Interferon modulation of cellular microRNAs in the Hepatitis C antiviral defense

描述（由申请人提供）：在世界范围内，大约2%的人口感染丙型肝炎病毒（HCV），其中50-80%发展为持续性感染，并有很大的风险发展为肝细胞癌。目前，唯一被批准用于治疗慢性HCV感染的疗法是I型干扰素（IFNa/p）和利巴韦林的联合治疗，治疗反应在42%至82%之间，持续病毒清除。即使在没有持续反应的患者中，干扰素治疗通常也会导致HCV病毒载量的快速下降；因此，尽管有其他抗病毒药物的发展，干扰素可能会继续用于治疗，无论是联合治疗还是作为降低病毒载量的初始预处理。在HCV抗病毒治疗中，IFN的作用机制（或对IFN的耐药性）尚不清楚；然而，了解这些机制对于解释未来丙型肝炎病毒的抗病毒治疗至关重要。MicroRNAs （miRs）是一种新发现的非编码RNA，可促进mRNA降解和/或减弱蛋白质翻译，从而为蛋白质表达水平提供额外的转录后控制。我们最近发现干扰素转录调节许多细胞microrna （miRs）。这些IFNo/p诱导的miRs中有6个预测了HCV基因组RNA中的靶标。更有趣的是，我们还发现IFNo/p能有效抑制肝脏特异性miR的表达，而miR已被证明对HCV的复制是绝对必要的。我们的初步研究结果使我们假设ifn介导的HCV复制抑制涉及诱导或抑制细胞miRs。本文概述的研究旨在阐明IFNa/p通过调节细胞miRs的表达来抑制HCV复制的分子机制。此外，我们建议分析这些干扰素调节的miRs在清除或持续HCV感染过程中的表达水平。我们的模型不仅为IFNa/p特异性减弱HCV感染提供了新的分子基础，而且为干扰素的抗病毒作用提供了新的机制范式。

DESCRIPTION (provided by applicant): Worldwide, approximately 2% of the population is infected with Hepatitis C virus (HCV) and 50-80% of those develops into persistent infections and are at great risk of developing hepatocellular carcinoma. Currently, the only approved therapy for treatment of chronic HCV infection is a combination of type I interferon (IFNa/p) and ribavirin with a response to treatment between 42% and 82% sustained viral clearance. Even in patients without sustained responses, IFN therapy usually results in a rapid decline in HCV viral load; therefore, IFN will likely continue to be used in treatment either in combination therapies or as an initial pre-treatment to reduce viral load, despite the development of other antivirals. The mechanisms of actions of IFN (or resistance to IFN) during antiviral therapy for HCV are not clear; yet, understanding these mechanisms is critical for interpretation of future antiviral treatments for HCV. MicroRNAs (miRs) represent a newly identified non-coding RNA species that promotes mRNA degradation and/or attenuates protein translation, thus providing additional post-transcriptional control over protein expression levels. We recently discovered that interferons transcriptionally regulate numerous cellular microRNAs (miRs). Six of these IFNo/p-induced miRs have predicted targets within the HCV genomic RNA. Even more intriguing, we also found that IFNo/p potently inhibit the expression of a liver- specific miR that has been demonstrated to be absolutely indispensible for replication of HCV. Our preliminary findings lead us to the hypothesis that IFN-mediated inhibition of HCV replication involves the induction or suppression of cellular miRs. The studies outlined in this proposal are aimed to elucidate the molecular mechanism underlying the IFNa/p-mediated suppression of HCV replication through modulation of the expression of cellular miRs. In addition, we propose to analyze the expression levels of these interferon-regulated miRs during the course of clearing or persistent HCV infections. Our model offers not only a new molecular basis by which IFNa/p specifically attenuate HCV infection, but also provides a novel mechanistic paradigm for the antiviral actions of interferons.