Clinical Outcomes and the HCV Core Gene

临床结果和 HCV 核心基因

• 批准号: 8314444
• 负责人: Andrea D. Branch
• 金额: $ 6.99万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8314444
• 关键词: Accounting; Antibodies; Antiviral Agents; Antiviral Response; Arsenites; Automobile Driving; Basic Science; Binding; Biological Assay; Blood; C-terminal; Cancer Etiology; Cell Culture Techniques; Cellular Stress; Chronic Hepatitis C; Clinical; Clinical Research; Codon Nucleotides; Commit; Core Protein; Data; Detection; Development; Disease; Disease Progression; Future; Gene Expression; Genes; Genome; Genotype; Goals; HCV Vaccine; Health; Hepatitis C; Hepatitis C virus; Human Virus; Individual; Infection; Infectious hepatitides; Initiator Codon; Injury; Insulin Resistance; Interferon Type I; Interferons; Internal Ribosome Entry Site; Intervention; Kinetics; Life Cycle Stages; Liver; Liver diseases; Luciferases; Malignant neoplasm of liver; Mediating; Messenger RNA; Modeling; Molecular; Monitor; Mutagenesis; Mutation; N-terminal; Outcome; Pathway interactions; Patients; Pattern; Point Mutation; Production; Property; Protein Biosynthesis; Protein Family; Proteins; Publishing; RNA; RNA Probes; Reporter; Research; Resistance; Ribavirin; Ribosomes; Signal Transduction; Site; Staging; Structure; Testing; Transcript; Transgenic Organisms; Translation Initiation; Translations; Treatment Failure; Treatment outcome; Viral; Viral Genes; Viral Proteins; Virus; Western Blotting; adverse outcome; base; circular RNA; clinically significant; fitness; inhibitor/antagonist; insight; interest; member; novel; public health relevance; research study; response; therapy design; tool; viral RNA; viral resistance; virus core; virus pathogenesis

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. PUBLIC HEALTH RELEVANCE: Clinical studies of liver disease patients with chronic hepatitis C virus (HCV) infection provide vital information about viral and host determinants of treatment outcome and disease progression. It is thus highly significant that clinical studies have identified two mutations in HCV that are strongly associated with treatment failure and the development of liver cancer. This project investigates the action of these mutations at the molecular level, with the ultimate goal of developing interventions to block the effects of the viral genes influenced by the disease- associated mutations.

描述（由申请人提供）：对于丙型肝炎病毒（HCV）感染患者的终阶段肝病和肝癌是主要健康问题。 HCV的当前疗法旨在停止和扭转肝损伤的进展。这些疗法基于干扰素（IFN），并有望继续基于可预见的未来IFN。宿主和病毒因素都会影响治疗结果。已发表的数据表明，核心基因中的病毒点突变与治疗衰竭和胰岛素抵抗有关。引人注目的是，这些相同的突变（在密码子70和91中）与肝癌的发展有关。这些高度特异性的病毒点突变为研究与分子水平的HCV相关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中与疾病相关的突变对HCV基因的表达具有深远的影响：它们改变了两种新鉴定的病毒蛋白，70米霉蛋白和91个米诺科蛋白的水平。在一个重大发现中，我们发现密码子91中与疾病相关的突变增强了密码子91上蛋白质合成的内部起始。我们的数据增加了早期的证据，即HCV使用翻译起始的“不同”模式来逃避细胞的抗病毒防御措施并增加病毒拟合度。为了说明Minicore的产生，我们建议核心基因包含广泛而高度保守的翻译机，该机器促进了在特定位点的蛋白质合成的内部起始，驱动Minicore合成并增强了IFN耐药性和病毒持久性。密码子70和91中突变对病毒的IFN敏感性以及Minicore蛋白的结构和功能的影响将在AIM I中进行研究。将在AIM II中确定转化机的特性以及与疾病相关突变对其活性的影响。实现我们的目标将填补对HCV生命周期的理解，并提供设计干预措施以阻止转化机的作用并抑制Minicore蛋白在患者中的影响所需的基本信息。 公共卫生相关性：慢性丙型肝炎病毒（HCV）感染的肝病患者的临床研究提供了有关治疗结果和疾病进展的病毒和宿主决定因素的重要信息。因此，临床研究已经确定了与治疗衰竭和肝癌发展密切相关的HCV中的两个突变，这是非常重要的。该项目研究了这些突变在分子水平上的作用，其最终目的是开发干预措施，以阻止受疾病相关突变影响的病毒基因的影响。