Hepatitis B Virus Virology and Replication

Hepatitis B virus (HBV) is an enveloped virus with an internal icosahedral nucleocapsid (NC) enclosing a partially double-stranded, relaxed circular DNA (rcDNA) genome, which is replicated through reverse transcription of a RNA intermediate, the pregenomic RNA (pgRNA). The virus specifically infects human hepatocytes by binding the cell surface receptor, sodium taurocholate cotransporting polypeptide, which was only recently identified. Upon cell entry, HBV is believed to deliver its internal NC to the nuclear pore complex where rcDNA is released into the nucleus. rcDNA is then converted, in an ill-understood process, to a covalently closed circular DNA (cccDNA), which serves as the transcriptional template for the production of all viral RNAs, subject to regulation by epigenetic mechanisms as well as ubiquitous and liver-enriched transcriptional factors. Upon translation, the viral reverse transcriptase assembles with pgRNA, with the help of host factors, into a ribonucleoprotein complex, which triggers initiation of viral reverse transcription using a novel protein priming mechanism as well as the assembly of immature progeny NCs with the viral capsid protein. Reverse transcription within NCs then converts pgRNA into the mature rcDNA, which can be recycled back to the nucleus for conversion to more cccDNA, or secreted in progeny virions extracellularly with the viral envelope proteins, completing the life cycle. The only target in this life cycle that has been exploited successfully so far for antiviral therapy is the DNA synthesis activity of the viral reverse transcriptase, but others are being actively explored. HBV replication also leads to the secretion of a large excess of subviral particles and a soluble antigen, which are nonessential for the virus but have greatly contributed, and will continue to contribute, to the diagnosis and prevention of HBV infections.