Cyclosporin A inhibits hepatitis C virus replication and restores interferon-alpha expression in hepatocytes.

Hepatitis C virus (HCV) infection is the leading indication for liver transplantation and a major cause of graft failure. This study investigated whether cyclosporin A (CsA), a widely used immunosuppressant for organ transplantation, inhibits full cycle HCV replication and restores type I interferon (IFN) signaling pathway in human hepatocytes. CsA treatment of hepatocytes before, during, and after HCV infection significantly inhibited full cycle viral replication, which is evidenced by decreased expression of HCV RNA, protein, and infectious viruses in human hepatocytes. The suppression of HCV replication by CsA was associated with elevated levels of endogenous IFN-α in infected hepatocytes. Although CsA had little effect on IFN-α signaling pathway in uninfected hepatocytes, CsA treatment of HCV-infected hepatocytes specifically upregulated the expression of IFN regulatory factor-1 and inhibited the expression of suppressor of cytokine signaling-1 and protein inhibitor of activated signal transducers and activators of transcription-x, the primary negative regulators of IFN signaling pathway. These findings provide additional evidence to support the development of CsA-based prevention/treatment of HCV infection for transplant recipients.