Molecular Target(s) for Interruption of HBV Infection

描述(申请人提供)：乙肝病毒(乙肝病毒)是一种致癌病毒。据估计，全世界有4亿人感染了乙肝病毒，导致慢性肝炎、肝硬变和肝细胞癌。由于信号强度低，进入过程的暂时性和动态性，以及缺乏系统的方法来识别单个步骤所需的细胞成分，因此对乙肝病毒感染的早期事件的定义很差。一旦表征，这些宿主因素可能成为治疗干预的关键靶点，从而降低慢性肝炎和随后发生的肝癌的发生率。鸭乙型肝炎病毒(DHBV)是一种与之相关的嗜肝DNA病毒，可作为识别病毒受体/辅助因子的模型系统，并可用于评价干预肝炎病毒感染的新的分子靶点。我们已经鉴定并克隆了S病毒前包膜相互作用蛋白：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，但不能增加细胞系对DHBV的易感性，这表明其他细胞辅助因子对于建立有效的病毒感染是必要的。P120仅分布在D乙肝病毒感染组织中，对D乙肝病毒生命周期的结合后步骤是必不可少的。在体外，最佳的p120结合需要截断前S结构域，该结构域包含一个推测为原蛋白转换酶PC7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与宿主的相互作用，并确定用于治疗干预的细胞靶点。本申请将启动对p120动作模式的研究。具体目标是：(一)。研究p120介导产生性DHBV感染的分子基础；确定原蛋白转换酶对DHBV感染性的贡献；以及(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，并可能导致新的抗病毒策略的发展，以预防乙肝病毒诱导的肝癌。

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.