Role of Human Apolipoprotein E in Hepatitis B Virus Infection and Morphogenesis

人载脂蛋白 E 在乙型肝炎病毒感染和形态发生中的作用

基本信息

批准号：
10462638
负责人：
GUANGXIANG George LUO
金额：
$ 42.04万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-22 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10462638
关键词：
Affect Antibodies Antiviral Agents Antiviral Therapy Apolipoprotein E Binding Biological Assay Biology Cell Culture System Cell Culture Techniques Cell Line Cessation of life Chronic Chronic Hepatitis Chronic Hepatitis B Circular DNA Cirrhosis Clinical Co-Immunoprecipitations Cysteine DNA Viruses Data Development Electron Microscopy Family Family member Fibrosis Genes Genome Glucosamine Glypican Goals Hepadnaviridae Heparan Sulfate Proteoglycan Heparin Hepatitis B Hepatitis B Vaccines Hepatitis B Virus Hepatocyte Human Immunologics Individual Infection Infectious hepatitides Interferons Knock-out Knowledge LDL-Receptor Related Protein 1 Liver diseases Low Density Lipoprotein Receptor Mediating Mediation Molecular Molecular Target Monoclonal Antibodies Morphogenesis Mus Mutagenesis Outcome Patients Persons Phosphorylation Physiological Play Primary carcinoma of the liver cells Production Proteins Public Health Risk Role Small Interfering RNA Surface Testing Therapeutic United States Vaccines Viral hepatitis Virion Virus Virus Diseases Virus Replication World Health Organization antiviral drug development base chronic liver disease drug development drug discovery env Gene Products global health glycosylation in vivo inhibitor knock-down novel nucleoside analog prevent proteoglycan core protein prototype receptor receptor binding virus envelope virus host interaction

项目摘要

Summary Hepatitis B virus (HBV) is a common cause of human liver diseases, including chronic hepatitis, steatosis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HBV chronically infects more than 250 million people worldwide, including 1.25 million in the United States. Although HBV vaccine has greatly contributed to the reduction of new cases of HBV infection and HCC, it does not offer therapeutic benefits to the hundreds of millions of chronic HBV carriers. The World Health Organization has called for the elimination of viral hepatitis as a public health threat by the year 2030. The biggest challenge to curing chronic hepatitis B is the elimination of HBV covalently closed circular DNA (cccDNA), which is the molecular basis for persistent HBV replication. Existing antiviral therapies with interferon and/or nucleoside analogs can effectively suppress HBV replication but do not significantly affect the level of HBV cccDNA. Thus, there is an urgent need to discover and develop new classes of antiviral drugs capable of eliminating chronic HBV infection. In this regard, a more thorough understanding of HBV infection, replication, and morphogenesis holds a great promise to identify novel targets for antiviral drug discovery and development. Through preliminary studies, we have discovered that human apolipoprotein E (apoE) is associated with infectious HBV. More importantly, our preliminary data suggest that apoE plays critical roles in both HBV infection and morphogenesis. ApoE-specific antibodies could efficiently neutralize HBV infectivity. Also, knockdown of apoE expression or knockout of apoE gene resulted in a remarkable reduction of HBV infection and production. Based on these novel findings, we hypothesize that apoE is incorporated into HBV virions and plays important roles in HBV infection and morphogenesis in vivo. The overall goal of this application is to determine the role and underlying molecular mechanisms of apoE in the promotion of HBV infection and morphogenesis in cell culture and in vivo. Our specific aims are: 1) to determine the importance of apoE in the infection and morphogenesis of clinical HBV isolates; 2) to determine apoE-binding receptors and apoE-receptor interactions important for efficient HBV infection; and 3) to illustrate the underlying molecular mechanism of apoE-mediated promotion of HBV morphogenesis. The successful completion of this application will result in a paradigm change regarding the roles of cellular proteins in HBV infection and morphogenesis. The outcomes of our studies will also provide novel molecular targets for discovery and development of antiviral drugs towards the ultimate elimination of HBV infection.

概括丙型肝炎病毒（HBV）是人肝病的常见原因，包括慢性肝炎，脂肪变性，纤维化，肝硬化和肝细胞癌（HCC）。 HBV长期感染超过2.5亿人全球，包括美国125万。尽管HBV疫苗对减少HBV感染和HCC的新病例，它没有为数百种提供治疗效益数百万慢性HBV载体。世界卫生组织呼吁消除病毒肝炎到2030年，公共卫生威胁。治愈慢性乙型肝炎的最大挑战是消除 HBV共价闭合圆形DNA（CCCDNA），这是持续HBV复制的分子基础。干扰素和/或核苷类似物现有的抗病毒疗法可以有效抑制HBV复制但不要显着影响HBV CCCDNA的水平。因此，迫切需要发现和发展能够消除慢性HBV感染的新型抗病毒药物。在这方面，一个更彻底的对HBV感染，复制和形态发生的理解是一个巨大的希望，可以识别新目标用于抗病毒药物发现和发育。通过初步研究，我们发现人类载脂蛋白E（APOE）与感染性HBV有关。更重要的是，我们的初步数据表明 APOE在HBV感染和形态发生中扮演关键作用。 APOE特异性抗体可以有效中和HBV感染力。同样，敲除apoE表达或apoE基因的敲除导致A HBV感染和生产的显着减少。基于这些新颖的发现，我们假设 APOE被纳入HBV病毒体中，并在体内在HBV感染和形态发生中起重要作用。这该应用的总体目标是确定APOE在APOE中的作用和潜在分子机制促进细胞培养和体内HBV感染和形态发生。我们的具体目的是：1）确定 APOE在临床HBV分离株的感染和形态发生中的重要性； 2）确定apoe结合受体和APOE受体相互作用对于有效的HBV感染很重要； 3）说明基础 APOE介导的HBV形态发生的分子机制。成功完成应用将导致有关细胞蛋白在HBV感染和形态发生。我们研究的结果还将为发现和开发抗病毒药物以最终消除HBV感染。