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

总结 B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）。HBV慢性感染超过2.5亿人 全球范围内，包括125万在美国。虽然乙肝疫苗在很大程度上促进了 虽然减少了HBV感染和HCC的新病例，但它并没有为数百名患者提供治疗益处。 数百万慢性HBV携带者。世界卫生组织呼吁消除病毒性肝炎， 到2030年将对公众健康构成威胁治疗慢性B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/或核苷类似物的抗病毒治疗可以有效地抑制HBV复制 但不显著影响HBV cccDNA的水平。因此，迫切需要发现和开发 新型抗病毒药物能够消除慢性HBV感染。在这方面，一个更彻底的 对HBV感染、复制和形态发生的理解，为识别新的靶点提供了巨大的希望 用于抗病毒药物的发现和开发。通过初步研究，我们发现， 载脂蛋白E（apoE）与感染性HBV相关。更重要的是，我们的初步数据表明， 载脂蛋白E在HBV感染和形态发生中起关键作用。ApoE特异性抗体可以有效地 中和HBV的传染性。此外，敲低apoE表达或敲除apoE基因导致了 显著降低HBV感染和产生。基于这些新的发现，我们假设， 载脂蛋白E被整合到HBV病毒粒子中，在体内HBV感染和形态发生中起重要作用。的 本申请的总体目标是确定apoE在肿瘤中的作用和潜在的分子机制。 在细胞培养物和体内促进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）测定apoE结合 受体和apoE-受体相互作用对有效的HBV感染很重要;和3）阐明潜在的 载脂蛋白E介导的促进HBV形态发生的分子机制成功完成本 应用将导致关于细胞蛋白在HBV感染中的作用的范式改变， 形态发生我们的研究成果也将为发现和治疗提供新的分子靶点。 开发抗病毒药物，最终消除HBV感染。

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.