Determination of host factor for hepatitis C virus replication

丙型肝炎病毒是慢性肝病最常见的原因。然而，目前可用的治疗方法的疗效是有限的。我们最近报道了干扰素-a/环孢素A联合治疗的效果。在本研究中，我们研究了环孢素A对丙型肝炎病毒复制的影响及其机制，并在体外评价了环孢素A对丙型肝炎病毒复制的影响。利用小干扰RNA下调三种具有代表性的亲环素(A、B和F)和Pin-1的基因表达，以阐明哪种亲环素(S)与丙型肝炎病毒RNA复制有关。与单一干扰素治疗相比，干扰素-a联合环孢素A治疗加快了血清丙型肝炎病毒RNA的下降速度。环孢菌素A和其他亲环素的肽-脯氨基顺反异构酶活性的抑制剂抑制了丙型肝炎病毒复制子细胞和细胞培养系统中的丙型肝炎病毒RNA的复制。相反，FK506对丙型肝炎病毒的RNA复制没有任何抑制作用。这些结果表明，亲环素是体外丙型肝炎病毒RNA复制的关键成分。此外，亲环素B、亲环素F和亲环素的其他成员似乎参与了体外丙型肝炎病毒的RNA复制。亲环素是丙型肝炎病毒RNA在体外复制所必需的物质，因此其有效的抑制剂有望成为抗丙型肝炎病毒的药物。

Hepatitis C virus is the most common cause of chronic liver disease. However, the efficacy of currently available treatments is limited. We recently reported the effects of combined interferon-a/cyclosporin A treatment. In the present study, we examined the effects and mechanism of cyclosporin A on HCV replication.We evaluated the effect of cyclosporin A on the replication of HCV in vitro. The gene expression of three representative cyclophilins (A, B and F) and Pin-1 were knocked down using small interfering RNAs to clarify which cyclophilin(s) is associated with HCV RNA replication.Interferon-a combined cyclosporin A treatment accelerated the rate of reduction in serum HCV RNA compared to interferon monotherapy. Cyclosporin A and other inhibitors of the peptidyl-prolyl cis-trans isomerase activity of cyclophilins inhibited HCV RNA replication in HCV replicon cells and in a cell culture system. In contrast, FK506 did not have any inhibitory effect on HCV RNA replication.These findings indicate that cyclophilins are a crucial component of HCV RNA replication in vitro. Furthermore, cyclophilin B, cyclophilin F and other members of the cyclophilins appear to be involved in HCV RNA replication in vitro. Cyclophilins are essential for HCV RNA replication in vitro, and thus their potent inhibitors are promising anti-HCV drugs.