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有限。我们最近报道了干扰素-α/环孢菌素A联合治疗的效果。本研究旨在探讨环孢素A对HCV复制的影响及其机制，并在体外研究环孢素A对HCV复制的影响。用小分子干扰RNA敲除三种代表性亲环素（A、B和F）和Pin-1的基因表达，以阐明哪种亲环素（s）与HCV RNA复制相关。环孢菌素A和亲环素的肽基脯氨酰顺反异构酶活性的其他抑制剂抑制HCV复制子细胞和细胞培养系统中的HCV RNA复制。FK 506对HCVRNA复制无抑制作用，表明亲环素是体外HCVRNA复制的重要组成部分。此外，亲环素B、亲环素F和亲环素的其他成员似乎参与体外HCV RNA复制。亲环素是HCV RNA体外复制所必需的，因此其有效抑制剂是有希望的抗HCV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.