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Mycophenolic acid augments interferon‐stimulated gene expression and inhibits hepatitis C Virus infection in vitro and in vivo
Author(s) -
Pan Qiuwei,
de Ruiter Petra E.,
Metselaar Herold J.,
Kwekkeboom Jaap,
de Jonge Jeroen,
Tilanus Hugo W.,
Janssen Harry L.A.,
van der Laan Luc J.W.
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.25562
Subject(s) - imp dehydrogenase , interferon , in vivo , biology , hepatitis c virus , virology , viral replication , gene knockdown , interferon stimulated gene , in vitro , mycophenolic acid , virus , immune system , apoptosis , transplantation , immunology , innate immune system , biochemistry , medicine , surgery , microbiology and biotechnology
Mycophenolic acid (MPA) is a highly effective immunosuppressant that has broad antiviral activity against different viruses and can act in synergy with interferon‐α (IFN‐α) on hepatitis C virus (HCV) replication. MPA is a potent inosine monophosphate dehydrogenase (IMPDH) inhibitor but the antiviral mechanisms are less understood. The aim of this study was to investigate the inhibition of HCV infection by MPA and the molecular basis for its synergy with IFN‐α. The role of IMPDH and interferon‐stimulated genes (ISGs) was investigated in two HCV models using gain‐ or loss‐of‐function approaches. The in vivo effect of MPA treatment was studied in NOD/SCID mice engrafted with HCV replicon cells. Potent antiviral effects of MPA at clinically relevant concentrations were observed with both the subgenomic and JFH1‐derived infectious HCV models. MPA treatment in mice resulted in a specific and robust inhibition of HCV replication. Ectopic expression of an MPA‐resistant IMPDH2 mutant in HCV host cells completely reversed the antiproliferative effect of MPA but only partially affected the antiviral potency. However, similar to ribavirin, MPA induced expression of multiple antiviral ISGs, including interferon regulatory factor 1 (IRF1). Cotreatment of MPA with IFN‐α resulted in additive effects on ISG expression and enhanced IFN‐induced luciferase reporter activity. Knockdown of IRF1, but not IFITM3, significantly attenuated the inhibition of HCV replication by MPA. Conclusion : MPA exerts a potent anti‐HCV effect in vitro and in mice and acts in synergy with IFN‐α. MPA's antiviral activity partially depends on IMPDH but also involves stimulation of ISGs, providing a molecular basis for its synergy with IFN‐α. (H EPATOLOGY 2012;55:1673–1683)