Clinical Outcomes and the HCV Core Gene

描述（由申请人提供）：终末期肝病和肝癌是丙型肝炎病毒（HCV）感染者的主要健康问题。目前的HCV治疗旨在阻止和逆转肝损伤的进展。这些疗法是基于干扰素（IFN），预计在可预见的未来将继续基于IFN。宿主和病毒因素都会影响治疗结果。已发表的数据显示，核心基因中的病毒点突变与治疗失败和胰岛素抵抗有关。非常有趣的是，这些相同的突变（密码子70和91）与肝癌的发展有关。这些高度特异性的病毒点突变为在分子水平上研究HCV相关的肝损伤和治疗失败提供了独特的机会。我们最近发现，密码子70和91中的疾病相关突变对HCV基因表达有深远的影响：它们改变了两种新鉴定的病毒蛋白质70 minicore蛋白和91 minicore蛋白的水平。在一项重大发现中，我们发现91号密码子中的疾病相关突变增强了91号密码子处蛋白质合成的内部起始。我们的数据增加了早期的证据表明，HCV使用“发散”的翻译起始模式，以逃避细胞的抗病毒防御和增加病毒的适应性。为了解释minicore的产生，我们提出核心基因包含一个广泛的和高度保守的翻译机器，促进内部启动蛋白质合成在特定的网站，驱动minicore合成和增强IFN抗性和病毒持久性。密码子70和91的突变对病毒的IFN敏感性以及对微核心蛋白的结构和功能的影响将在目的I中研究。翻译机器的性质和疾病相关突变对其活性的影响将在目的II中确定。我们目标的实现将填补对HCV生命周期理解的根本空白，并提供设计干预措施所需的基本信息，以阻断翻译机器的作用，并抑制微核心蛋白对患者的影响。

DESCRIPTION (provided by applicant): End stage liver disease and liver cancer are major health concerns for individuals with hepatitis C virus (HCV) infection. Current therapies for HCV aim to halt and reverse the progression of liver injury. These therapies are based on interferon (IFN) and are expected to continue to be based on IFN for the foreseeable future. Both host and viral factors influence treatment outcome. Published data show that viral point mutations in the core gene are associated with treatment failure and insulin resistance. Of great interest, these same mutations (in codons 70 and 91) are associated with the development of liver cancer. These highly specific viral point mutations provide a unique opportunity to investigate HCV-related liver damage and treatment failure at the molecular level. We recently discovered that the disease-associated mutations in codons 70 and 91 have a profound effect on HCV gene expression: They alter the level of two newly identified viral proteins, 70 minicore protein and 91 minicore protein. In a major finding, we discovered that the disease-associated mutation in codon 91 enhances the internal initiation of protein synthesis at codon 91. Our data add to earlier evidence that HCV uses "divergent" modes of translation initiation to evade cellular antiviral defenses and to increase viral fitness. To account for minicore production, we propose that the core gene contains an extensive and highly conserved translational machine that promotes the internal initiation of protein synthesis at specific sites, driving minicore synthesis and enhancing IFN resistance and viral persistence. The impact of mutations in codons 70 and 91 on the IFN sensitivity of viruses and on the structure and function of minicore proteins will be investigated in Aim I. The properties of the translational machine and the effect of the disease-associated mutations on its activity will be determined in Aim II. Accomplishment of our Aims will fill fundamental gaps in the understanding of the HCV life cycle and provide basic information needed to design interventions to block the action of the translational machine and to inhibit the effects of the minicore proteins in patients.