Objective: It is well known that cyclosporine A (CsA), a widely used immunosuppressant for clinical organ transplantation, has the ability to inhibit HCV replication. In this study, the effects of several other immunosuppressants, including mycophenolic acid (MPA), rapamycin and FK-506, on HCV replication were examined in human hepatocytes.
Methods: HCV JFH-l-infected hepatocytes were treated with immunosuppressants or with control vehicles. The levels of viral RNA and the expression of HCV core protein were determined by quantitative real-time RT-PCR and Western Blot assay, respectively.
Results: MPA-treated cells showed significant decreases in both viral RNA and HCV Core protein expression compared with the control cells. Moreover, MPA treatments of hepatocytes before, during or after HCV infection could significantly inhibit viral replication. In contrast, rapamycin and FK-506 had little effect on HCV replication. Mechanism research disclosed that the inhibition of HCV replication by MPA was mainly due to its depletion of guanosine, a purine nucleoside crucial for synthesis of guanosine triphosphate (GTP), which is required for initiation of HCV RNA replication. The supplement of exogenous guanosine could reverse most of anti-HCV effect of MPA.
Conclusion: These results indicate that MPA, through the depletion of guanosine, inhibits HCV JFH-1 replication in hepatocytes, suggesting that MPA may be beneficial for HCV-infected transplant recipients.