Abstract
Chronic hepatitis B virus (HBV) infection puts more than 250 million people at a greatly increased risk to develop end-stage liver disease. Like all hepadnaviruses, HBV replicates via protein-primed reverse transcription of a pregenomic (pg) RNA, yielding an unusually structured, viral polymerase-linked relaxed-circular (RC) DNA as genome in infectious particles. Upon infection, RC-DNA is converted into nuclear covalently closed circular (ccc) DNA. Associating with cellular proteins into an episomal minichromosome, cccDNA acts as template for new viral RNAs, ensuring formation of progeny virions. Hence, cccDNA represents the viral persistence reservoir that is not directly targeted by current anti-HBV therapeutics. Eliminating cccDNA will thus be at the heart of a cure for chronic hepatitis B. The low production of HBV cccDNA in most experimental models and the associated problems in reliable cccDNA quantitation have long hampered a deeper understanding of cccDNA molecular biology. Recent advancements including cccDNA-dependent cell culture systems have begun to identify select host DNA repair enzymes that HBV usurps for RC-DNA to cccDNA conversion. While this list is bound to grow, it may represent just one facet of a broader interaction with the cellular DNA damage response (DDR), a network of pathways that sense and repair aberrant DNA structures and in the process profoundly affect the cell cycle, up to inducing cell death if repair fails. Given the divergent interactions between other viruses and the DDR it will be intriguing to see how HBV copes with this multipronged host system.
Highlights
Hepatitis B virus (HBV) is the prototypic member of the hepadnaviruses, a family of small enveloped hepatotropic viruses that replicate their tiny (~3 kb) DNA genomes through reverse transcription
There are still technical obstacles hampering high-throughput approaches for the global involved in the process, yet several lines of evidence support a crucial role for the cellular DNA damage response (DDR); identification of host factors involved in the process, yet several lines of evidence support a crucial at present many options are open as to how such an interaction may manifest itself for HBV
Hepadnaviral genomes are amongst the smallest animal virus genomes known, implying a may manifest itself for HBV
Summary
Hepatitis B virus (HBV) is the prototypic member of the hepadnaviruses, a family of small enveloped hepatotropic viruses that replicate their tiny (~3 kb) DNA genomes through reverse transcription. As HCV is an RNA virus and RNA has a limited life-span, blocking replication for a finite time is sufficient to eliminate the virus. This is achieved by recently introduced direct acting antivirals, and chronic hepatitis C can be cured in most patients [4,5]. Either therapy may achieve control of infection but rarely leads to a cure because from acute self-limited hepatitis.
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