Mycophenolic acid inhibits hepatitis C virus replication and acts in synergy with cyclosporin A and interferon-α
Mycophenolic acid inhibits hepatitis C virus replication and acts in synergy with cyclosporin A and interferon-α
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DOI：
10.1053/j.gastro.2006.08.027
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发表时间：
2006-11-01
期刊：
影响因子：
29.4
通讯作者：
Van der Laan, Luc J. W.
中科院分区：
文献类型：
--
作者：
Henry, Scot D.;Metselaar, Herold J.;Van der Laan, Luc J. W.
背景与目的：慢性丙型肝炎病毒（HCV）感染是肝移植的主要指征。临床证据表明，特定的免疫抑制剂可能对HCV复发有影响。环孢素A （CsA）通过阻断病毒RNA聚合酶NS5B特异性抑制HCV复制。在这项研究中，我们研究了霉酚酸（MPA）和其他免疫抑制剂对HCV复制的影响。方法：采用含荧光素酶报告基因的hcv复制模型，对mPA等化合物进行体外检测。结果：在临床相关浓度（1.0-6.0 μ g/mL）下，MPA可抑制HCV复制约75%。CsA和干扰素(IFN)- α也表现出剂量依赖性抑制作用。在这些短期（18小时）的实验中，MPA没有抑制细胞增殖或诱导细胞死亡，这可能是抗病毒作用的原因。与MPA对西尼罗病毒的抗病毒作用相反，MPA对HCV复制的影响与鸟苷无关。当MPA和CsA联合使用时，对复制有明显的协同抑制作用，最高剂量时达到90%的最大抑制作用。在次优浓度的ifn - α与MPA或CsA的协同作用下观察到。MPA、CsA和IFN-a抑制HCV的动力学明显不同，ifn - α的作用最早。他克莫司或雷帕霉素未见特异性抑制作用。结论：免疫抑制药物MPA与CsA一样具有抑制HCV复制的作用。MPA具有独特的抗hcv作用机制，不依赖于细胞增殖和鸟苷耗竭。
Background & Aims: Chronic hepatitis C virus (HCV) infection is the leading indication for liver transplantation. Clinical evidence suggests that particular immunosuppressive agents can have an influence on HCV recurrence. Cyclosporine A (CsA) specifically inhibits HCV replication through blocking the viral RNA polymerase enzyme NS5B. In this study, we investigated the effect of mycophenolic acid (MPA) and other immunosuppressants on HCV replication. Methods: mPA and other compounds were tested in vitro using an HCV-replication model containing a luciferase reporter gene. Results: At clinically relevant concentrations (1.0-6.0 mu g/mL), MPA inhibited HCV replication to approximately 75%. CsA and interferon (IFN)-alpha also showed inhibition in a dose-dependent manner. In these short-term (18 hours) experiments, MPA did not inhibit cell proliferation or induce cell death, which could have accounted for the antiviral effect. in contrast to the antiviral activity of MPA against West Nile virus, the effect of MPA on HCV replication was guanosine independent. When combined, MPA and CsA showed significant synergistic inhibition of replication, reaching maximum inhibition of similar to 90% at the highest doses. Synergistic effects were observed with suboptimal concentrations of IFN-alpha with MPA or CsA. The kinetics of HCV inhibition by MPA, CsA, and IFN-a were clearly distinct, with earliest effects seen with IFN-alpha. No specific inhibitory effects were observed with tacrolimus or rapamycin. Conclusions: The immunosuppressive drug MPA is as potent as CsA as an inhibitor of HCV replication. MPA was shown to have a distinct anti-HCV mechanism of action, independent of cell proliferation and guanosine depletion.