Mycophenolic acid inhibits hepatitis C virus replication and acts in synergy with cyclosporin A and interferon-alpha.
OBJECTIVE
Chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation. Clinical evidence suggests that particular immunosuppressive agents can have an influence on HCV recurrence. Cyclosporine A (CsA) specifically inhibits HCV replication through blocking the viral RNA polymerase enzyme NS5B. In this study, we investigated the effect of mycophenolic acid (MPA) and other immunosuppressants on HCV replication.


METHODS
MPA and other compounds were tested in vitro using an HCV-replication model containing a luciferase reporter gene.


RESULTS
At clinically relevant concentrations (1.0-6.0 microg/mL), MPA inhibited HCV replication to approximately 75%. CsA and interferon (IFN)-alpha also showed inhibition in a dose-dependent manner. In these short-term (18 hours) experiments, MPA did not inhibit cell proliferation or induce cell death, which could have accounted for the antiviral effect. In contrast to the antiviral activity of MPA against West Nile virus, the effect of MPA on HCV replication was guanosine independent. When combined, MPA and CsA showed significant synergistic inhibition of replication, reaching maximum inhibition of approximately 90% at the highest doses. Synergistic effects were observed with suboptimal concentrations of IFN-alpha with MPA or CsA. The kinetics of HCV inhibition by MPA, CsA, and IFN-alpha were clearly distinct, with earliest effects seen with IFN-alpha. No specific inhibitory effects were observed with tacrolimus or rapamycin.


CONCLUSIONS
The immunosuppressive drug MPA is as potent as CsA as an inhibitor of HCV replication. MPA was shown to have a distinct anti-HCV mechanism of action, independent of cell proliferation and guanosine depletion.
Henry
Scot D
SD
Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
Metselaar
Herold J
HJ
Lonsdale
Richard C B
RC
Kok
Alice
A
Haagmans
Bart L
BL
Tilanus
Hugo W
HW
van der Laan
Luc J W
LJ
D000998:Antiviral Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D006151:Guanosine / Q000037:antagonists & inhibitors; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016898:Interferon-alpha / Q000494:pharmacology*; D009173:Mycophenolic Acid / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D016572:Cyclosporine; D006151:Guanosine; D007166:Immunosuppressive Agents; D016898:Interferon-alpha; D009173:Mycophenolic Acid; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase