547:Myxovirus Resistance Proteins; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012254:Ribavirin / Q000494:pharmacology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D012254:Ribavirin; D019204:GTP-Binding Proteins