Replication of Subgenomic Hepatitis C Virus Replicons in Mouse Fibroblasts Is Facilitated by Deletion of Interferon Regulatory Factor 3 and Expression of Liver-Specific MicroRNA 122
Replication of Subgenomic Hepatitis C Virus Replicons in Mouse Fibroblasts Is Facilitated by Deletion of Interferon Regulatory Factor 3 and Expression of Liver-Specific MicroRNA 122
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DOI：
10.1128/jvi.00559-10
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发表时间：
2010-09-15
影响因子：
5.4
通讯作者：
Richardson, Christopher D.
中科院分区：
文献类型：
--
作者：
Lin, Liang-Tzung;Noyce, Ryan S.;Richardson, Christopher D.
丙型肝炎病毒（HCV）感染导致显著的发病率，有效的小鼠模型将极大地促进病毒的研究和有效的疫苗和新的治疗药物的开发。病毒复制所需的进入因子、先天免疫和宿主因子代表了限制HCV感染小鼠细胞的最初屏障。本文的实验考虑了病毒感染的早期阶段，并研究了干扰素调节因子（IRF-3和IRF-9）和microRNA（miR-122）在含有病毒亚基因组复制子的小鼠胚胎成纤维细胞（MEFs）中促进HCV复制的作用。虽然野生型鼠成纤维细胞的HCV RNA复制受到限制，但单独缺失IRF-3可促进这些细胞中的复制子活性。这种作用被认为与IRF-3介导的I型干扰素合成的失活有关。IRF-9的额外缺失产生IRF-3（-/-）IRF-9（-/-）MEF，其阻断I型干扰素信号传导，不增加HCV复制。肝脏特异性miR-122在MEFs中的表达进一步刺激了啮齿动物成纤维细胞中HCV复制子的合成。miR-122表达和IRF-3缺失的联合作用产生了HCV亚基因组复制的协同刺激。miR-122和IRF-3是能够影响HCV复制的独立宿主因子，我们的研究结果可能有助于建立支持HCV生长和颗粒形成的小鼠模型和其他细胞系统。
Hepatitis C virus (HCV) infection causes significant morbidity, and efficient mouse models would greatly facilitate virus studies and the development of effective vaccines and new therapeutic agents. Entry factors, innate immunity, and host factors needed for viral replication represent the initial barriers that restrict HCV infection of mouse cells. Experiments in this paper consider early postentry steps of viral infection and investigate the roles of interferon regulatory factors (IRF-3 and IRF-9) and microRNA (miR-122) in promoting HCV replication in mouse embryo fibroblasts (MEFs) that contain viral subgenomic replicons. While wild-type murine fibroblasts are restricted for HCV RNA replication, deletion of IRF-3 alone can facilitate replicon activity in these cells. This effect is thought to be related to the inactivation of the type I interferon synthesis mediated by IRF-3. Additional deletion of IRF-9 to yield IRF-3(-/-) IRF-9(-/-) MEFs, which have blocked type I interferon signaling, did not increase HCV replication. Expression of liver-specific miR-122 in MEFs further stimulated the synthesis of HCV replicons in the rodent fibroblasts. The combined effects of miR-122 expression and deletion of IRF-3 produced a cooperative stimulation of HCV subgenome replication. miR-122 and IRF-3 are independent host factors that are capable of influencing HCV replication, and our findings could help to establish mouse models and other cell systems that support HCV growth and particle formation.