Molecular Target(s) for Interruption of HBV Infection

描述（由申请人提供）：乙型肝炎病毒（HBV）是一种致癌病毒。全世界估计有4亿人感染乙肝病毒，导致慢性肝炎、肝硬化和肝细胞癌（HCC）。由于低信号强度、进入过程的短暂性和动态性，以及缺乏系统的方法来识别各个步骤所需的细胞成分，HBV感染的早期事件定义不清。一旦确定，这些宿主因子可能成为治疗干预的关键靶点，从而降低慢性肝炎和随后的肝癌的发病率。鸭乙型肝炎病毒（DHBV）是一种相关的嗜肝DNA病毒，可作为鉴定病毒受体/辅助因子以及评估干预肝病毒感染的新分子靶点的模型系统。我们之前已经鉴定并克隆了两个DHBV前s包膜相互作用蛋白：p170（羧肽酶D， DCPD）和p120（甘氨酸脱羧酶）。DCPD已被确定为DHBV对接受体，但未能赋予细胞系DHBV易感性，这表明其他细胞辅助因子对于建立生产性病毒感染是必要的。p120仅分布在DHBV可感染的组织中，对DHBV生命周期的结合后步骤至关重要。p120在体外的最佳结合需要截断前s结构域，该结构域包含一个假定的PC7（一种蛋白转化酶）的切割位点。我们的长期目标是了解病毒进入途径中的病毒-宿主相互作用，并确定治疗干预的细胞靶点。本申请将启动对p120作用方式的调查。我们的具体目标是：(1)。研究p120介导多产性DHBV感染的分子基础；(2）. 确定蛋白转化酶对DHBV感染的贡献；和(3)。评价p120和DCPD作为干预DHBV感染的分子靶点。我们希望这些研究将有助于了解肝病毒感染的早期事件，并可能导致开发新的抗病毒策略来预防HBV诱导的肝癌。

DESCRIPTION (provided by applicant): Hepatitis B virus (HBV) is an oncogenic virus. An estimated 400 million individuals worldwide are infected with HBV leading to chronic hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The early events of HBV infection are poorly defined due to the low signal intensity, transient and dynamic nature of the entry process, and lack of a systemic approach to identify the cellular components required for individual steps. Once characterized, these host factors may serve as critical targets for therapeutic intervention, thus reducing the rate of chronic hepatitis and ensuing liver cancer. Duck hepatitis B virus (DHBV), the related hepatotropic DNA virus may serve as a model system for the identification of viral receptor/co-factors as well as for the evaluation of novel molecular targets for intervention of hepadnavirus infection. We have previously identified and cloned two DHBV pre-S envelope-interacting proteins: p170 (carboxypeptidase D, DCPD) and p120 (glycine decarboxylase). The DCPD has been established as a DHBV docking receptor but fails to confer DHBV susceptibility of cell lines, suggesting that other cellular co-factors are necessary for establishing productive viral infection. The p120 is distributed only in DHBV infectible tissues and essential for a post-binding step of the DHBV life cycle. Optimal p120 binding in vitro requires truncation of the pre-S domain, which contains a putative cleavage site for PC7, a proprotein convertase. Our long-term goal is to understand virus-host interactions in the viral entry pathway and identify cellular targets for therapeutic intervention. The present application will initiate investigations on the mode of p120 action. Our specific aims are: (1). Investigate the molecular basis whereby p120 mediates productive DHBV infection; (2). Determine the contribution of proprotein convertases to DHBV infectivity; and (3). Evaluate p120 as well as DCPD as molecular targets for intervention of DHBV infection. We hope these studies will contribute to the understanding of the early events of hepadnavirus infection and may lead to the development of novel antiviral strategies for prevention of HBV induced liver cancer.