Effect of antimetabolite immunosuppressants on Flaviviridae, including hepatitis C virus.
BACKGROUND
Recurrence of hepatitis C virus (HCV) after liver transplantation is almost universal and decreases both graft and patient survival. Medications that alter nucleic acid metabolism, including some common immunosuppressants used in HCV-infected patients, may affect viral replication.


METHODS
Bovine viral diarrhea virus (BVDV) is in the Flaviviridae family and is closely related to HCV. We measured the effect of two immunosuppressants, azathioprine (AZA) and mycophenolate acid (MPA), on both BVDV replication by plaque assay and host-cell replication by flow cytometry. We also compared the effect of ribavirin and AZA on the level of HCV replicon RNA by real-time reverse-transcriptase polymerase chain reaction.


RESULTS
At doses that achieved similar cytotoxicity, AZA decreased BVDV replication 10 times more than MPA. The inhibition of BVDV by AZA occurred at lower doses than the cellular cytotoxicity and did not depend on cytotoxicity. A two-log reduction in viral titers occurred despite blocking the cytotoxicity of AZA by inhibiting ribonucleotide reductase with high concentrations of thymidine. A metabolite of AZA, 6-mercaptopurine, still possessed this antiviral effect, but a metabolite further downstream, 6-thioguanine, did not, even though 6-thioguanine is the metabolite responsible for cellular toxicity. The effect of AZA on a HCV replicon was at least as large as that of ribavirin.


CONCLUSIONS
This report suggests that AZA is a more potent antiviral than MPA for Flaviviridae and may exert a specific antiviral effect on HCV. Additional clinical studies to investigate this previously unanticipated antiviral effect of AZA on HCV in the posttransplant setting are indicated.
Stangl
Jason R
JR
Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Carroll
Kathleen L
KL
Illichmann
Mitchell
M
Striker
Robert
R
D000818:Animals; D000963:Antimetabolites / Q000009:adverse effects / Q000494:pharmacology*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology; D001379:Azathioprine / Q000008:administration & dosage / Q000494:pharmacology*; D002417:Cattle; D002460:Cell Line; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015122:Mercaptopurine / Q000494:pharmacology; D009173:Mycophenolic Acid / Q000494:pharmacology*; D012093:Replicon / Q000187:drug effects; D012254:Ribavirin / Q000008:administration & dosage / Q000494:pharmacology; D013866:Thioguanine / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
D000963:Antimetabolites; D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D012254:Ribavirin; D015122:Mercaptopurine; D013866:Thioguanine; D009173:Mycophenolic Acid; D001379:Azathioprine