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：
10119861
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/10119861
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 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 base chronic liver disease drug development drug discovery env Gene Products global health glycosylation in vivo inhibitor/antagonist 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.

概括乙型肝炎病毒（HBV）是人类肝脏疾病的常见原因，包括慢性肝炎、脂肪变性、纤维化、肝硬化和肝细胞癌（HCC）。乙肝病毒长期感染超过 2.5 亿人全球有 125 万，其中美国有 125 万。尽管乙肝疫苗对乙肝疫苗的研发做出了巨大的贡献。减少了新发 HBV 感染和 HCC 病例，但它并没有为数百名患者提供治疗益处数百万慢性乙肝病毒携带者。世界卫生组织呼吁消除病毒性肝炎到 2030 年，它将成为公共卫生威胁。治愈慢性乙型肝炎的最大挑战是消除 HBV 共价闭合环状 DNA (cccDNA)，是 HBV 持续复制的分子基础。现有的干扰素和/或核苷类似物抗病毒疗法可以有效抑制乙型肝炎病毒复制但不显着影响HBV cccDNA水平。因此，迫切需要发现和开发能够消除慢性乙型肝炎病毒感染的新型抗病毒药物。对此，更彻底对 HBV 感染、复制和形态发生的了解为识别新靶点带来了巨大希望用于抗病毒药物的发现和开发。通过初步研究，我们发现人类载脂蛋白 E (apoE) 与传染性 HBV 相关。更重要的是，我们的初步数据表明 apoE 在 HBV 感染和形态发生中发挥着关键作用。 ApoE 特异性抗体可以有效中和乙肝病毒的传染性。此外，敲低 apoE 表达或敲除 apoE 基因也会导致显着减少乙型肝炎病毒感染和产生。基于这些新发现，我们假设 apoE 掺入 HBV 病毒体中，在 HBV 感染和体内形态发生中发挥重要作用。这本申请的总体目标是确定 apoE 在促进细胞培养和体内的 HBV 感染和形态发生。我们的具体目标是：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 HBV 感染很重要； 3）说明底层 apoE 介导的促进 HBV 形态发生的分子机制。本次活动的顺利完成应用将导致关于细胞蛋白在乙型肝炎病毒感染中的作用的范式改变形态发生。我们的研究结果还将提供新的分子靶标的发现和开发抗病毒药物以最终消除乙型肝炎病毒感染。