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）感染个体的主要健康问题。目前丙肝病毒的治疗旨在阻止和逆转肝损伤的进展。这些治疗基于干扰素（IFN），预计在可预见的未来将继续以干扰素为基础。宿主和病毒因素都影响治疗结果。已发表的数据显示，核心基因的病毒点突变与治疗失败和胰岛素抵抗有关。令人感兴趣的是，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：它们改变了两种新发现的病毒蛋白，70 minicore蛋白和91 minicore蛋白的水平。在一项重大发现中，我们发现密码子91的疾病相关突变增强了密码子91蛋白合成的内部起始。我们的数据为先前的证据提供了新的证据，即HCV使用“发散”的翻译起始模式来逃避细胞抗病毒防御并增加病毒适应性。为了解释微核的产生，我们提出核心基因包含一个广泛且高度保守的翻译机器，该机器促进特定位点蛋白质合成的内部起始，驱动微核合成并增强IFN抗性和病毒持久性。在Aim i中，将研究密码子70和91突变对病毒IFN敏感性以及对微核蛋白结构和功能的影响。在Aim II中，将确定翻译机器的特性以及与疾病相关的突变对其活性的影响。实现我们的目标将填补对HCV生命周期理解的基本空白，并提供设计干预措施所需的基本信息，以阻断转译机的作用并抑制患者体内微核蛋白的作用。

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.