Persistence of hepatitis B virus covalently closed circular DNA in hepatocytes: molecular mechanisms and clinical significance

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Abstract

Covalently closed circular DNA (cccDNA) is the transcriptional template of hepatitis B virus (HBV). Extensive research over the past decades has unveiled the important role of cccDNA in the natural history and antiviral treatment of chronic HBV infection. cccDNA can persist in patients recovering from acute HBV infection for decades. This explains why HBV reactivation occasionally occurs in patients with resolved hepatitis B receiving intensive immunosuppressive agents. In addition, although advances in antiviral treatment dramatically improve the adverse outcomes of chronic hepatitis B (CHB), accumulating evidence demonstrates that current antiviral treatments alone, be they nucleos(t)ide analogs (NAs) or interferon (IFN), fail to cure most CHB patients because of the persistent cccDNA. NA suppresses HBV replication by directly inhibiting viral polymerase, while IFN enhances host immunity against HBV infection. Viral rebound often occurs after discontinuation of antiviral treatment. The loss of cccDNA can be induced by non-cytolytic destruction of cccDNA or immune-mediated killing of infected hepatocytes. It is known that NA has no direct effect on viral transcription or cccDNA stability. Therefore, the long half-life of hepatocytes leads to a very slow decline in cccDNA in patients under antiviral therapy. Novel antiviral agents targeting cccDNA or cccDNA-containing hepatocytes are thus required for curing chronic HBV infection.

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Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

Huan Yan, Guocai Zhong, Guangwei Xu … (2012)

Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157–165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV. DOI: http://dx.doi.org/10.7554/eLife.00049.001

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IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome.

Laura Belloni, Lena Allweiss, Francesca Guerrieri … (2012)

HBV infection remains a leading cause of death worldwide. IFN-α inhibits viral replication in vitro and in vivo, and pegylated IFN-α is a commonly administered treatment for individuals infected with HBV. The HBV genome contains a typical IFN-stimulated response element (ISRE), but the molecular mechanisms by which IFN-α suppresses HBV replication have not been established in relevant experimental systems. Here, we show that IFN-α inhibits HBV replication by decreasing the transcription of pregenomic RNA (pgRNA) and subgenomic RNA from the HBV covalently closed circular DNA (cccDNA) minichromosome, both in cultured cells in which HBV is replicating and in mice whose livers have been repopulated with human hepatocytes and infected with HBV. Administration of IFN-α resulted in cccDNA-bound histone hypoacetylation as well as active recruitment to the cccDNA of transcriptional corepressors. IFN-α treatment also reduced binding of the STAT1 and STAT2 transcription factors to active cccDNA. The inhibitory activity of IFN-α was linked to the IRSE, as IRSE-mutant HBV transcribed less pgRNA and could not be repressed by IFN-α treatment. Our results identify a molecular mechanism whereby IFN-α mediates epigenetic repression of HBV cccDNA transcriptional activity, which may assist in the development of novel effective therapeutics.

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Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function.

Laura Belloni, Teresa Pollicino, Francesca De Nicola … (2009)

HBV cccDNA, the template for transcription of all viral mRNAs, accumulates in the nucleus of infected cells as a stable episome organized into minichromosomes by histones and non-histone viral and cellular proteins. Using a cccDNA-specific chromatin immunoprecipitation (ChIP)-based quantitative assay, we have previously shown that transcription of the HBV minichromosome is regulated by epigenetic changes of cccDNA-bound histones and that modulation of the acetylation status of cccDNA-bound H3/H4 histones impacts on HBV replication. We now show that the cellular histone acetyltransferases CBP, p300, and PCAF/GCN5, and the histone deacetylases HDAC1 and hSirt1 are all recruited in vivo onto the cccDNA. We also found that the HBx regulatory protein produced in HBV replicating cells is recruited onto the cccDNA minichromosome, and the kinetics of HBx recruitment on the cccDNA parallels the HBV replication. As expected, an HBV mutant that does not express HBx is impaired in its replication, and exogenously expressed HBx transcomplements the replication defects. p300 recruitment is severely impaired, and cccDNA-bound histones are rapidly hypoacetylated in cells replicating the HBx mutant, whereas the recruitment of the histone deacetylases hSirt1 and HDAC1 is increased and occurs at earlier times. Finally, HBx mutant cccDNA transcribes significantly less pgRNA. Altogether our results further support the existence of a complex network of epigenetic events that influence cccDNA function and HBV replication and identify an epigenetic mechanism (i.e., to prevent cccDNA deacetylation) by which HBx controls HBV replication.

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Author and article information

Journal

Journal ID (nlm-ta): Emerg Microbes Infect

Journal ID (iso-abbrev): Emerg Microbes Infect

Title: Emerging Microbes & Infections

Publisher: Nature Publishing Group

ISSN (Electronic): 2222-1751

Publication date (Print): September 2014

Publication date (Electronic): 17 September 2014

Publication date PMC-release: 1 September 2014

Volume: 3

Issue: 9

Page: e64

Affiliations

[1 ]Department of Microbiology, National Taiwan University College of Medicine , Taipei 10002, Taiwan, China

[2 ]Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine , Taipei 10002, Taiwan, China

[3 ]Department of Internal Medicine, National Taiwan University Hospital , Taipei 10002, Taiwan, China

[4 ]Hepatitis Research Center, National Taiwan University Hospital , Taipei 10002, Taiwan, China

[5 ]Department of Medical Research, National Taiwan University Hospital , Taipei 10002, Taiwan, China

Author notes

[* ]E-mail: kaojh@ 123456ntu.edu.tw

Article

Publisher Item ID: emi201464

DOI: 10.1038/emi.2014.64

PMC ID: 4185362

PubMed ID: 26038757

SO-VID: 34b605c8-bfe4-4819-81a6-03a08ae6ba3f

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

History

Date received : 23 May 2014

Date revision received : 17 July 2014

Date accepted : 21 July 2014

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Persistence of hepatitis B virus covalently closed circular DNA in hepatocytes: molecular mechanisms and clinical significance

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Point-Of-Care Testing for Hepatitis

Most cited references 85

Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

IFN-α inhibits HBV transcription and replication in cell culture and in humanized mice by targeting the epigenetic regulation of the nuclear cccDNA minichromosome.

Nuclear HBx binds the HBV minichromosome and modifies the epigenetic regulation of cccDNA function.

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Cited by 42

Most referenced authors 1,349