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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Interferon-inducible cholesterol-25-hydroxylase restricts hepatitis C virus replication through blockage of membranous web formation
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Interferon-inducible cholesterol-25-hydroxylase restricts hepatitis C virus replication through blockage of membranous web formation

机译：干扰素诱导的胆固醇25-羟化酶通过阻止膜网的形成来限制丙型肝炎病毒的复制

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摘要

Hepatitis C virus (HCV) is a positive-strand RNA virus that primarily infects human hepatocytes. Infections with HCV constitute a global health problem, with 180 million people currently chronically infected. Recent studies have reported that cholesterol 25-hydroxylase (CH25H) is expressed as an interferon-stimulated gene and mediates antiviral activities against different enveloped viruses through the production of 25-hydroxycholesterol (25HC). However, the intrinsic regulation of human CH25H (hCH25H) expression within the liver as well as its mechanistic effects on HCV infectivity remain elusive. In this study, we characterized the expression of hCH25H using liver biopsies and primary human hepatocytes. In addition, the antiviral properties of this protein and its enzymatic product, 25HC, were further characterized against HCV in tissue culture. Levels of hCH25H messenger RNA were significantly up-regulated both in HCV-positive liver biopsies and in HCV-infected primary human hepatocytes. The expression of hCH25H in primary human hepatocytes was primarily and transiently induced by type I interferon. Transient expression of hCH25H in human hepatoma cells restricted HCV infection in a genotype-independent manner. This inhibition required the enzymatic activity of CH25H. We observed an inhibition of viral membrane fusion during the entry process by 25HC, which was not due to a virucidal effect. Yet the primary effect by 25HC on HCV was at the level of RNA replication, which was observed using subgenomic replicons of two different genotypes. Further analysis using electron microscopy revealed that 25HC inhibited formation of the membranous web, the HCV replication factory, independent of RNA replication. Conclusion: Infection with HCV causes up-regulation of interferon-inducible CH25H in vivo, and its product, 25HC, restricts HCV primarily at the level of RNA replication by preventing formation of the viral replication factory. (Hepatology 2015;62:702-714)
机译：丙型肝炎病毒（HCV）是一种正链RNA病毒，主要感染人肝细胞。 HCV感染构成全球健康问题，目前有1.8亿人被慢性感染。最近的研究报道胆固醇25-羟化酶（CH25H）被表达为干扰素刺激的基因，并通过产生25-羟胆固醇（25HC）介导针对不同包膜病毒的抗病毒活性。然而，人类CH25H（hCH25H）在肝脏内表达的内在调节及其对HCV感染性的机制作用仍然难以捉摸。在这项研究中，我们使用肝活检和原代人肝细胞表征了hCH25H的表达。此外，该蛋白及其酶促产物25HC的抗病毒特性在组织培养中进一步针对HCV进行了表征。在HCV阳性肝活检和HCV感染的原代人肝细胞中，hCH25H信使RNA的水平均显着上调。 hCH25H在人原代肝细胞中的表达主要由I型干扰素短暂诱导。 hCH25H在人类肝癌细胞中的瞬时表达以基因型非依赖性方式限制了HCV感染。这种抑制需要CH25H的酶促活性。我们观察到25HC在进入过程中对病毒膜融合的抑制，这不是由于杀病毒作用引起的。然而25HC对HCV的主要作用是在RNA复制水平，这是使用两种不同基因型的亚基因组复制子观察到的。使用电子显微镜的进一步分析表明，25HC抑制了膜网的形成，即HCV复制工厂，而与RNA复制无关。结论：HCV感染会导致体内干扰素诱导的CH25H上调，其产物25HC通过阻止病毒复制工厂的形成，主要在RNA复制水平上限制HCV。 （肝病2015; 62：702-714）

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