Mechanisms of Hepadnavirus Assembly and Replication

摘要

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.