Singh P, Kairuz D, Arbuthnot P, Bloom K. Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach. World J Gastroenterol 2021; 27(23): 3182-3207 [PMID: 34163105 DOI: 10.3748/wjg.v27.i23.3182]
Corresponding Author of This Article
Kristie Bloom, MSc, PhD, Academic Research, Research Scientist, Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg 2050, Gauteng, South Africa. kristie.bloom@wits.ac.za
Research Domain of This Article
Virology
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastroenterol. Jun 21, 2021; 27(23): 3182-3207 Published online Jun 21, 2021. doi: 10.3748/wjg.v27.i23.3182
Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach
Prashika Singh, Dylan Kairuz, Patrick Arbuthnot, Kristie Bloom
Prashika Singh, Dylan Kairuz, Patrick Arbuthnot, Kristie Bloom, Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Johannesburg 2050, Gauteng, South Africa
Author contributions: Singh P, Kairuz D, Arbuthnot P and Bloom K contributed to the writing and critical revision of the manuscript.
Conflict-of-interest statement: The authors declare no conflict-of-interest.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Kristie Bloom, MSc, PhD, Academic Research, Research Scientist, Wits/SAMRC Antiviral Gene Therapy Research Unit, School of Pathology, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg 2050, Gauteng, South Africa. kristie.bloom@wits.ac.za
Received: January 29, 2021 Peer-review started: January 29, 2021 First decision: March 14, 2021 Revised: March 23, 2021 Accepted: May 7, 2021 Article in press: May 7, 2021 Published online: June 21, 2021
Abstract
Global prophylactic vaccination programmes have helped to curb new hepatitis B virus (HBV) infections. However, it is estimated that nearly 300 million people are chronically infected and have a high risk of developing hepatocellular carcinoma. As such, HBV remains a serious health priority and the development of novel curative therapeutics is urgently needed. Chronic HBV infection has been attributed to the persistence of the covalently closed circular DNA (cccDNA) which establishes itself as a minichromosome in the nucleus of hepatocytes. As the viral transcription intermediate, the cccDNA is responsible for producing new virions and perpetuating infection. HBV is dependent on various host factors for cccDNA formation and the minichromosome is amenable to epigenetic modifications. Two HBV proteins, X (HBx) and core (HBc) promote viral replication by modulating the cccDNA epigenome and regulating host cell responses. This includes viral and host gene expression, chromatin remodeling, DNA methylation, the antiviral immune response, apoptosis, and ubiquitination. Elimination of the cccDNA minichromosome would result in a sterilizing cure; however, this may be difficult to achieve. Epigenetic therapies could permanently silence the cccDNA minichromosome and promote a functional cure. This review explores the cccDNA epigenome, how host and viral factors influence transcription, and the recent epigenetic therapies and epigenome engineering approaches that have been described.
Core Tip: Epigenetic regulation of the hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) minichromosome is important for establishing and maintaining infection. To do this HBV manipulates several cellular pathways, resulting in an intricate and complex interplay between the virus and the host. Epigenetic silencing of the cccDNA could permanently inhibit viral transcription. Therapies such as immune modulators, small molecules, and epigenome engineering tools could silence HBV DNA to promote a functional cure.
