Regulation of the hepatitis C virus genome replication by miR-199a
Regulation of the hepatitis C virus genome replication by miR-199a
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DOI：
10.1016/j.jhep.2008.06.010
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发表时间：
2009-03-01
影响因子：
25.7
通讯作者：
Shimotohno, Kunitada
中科院分区：
文献类型：
--
作者：
Murakami, Yoshiki;Aly, Hussein H.;Shimotohno, Kunitada
背景/目的：丙型肝炎病毒（HCV）感染导致慢性肝炎和肝细胞癌。目前的抗-HCV疗法是基于干扰素疗法，这是不够有效的。microRNA（miRNAs）是一种调控基因表达的非编码RNA，近年来研究表明其在病毒复制过程中发挥重要作用。方法：基于算法搜索靶向HCV基因组的miRNAs，得到一个miRNAs，miR-199 a *，其序列与HCV基因组相似，在HCV基因型中是保守的。miR-199 a * 在两种携带复制子的细胞中过表达抑制HCV基因组复制（复制子细胞）HCV-1b或-2a，然而，特异性反义寡核苷酸（阿索）的miRNA抑制加速病毒复制。在用HCV基因型1b和2a感染患者的血清感染永生化肝细胞之前，用miR-199 a * 转染可降低HCV RNA复制活性。复制子中miR-199 a * 靶位点的突变降低了miR-199 a * 的作用。当miR-199 a * 过表达至复制子细胞时，HCV复制子RNA积累至RNA诱导沉默复合物（RISC）。miR-199 a * 的这种抗病毒作用不依赖于干扰素途径。结论：本研究结果表明miR-199 a * 直接调节HCV复制，可能作为一种新型抗病毒疗法。(C)2008年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: Hepatitis C virus (HCV) infection causes chronic hepatitis and hepatocellular carcinoma. Current anti-HCV therapies are based on interferon therapy, which is insufficiently effective. microRNAs (miRNAs) are non-coding RNAs that regulate gene expression, and they have recently been shown to play an important role in viral replication.Methods:An algorithm-based search for miRNAs that target the HCV genome yielded one miRNA, miR-199a*, with a sequence similar to the HCV genome that is conserved among HCV genotypes.Results: Overexpression of miR-199a* inhibited HCV genome replication in two cells bearing replicons (replicon cell) HCV-1b or -2a, however, miRNA inhibition by specific antisense oligonucleotide (ASO) accelerated viral replication. Prior transfection of immortalized hepatocytes which were infected with serum of HCV genotype 1b and 2a-infected patients, with miR-199a* reduced HCV RNA replication activity. Mutation in the miR-199a* target site in the replicon reduced the effect of the miR-199a*. HCV replicon RNA is accumulated to the RNA-induced silencing complex (RISC) when miR-199a* was overexpressed to the replicon cell. This antiviral effect by miR-199a* was independent of the interferon pathway.Conclusions:The results of this study suggest that miR-199a* directly regulates HCV replication and may serve as a novel antiviral therapy. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.