Epigenetic regulation of covalently closed circular DNA minichromosome in hepatitis B virus infection
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Biophysics Reports
REVIEW
Epigenetic regulation of covalently closed circular DNA minichromosome in hepatitis B virus infection Zhaoning Wang1,2, Weiwei Wang2, Lanfeng Wang2& 1 2
School of Life Sciences, Shanghai University, Shanghai 200444, China The Center for Microbes, Development and Health, CAS Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
Received: 17 April 2020 / Accepted: 25 May 2020
Abstract
Hepatitis B is caused by hepatitis B virus (HBV), and persistent HBV infection is a global public health problem, with 257 million people as HBV chronic carriers. Viral covalently closed circular DNA (cccDNA) is a key factor to establish persistent infection in infected hepatocytes. Current antiviral therapies have no direct impact on pre-existing cccDNA reservoir, which can be assembled into minichromosome by hijacking host factors. Understanding the mechanisms of epigenetic regulation in cccDNA minichromosome is crucial to develop new therapy on cccDNA, an attractive target for HBV cure. This review summarizes the current advances in epigenetic regulation of cccDNA minichromosome, which might provide clues to novel druggable targets to cure hepatitis B by either silencing or eliminating cccDNA reservoir.
Keywords HBV, cccDNA, Minichromosome, Epigenetic regulation
INTRODUCTION HBV infection remains a global health problem and results in approximately a million death annually. Although infection rate has decreased significantly due to effective vaccines, there are more than 257 million people worldwide suffering from HBV chronic infection, with high risk of developing to liver fibrosis, cirrhosis, and hepatocellular carcinoma (WHO 2017). Large number of HBV carriers can be asymptomatic for decades, because there is no therapy available to thoroughly eliminate HBV genome in patients. It has been reported that HBV chronic infection is dependent on the persistence of covalently closed circular DNA (cccDNA) in infected cellular nucleus (Ko¨ck et al. 2010). Currently, there are two categories of approved drugs for hepatitis B treatment. First, the immune modulator Peg-IFN can epigenetically control cccDNA minichromosome and regulate host antiviral immune responses & Correspondence: [email protected] (L. Wang)
Ó The Author(s) 2020
(Belloni et al. 2012; Shi et al. 2018). Second, nucleos(t)ide analogues (NAs) exhibit the repression of HBV polymerase (Lai et al. 2017; Papatheodoridis et al. 2002; TAK et al. 2016; Wong et al. 2013). Unfortunately, cccDNA is insensitive to antiviral therapy, leading to rapid reoccurrence of HBV replication in most patients once drug withdrawal (Hu et al. 2019). Besides potential serious side effects, long-term treatment with NAs can lead to drug resistance (Aspinall and Pockros 2004; Fontana 2009), although tenofovir alafenamide approved in 2016 has an excellent resistance profile in about 2-year test period (Agarwal et al. 2018). Therefore, it is urgent to develop novel therapies. The stable episomal c
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