Determination of host factor for hepatitis C virus replication

丙型肝炎病毒是慢性肝病最常见的病因。然而，目前可用的治疗方法的疗效有限。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HCV复制的作用和机制。我们评估了环孢素A对HCV体外复制的影响。三种具有代表性的亲环蛋白（A， B和F）和Pin-1的基因表达被小干扰RNA敲除，以澄清哪些亲环蛋白与HCV RNA复制相关。与干扰素单药治疗相比，干扰素A联合环孢素A治疗加速了血清HCV RNA的降低速度。在HCV复制子细胞和细胞培养系统中，环孢素A和其他亲环蛋白肽基脯氨酸顺式反式异构酶活性抑制剂抑制HCV RNA复制。相反，FK506对HCV RNA复制没有任何抑制作用。这些发现表明亲环蛋白是体外HCV RNA复制的关键成分。此外，亲环蛋白B、亲环蛋白F和其他亲环蛋白成员似乎参与了HCV RNA的体外复制。亲环蛋白是体外丙型肝炎病毒RNA复制所必需的，因此它们的有效抑制剂是有希望的抗丙型肝炎病毒药物。

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.