Mechanisms of Hepadnavirus Assembly and Replication

摘要 乙肝病毒(乙肝病毒)是慢性病毒性肝炎的主要原因，它极大地增加了患肝脏的风险 癌症和其他终末期肝病，如肝硬变。治愈慢性乙肝的主要障碍 感染是病毒Episome，即共价闭合环状DNA(CccDNA)在感染者体内的持久性 肝细胞尽管接受了抗病毒治疗。这项应用将解决病毒和宿主对HBVcccDNA的控制 在cccDNA形成的先决条件步骤形成，即病毒核衣壳的分解(去涂层)， 释放病毒松弛环状DNA(RcDNA)，将其转化为cccDNA。三个具体目标是 建议。目标1将定义脱壳的病毒衣壳决定因素。目标2将定义宿主决定因素 去涂层的能力。目标3将试图了解并克服小鼠肝细胞无法支持乙肝病毒的问题 CccDNA的形成，从而使小鼠肝细胞完全允许乙肝病毒的复制，并促进 建立完全易感的小鼠乙肝病毒感染和复制模型。

Abstract Hepatitis B virus (HBV) is a major cause of chronic viral hepatitis that increases dramatically the risk of liver cancer and other end-stage liver diseases such as cirrhosis. The major obstacle to curing chronic HBV infection is the persistence of the viral episome, the covalently closed circular DNA (cccDNA), in the infected hepatocytes despite antiviral treatment. This application will address viral and host control of HBV cccDNA formation at a prerequisite step for cccDNA formation, i.e., the disassembly of viral nucleocapsids (uncoating), which releases the viral relaxed circular DNA (rcDNA) for conversion to cccDNA. Three Specific Aims are proposed. Aim 1 will define the viral capsid determinants of uncoating. Aim 2 will define the host determinants of uncoating. Aim 3 will seek to understand, and to overcome, the failure of mouse hepatocytes to support HBV cccDNA formation, so as to render mouse hepatocytes fully permissive to HBV replication and facilitate the development of fully susceptible mouse models of HBV infection and replication.