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Viruses
Special Issues
Hepatitis B Virus: Its Life Cycle and the Therapeutic Targets
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Hepatitis B Virus: Its Life Cycle and the Therapeutic Targets

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 22702

Special Issue Editor

Prof. Dr. Keiji Ueda

E-Mail Website
Guest Editor
Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine.2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
Interests: Virus; Receptor; Gene Regulation; Replication; Virus-Host Interaction; Latent Infection; Lytic Infection; Virus engineering

Special Issue Information

Dear Colleagues,

We do not have many or good options to the save lives of HBV-infected people around the world. Finding NTCP (sodium taurocholate co-transporting peptide) has enabled us to analyze the HBV life cycle in vitro using human hepatoma cell lines, though it may not be enough. Much knowledge of the HBV life cycle has been accumulating, and thus it is time to think of the next generation of HBV therapy.

This Special Issue will accept all kinds of manuscripts (reviews, research articles, and short communications). Based on the HBV life cycle, what kind of therapy will be designed? What factors could be targets for HBV treatment? Conceptual ideas on HBV treatment and analyses on new compounds to act on cellular targets are also of interest. We would like to discuss the future of HBV treatment, with a view to conquering the infection.

Prof. Dr. Keiji Ueda
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Hepatitis B virus (HBV)
  • HBV infection system in vitro
  • Viral life cycle
  • Host and virus interaction
  • cccDNA

Published Papers (7 papers)

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Research

Jump to: Review, Other

14 pages, 1939 KiB  
Article
Analysis of the Physicochemical Properties, Replication and Pathophysiology of a Massively Glycosylated Hepatitis B Virus HBsAg Escape Mutant
by Md. Golzar Hossain, Yadarat Suwanmanee, Kaili Du and Keiji Ueda
Viruses 2021, 13(11), 2328; https://0-doi-org.brum.beds.ac.uk/10.3390/v13112328 - 22 Nov 2021
Cited by 2 | Viewed by 2344
Abstract
Mutations in HBsAg, the surface antigen of the hepatitis B virus (HBV), might affect the serum HBV DNA level of HBV-infected patients, since the reverse transcriptase (RT) domain of HBV polymerase overlaps with the HBsAg-coding region. We previously identified a diagnostic escape mutant [...] Read more.
Mutations in HBsAg, the surface antigen of the hepatitis B virus (HBV), might affect the serum HBV DNA level of HBV-infected patients, since the reverse transcriptase (RT) domain of HBV polymerase overlaps with the HBsAg-coding region. We previously identified a diagnostic escape mutant (W3S) HBV that produces massively glycosylated HBsAg. In this study, we constructed an HBV-producing vector that expresses W3S HBs (pHB-W3S) along with a wild-type HBV-producing plasmid (pHB-WT) in order to analyze the physicochemical properties, replication, and antiviral drug response of the mutant. Transfection of either pHB-WT or W3S into HepG2 cells yielded similar CsCl density profiles and eAg expression, as did transfection of a glycosylation defective mutant, pHB-W3S (N146G), in which a glycosylation site at the 146aa asparagine (N) site of HBs was mutated to glycine (G). Virion secretion, however, seemed to be severely impaired in cases of pHB-W3S and pHB-W3S (N146G), compared with pHB-WT, as determined by qPCR and Southern blot analysis. Furthermore, inhibition of glycosylation using tunicamycinTM on wild-type HBV production also reduced the virion secretion. These results suggested that the HBV core and Dane particle could be formed either by massively glycosylated or glycosylation-defective HBsAg, but reduced and/or almost completely blocked the virion secretion efficiency, indicating that balanced glycosylation of HBsAg is required for efficient release of HBV, and mutations inducing an imbalanced glycosylation of HBs would cause the virion to become stuck in the cells, which might be associated with various pathogeneses due to HBV infection. Full article
(This article belongs to the Special Issue Hepatitis B Virus: Its Life Cycle and the Therapeutic Targets)
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13 pages, 2335 KiB  
Article
Binding of Nanoparticles Harboring Recombinant Large Surface Protein of Hepatitis B Virus to Scavenger Receptor Class B Type 1
by Shuji Hinuma, Kazuyo Fujita and Shun’ichi Kuroda
Viruses 2021, 13(7), 1334; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071334 - 10 Jul 2021
Cited by 4 | Viewed by 2031
Abstract
(1) Background: As nanoparticles containing the hepatitis B virus (HBV) large (L) surface protein produced in yeast are expected to be useful as a carrier for targeting hepatocytes, they are also referred to as bio-nanocapsules (BNCs). However, a definitive cell membrane receptor for [...] Read more.
(1) Background: As nanoparticles containing the hepatitis B virus (HBV) large (L) surface protein produced in yeast are expected to be useful as a carrier for targeting hepatocytes, they are also referred to as bio-nanocapsules (BNCs). However, a definitive cell membrane receptor for BNC binding has not yet been identified. (2) Methods: By utilizing fluorescence-labeled BNCs, we examined BNC binding to the scavenger receptor class B type 1 (SR-B1) expressed in HEK293T cells. (3) Results: Analyses employing SR-B1 siRNA and expression of SR-B1 fused with a green fluorescent protein (SR-B1-GFP) indicated that BNCs bind to SR-B1. As mutagenesis induced in the SR-B1 extracellular domain abrogates or attenuates BNC binding and endocytosis via SR-B1 in HEK293T cells, it was suggested that the ligand-binding site of SR-B1 is similar or close among high-density lipoprotein (HDL), silica, liposomes, and BNCs. On the other hand, L protein was suggested to attenuate an interaction between phospholipids and SR-B1. (4) Conclusions: SR-B1 can function as a receptor for binding and endocytosis of BNCs in HEK293T cells. Being expressed various types of cells, it is suggested that functions as a receptor for BNCs not only in HEK293T cells but also in other types of cells. Full article
(This article belongs to the Special Issue Hepatitis B Virus: Its Life Cycle and the Therapeutic Targets)
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11 pages, 2591 KiB  
Article
HBV Pre-S1-Derived Myristoylated Peptide (Myr47): Identification of the Inhibitory Activity on the Cellular Uptake of Lipid Nanoparticles
by Masaya Nanahara, Ya-Ting Chang, Masaharu Somiya and Shun’ichi Kuroda
Viruses 2021, 13(5), 929; https://0-doi-org.brum.beds.ac.uk/10.3390/v13050929 - 17 May 2021
Cited by 4 | Viewed by 2610
Abstract
The Myr47 lipopeptide, consisting of hepatitis B virus (HBV) pre-S1 domain (myristoylated 2–48 peptide), is an effective commercialized anti-HBV drug that prevents the interaction of HBV with sodium taurocholate cotransporting polypeptide (NTCP) on human hepatocytes, an activity which requires both N-myristoylation residue and [...] Read more.
The Myr47 lipopeptide, consisting of hepatitis B virus (HBV) pre-S1 domain (myristoylated 2–48 peptide), is an effective commercialized anti-HBV drug that prevents the interaction of HBV with sodium taurocholate cotransporting polypeptide (NTCP) on human hepatocytes, an activity which requires both N-myristoylation residue and specific amino acid sequences. We recently reported that Myr47 reduces the cellular uptake of HBV surface antigen (HBsAg, subviral particle of HBV) in the absence of NTCP expression. In this study, we analyzed how Myr47 reduces the cellular uptake of lipid nanoparticles (including liposomes (LPs) and HBsAg) without NTCP expression. By using Myr47 mutants lacking the HBV infection inhibitory activity, they could reduce the cellular uptake of LPs in an N-myristoylation-dependent manner and an amino acid sequence-independent manner, not only in human liver-derived cells but also in human non-liver-derived cells. Moreover, Myr47 and its mutants could reduce the interaction of LPs with apolipoprotein E3 (ApoE3) in an N-myristoylation-dependent manner regardless of their amino acid sequences. From these results, lipopeptides are generally anchored by inserting their myristoyl residue into the lipid bilayer and can inhibit the interaction of LPs/HBsAg with apolipoprotein, thereby reducing the cellular uptake of LPs/HBsAg. Similarly, Myr47 would interact with HBV, inhibiting the uptake of HBV into human hepatic cells, while the inhibitory effect of Myr47 may be secondary to its ability to protect against HBV infection. Full article
(This article belongs to the Special Issue Hepatitis B Virus: Its Life Cycle and the Therapeutic Targets)
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Review

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11 pages, 1575 KiB  
Review
Challenges in the Application of Glyco-Technology to Hepatitis B Virus Therapy and Diagnosis
by Tsunenori Ouchida, Shinji Takamatsu, Megumi Maeda, Tatsuya Asuka, Chiharu Morita, Jumpei Kondo, Keiji Ueda and Eiji Miyoshi
Viruses 2021, 13(9), 1860; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091860 - 17 Sep 2021
Cited by 2 | Viewed by 2353
Abstract
Hepatitis B virus (HBV) is a major pathogen that causes acute/chronic hepatitis. Continuous HBV infection can lead to the development of hepatocellular carcinoma (HCC). Although several different anti-HBV treatments are available for chronic hepatitis B patients, discontinuing these medications is difficult. Patients with [...] Read more.
Hepatitis B virus (HBV) is a major pathogen that causes acute/chronic hepatitis. Continuous HBV infection can lead to the development of hepatocellular carcinoma (HCC). Although several different anti-HBV treatments are available for chronic hepatitis B patients, discontinuing these medications is difficult. Patients with chronic hepatitis B at high risk for HCC therefore require close observation. However, no suitable biomarkers for detecting high-risk groups for HCC exist, except for serum HBV-DNA, but a number of HCC biomarkers are used clinically, such as alpha-fetoprotein (AFP) and protein induced by vitamin K absence-II (PIVKA-II). Glycosylation is an important post-translational protein modification involved in many human pathologic conditions. HBV surface proteins contain various oligosaccharides, and several reports have described their biological functions. Inhibition of HBV glycosylation represents a potential novel anti-HBV therapy. It is thought that glycosylation of hepatocytes/hepatoma cells is also important for HBV infection, as it prevents HBV from infecting cells other than hepatocytes, even if the cells express the HBV receptor. In this review, we summarize considerable research regarding the relationship between HBV and glycosylation as it relates to the development of novel diagnostic tests and therapies for HBV. Full article
(This article belongs to the Special Issue Hepatitis B Virus: Its Life Cycle and the Therapeutic Targets)
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10 pages, 900 KiB  
Review
Chronic Hepatitis B Treatment Strategies Using Polymerase Inhibitor-Based Combination Therapy
by Eriko Ohsaki, Yadarat Suwanmanee and Keiji Ueda
Viruses 2021, 13(9), 1691; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091691 - 26 Aug 2021
Cited by 5 | Viewed by 6518
Abstract
Viral polymerase is an essential enzyme for the amplification of the viral genome and is one of the major targets of antiviral therapies. However, a serious concern to be solved in hepatitis B virus (HBV) infection is the difficulty of eliminating covalently closed [...] Read more.
Viral polymerase is an essential enzyme for the amplification of the viral genome and is one of the major targets of antiviral therapies. However, a serious concern to be solved in hepatitis B virus (HBV) infection is the difficulty of eliminating covalently closed circular (ccc) DNA. More recently, therapeutic strategies targeting various stages of the HBV lifecycle have been attempted. Although cccDNA-targeted therapies are attractive, there are still many problems to be overcome, and the development of novel polymerase inhibitors remains an important issue. Interferons and nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are the only therapeutic options currently available for HBV infection. Many studies have reported that the combination of interferons and NRTI causes the loss of hepatitis B surface antigen (HBsAg), which is suggestive of seroconversion. Although NRTIs do not directly target cccDNA, they can strongly reduce the serum viral DNA load and could suppress the recycling step of cccDNA formation, improve liver fibrosis/cirrhosis, and reduce the risk of hepatocellular carcinoma. Here, we review recent studies on combination therapies using polymerase inhibitors and discuss the future directions of therapeutic strategies for HBV infection. Full article
(This article belongs to the Special Issue Hepatitis B Virus: Its Life Cycle and the Therapeutic Targets)
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Other

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11 pages, 1556 KiB  
Brief Report
HepG2-NTCP Subclones Exhibiting High Susceptibility to Hepatitis B Virus Infection
by Muhammad Atif Zahoor, Adrian Kuipery, Alexander I. Mosa, Adam J. Gehring and Jordan J. Feld
Viruses 2022, 14(8), 1800; https://0-doi-org.brum.beds.ac.uk/10.3390/v14081800 - 17 Aug 2022
Cited by 1 | Viewed by 2015
Abstract
HepG2 cells reconstituted with Hepatitis B virus (HBV) entry receptor sodium taurocholate co-transporting polypeptide (NTCP) are widely used as a convenient in vitro cell culture infection model for HBV replication studies. As such, it is pertinent that HBV infectivity is maintained at steady-state [...] Read more.
HepG2 cells reconstituted with Hepatitis B virus (HBV) entry receptor sodium taurocholate co-transporting polypeptide (NTCP) are widely used as a convenient in vitro cell culture infection model for HBV replication studies. As such, it is pertinent that HBV infectivity is maintained at steady-state levels for an accurate interpretation of in vitro data. However, variations in the HBV infection efficiency due to imbalanced NTCP expression levels in the HepG2 cell line may affect experimental results. In this study, we performed single cell-cloning of HepG2-NTCP-A3 parental cells via limiting dilution and obtained multiple subclones with increased permissiveness to HBV. Specifically, one subclone (HepG2-NTCP-A3/C2) yielded more than four-fold higher HBV infection compared to the HepG2-NTCP-A3 parental clone. In addition, though HBV infectivity was universally reduced in the absence of polyethylene glycol (PEG), subclone C2 maintained relatively greater permissiveness under PEG-free conditions, suggesting the functional heterogeneity within parental HepG2-NTCP-A3 may be exploitable in developing a PEG-free HBV infection model. The increased viral production correlated with increased intracellular viral antigen expression as evidenced through HBcAg immunofluorescence staining. Further, these subclones were found to express different levels of NTCP, albeit with no remarkable morphology or cell growth differences. In conclusion, we isolated the subclones of HepG2-NTCP-A3 which support efficient HBV production and thus provide an improved in vitro HBV infection model. Full article
(This article belongs to the Special Issue Hepatitis B Virus: Its Life Cycle and the Therapeutic Targets)
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16 pages, 2182 KiB  
Protocol
Rapid and Robust Continuous Purification of High-Titer Hepatitis B Virus for In Vitro and In Vivo Applications
by Jochen M. Wettengel, Bianca Linden, Knud Esser, Michael Laue, Benjamin J. Burwitz and Ulrike Protzer
Viruses 2021, 13(8), 1503; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081503 - 30 Jul 2021
Cited by 8 | Viewed by 3282
Abstract
Available treatments for hepatitis B can control the virus but are rarely curative. This led to a global initiative to design new curative therapies for the 257 million patients affected. Discovery and development of these new therapies is contingent upon functional in vitro [...] Read more.
Available treatments for hepatitis B can control the virus but are rarely curative. This led to a global initiative to design new curative therapies for the 257 million patients affected. Discovery and development of these new therapies is contingent upon functional in vitro and in vivo hepatitis B virus (HBV) infection models. However, low titer and impurity of conventional HBV stocks reduce significance of in vitro infections and moreover limit challenge doses in current in vivo models. Therefore, there is a critical need for a robust, simple and reproducible protocol to generate high-purity and high-titer infectious HBV stocks. Here, we outline a three-step protocol for continuous production of high-quality HBV stocks from supernatants of HBV-replicating cell lines. This purification process takes less than 6 h, yields to high-titer stocks (up to 1 × 1011 enveloped, DNA-containing HBV particles/mL each week), and is with minimal equipment easily adaptable to most laboratory settings. Full article
(This article belongs to the Special Issue Hepatitis B Virus: Its Life Cycle and the Therapeutic Targets)
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