Hepatitis B Virus DNA Integration: In Vitro Models for Investigating Viral Pathogenesis and Persistence

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Abstract

Hepatitis B virus (HBV) is a globally-distributed pathogen and is a major cause of liver disease. HBV (or closely-related animal hepadnaviruses) can integrate into the host genome, but (unlike retroviruses) this integrated form is replication-defective. The specific role(s) of the integrated HBV DNA has been a long-standing topic of debate. Novel in vitro models of HBV infection combined with sensitive molecular assays now enable researchers to investigate this under-characterised phenomenon with greater ease and precision. This review covers the contributions these systems have made to understanding how HBV DNA integration induces liver cancer and facilitates viral persistence. We summarise the current findings into a working model of chronic HBV infection and discuss the clinical implications of this hypothetical framework on the upcoming therapeutic strategies used to curb HBV-associated pathogenesis.

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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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Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study

Joël Mossong, Homie Razavi, Stefan Zeuzem … (2018)

The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate viral hepatitis by 2030. Although no virological cure exists for hepatitis B virus (HBV) infection, existing therapies to control viral replication and prophylaxis to minimise mother-to-child transmission make elimination of HBV feasible. We aimed to estimate the national, regional, and global prevalence of HBsAg in the general population and in the population aged 5 years in 2016, as well as coverage of prophylaxis, diagnosis, and treatment.

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Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.

Akihiro Fujimoto, Mayuko Furuta, Yasushi Totoki … (2016)

Liver cancer, which is most often associated with virus infection, is prevalent worldwide, and its underlying etiology and genomic structure are heterogeneous. Here we provide a whole-genome landscape of somatic alterations in 300 liver cancers from Japanese individuals. Our comprehensive analysis identified point mutations, structural variations (STVs), and virus integrations, in noncoding and coding regions. We discovered mutational signatures related to liver carcinogenesis and recurrently mutated coding and noncoding regions, such as long intergenic noncoding RNA genes (NEAT1 and MALAT1), promoters, CTCF-binding sites, and regulatory regions. STV analysis found a significant association with replication timing and identified known (CDKN2A, CCND1, APC, and TERT) and new (ASH1L, NCOR1, and MACROD2) cancer-related genes that were recurrently affected by STVs, leading to altered expression. These results emphasize the value of whole-genome sequencing analysis in discovering cancer driver mutations and understanding comprehensive molecular profiles of liver cancer, especially with regard to STVs and noncoding mutations.

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Author and article information

Contributors

Fabien Zoulim: Role: Academic Editor

Duane P. Grandgenett: Role: Academic Editor

Journal

Journal ID (nlm-ta): Viruses

Journal ID (iso-abbrev): Viruses

Journal ID (publisher-id): viruses

Title: Viruses

Publisher: MDPI

ISSN (Electronic): 1999-4915

Publication date (Electronic): 26 January 2021

Publication date Collection: February 2021

Volume: 13

Issue: 2

Electronic Location Identifier: 180

Affiliations

[1 ]Storr Liver Centre, Faculty of Medicine and Health, Westmead Clinical School and Westmead Institute for Medical Research, The University of Sydney, Westmead, NSW 2145, Australia; hzha8212@ 123456uni.sydney.edu.au

[2 ]Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia

[3 ]Department of Infectious Diseases, Molecular Virology, Heidelberg University Hospital, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany; Stephan.Urban@ 123456med.uni-heidelberg.de

[4 ]German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany

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[* ]Correspondence: t.tu@ 123456sydney.edu.au

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Thomas Tu https://orcid.org/0000-0002-0482-4387

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Publisher ID: viruses-13-00180

DOI: 10.3390/v13020180

PMC ID: 7911709

PubMed ID: 33530322

SO-VID: 312ab289-b173-424e-9e19-29c7465822e0

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Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Hepatitis B Virus DNA Integration: In Vitro Models for Investigating Viral Pathogenesis and Persistence

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Most cited references 124

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

Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study

Whole-genome mutational landscape and characterization of noncoding and structural mutations in liver cancer.

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