Henry Scot D, Metselaar Herold J, Lonsdale Richard C B, Kok Alice, Haagmans Bart L, Tilanus Hugo W, van der Laan Luc J W
Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
Gastroenterology. 2006 Nov;131(5):1452-62. doi: 10.1053/j.gastro.2006.08.027. Epub 2006 Aug 14.
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.
MPA and other compounds were tested in vitro using an HCV-replication model containing a luciferase reporter gene.
At clinically relevant concentrations (1.0-6.0 microg/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 approximately 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-alpha were clearly distinct, with earliest effects seen with IFN-alpha. No specific inhibitory effects were observed with tacrolimus or rapamycin.
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.
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对HCV复发产生影响。环孢素A（CsA）通过阻断病毒RNA聚合酶NS5B特异性抑制HCV复制。在本研究中，我们调查了霉酚酸（MPA）和其他免疫抑制剂对HCV复制的影响。
使用含有荧光素酶报告基因的HCV复制模型在体外对MPA和其他化合物进行测试。
在临床相关浓度（1.0 - 6.0μg/mL）下，MPA将HCV复制抑制至约75%。CsA和干扰素（IFN）-α也呈剂量依赖性抑制。在这些短期（18小时）实验中，MPA未抑制细胞增殖或诱导细胞死亡，而这可能是抗病毒作用的原因。与MPA对西尼罗河病毒的抗病毒活性相反，MPA对HCV复制的作用不依赖鸟苷。联合使用时，MPA和CsA对复制表现出显著的协同抑制作用，在最高剂量时达到约90%的最大抑制率。MPA与次优浓度的IFN-α或CsA联合时观察到协同效应。MPA、CsA和IFN-α对HCV的抑制动力学明显不同，IFN-α的作用最早出现。他克莫司或雷帕霉素未观察到特异性抑制作用。
免疫抑制药物MPA作为HCV复制抑制剂与CsA一样有效。已证明MPA具有独特的抗HCV作用机制，与细胞增殖和鸟苷消耗无关。
