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，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，并有很大的发展为肝细胞癌的风险。目前，用于治疗慢性HCV感染的唯一批准的疗法是I型干扰素（IFNa/p）和利巴韦林的组合，其对治疗的响应在42%和82%之间，持续的病毒清除。即使在没有持续应答的患者中，IFN治疗通常也会导致HCV病毒载量快速下降;因此，尽管开发了其他抗病毒药物，但IFN可能会继续用于联合治疗或作为初始预治疗以降低病毒载量。在HCV抗病毒治疗过程中IFN的作用机制（或IFN耐药性）尚不清楚;然而，了解这些机制对于解释未来的HCV抗病毒治疗至关重要。microRNA（miRs）代表新鉴定的非编码RNA种类，其促进mRNA降解和/或减弱蛋白质翻译，从而提供对蛋白质表达水平的额外转录后控制。我们最近发现，干扰素转录调节许多细胞microRNA（miR）。这些IFNo/p诱导的miR中有六个预测了HCV基因组RNA内的靶点。甚至更有趣的是，我们还发现IFN 0/p有效地抑制肝特异性miR的表达，所述肝特异性miR已被证明是HCV复制绝对不可或缺的。我们的初步研究结果使我们的假设，干扰素介导的抑制HCV复制涉及诱导或抑制细胞的miR。本提案中概述的研究旨在阐明IFN α/β介导的通过调节细胞miR表达抑制HCV复制的分子机制。此外，我们建议在清除或持续HCV感染的过程中分析这些干扰素调节的miR的表达水平。我们的模型不仅提供了一个新的分子基础，IFNa/p特异性减弱HCV感染，但也提供了一个新的机制范式干扰素的抗病毒作用。

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.