Ribavirin enhances IFN-α signalling and MxA expression: a novel immune modulation mechanism during treatment of HCV

• Published in: PloS one 2011-11, Vol.6 (11), p.e27866
• Main Authors: Stevenson, Nigel J, Murphy, Alison G, Bourke, Nollaig M, Keogh, Catherine A, Hegarty, John E, O'Farrelly, Cliona
• Format: Article
• Language: English
• Subjects: Antiviral agents; Antiviral Agents - pharmacology; Biology; Blotting, Western; Cells, Cultured; Core protein; Fluorescent Antibody Technique; Gene expression; GTP-Binding Proteins - genetics; GTP-Binding Proteins - metabolism; Hepacivirus - drug effects; Hepacivirus - immunology; Hepacivirus - metabolism; Hepatitis C - drug therapy; Hepatitis C - immunology; Hepatitis C - virology; Hepatocytes; Hepatocytes - drug effects; Hepatocytes - immunology; Hepatocytes - metabolism; Humans; Immunity; Immunoenzyme Techniques; Immunomodulation; Immunoprecipitation; Interferon; Interferon-alpha - pharmacology; Kinases; Medicine; mRNA; Myxovirus Resistance Proteins; Nucleoside analogs; Phosphorylation; Phosphorylation - drug effects; Real-Time Polymerase Chain Reaction; Ribavirin; Ribavirin - pharmacology; RNA, Messenger - genetics; Rodents; Signal transduction; Signal Transduction - drug effects; Signal Transduction - genetics; Signaling; Stat1 protein; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Stat3 protein; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Viral Core Proteins - genetics; Viral Core Proteins - metabolism; Viral infections; Virus Replication - drug effects; Virus Replication - immunology
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0027866

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.