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Hepatitis Virus Infection and Molecular Research 2022
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Hepatitis Virus Infection and Molecular Research 2022

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 19024

Special Issue Editors

Dr. Tatsuo Kanda

E-Mail Website
Guest Editor
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo 173-8610, Japan
Interests: viral hepatitis; hepatocellular carcinoma; innate immunity; unfolded protein response
Special Issues, Collections and Topics in MDPI journals
Dr. Shingo Nakamoto

E-Mail Website
Guest Editor
Department of Molecular Virology, Chiba University, Graduate School of Medicine, Chiba, Japan
Interests: HCV

Special Issue Information

Dear Colleagues,

Welcome to this Special Issue, “Hepatitis Virus Infection and Molecular Research 2021,” of the International Journal of Molecular Sciences. Interferon-free treatment against hepatitis C virus (HCV) is available, and its efficacy is higher, with less adverse events and a shorter duration. However, there are several problems associated with this type of treatment, such as the occurrence of hepatocellular carcinoma (HCC) after sustained virological response (SVR), reactivation of hepatitis B virus (HBV), and drug resistance-associated substitutions (RASs). Unfortunately, although new cancer immune therapies, such as blockers of immune checkpoints, have good efficacies, they can cause liver injuries.

This Special Issue will present recent findings related to viral hepatitis, other liver diseases, and liver-related gastrointestinal diseases. Original research and review articles on all topics in this area are invited. We also have great interest in molecular research, such as resistance mutations and host responses. It is our greatest pleasure to invite research scientists and clinicians from all relevant fields to submit their articles for this Special Issue. Please accept my special thanks for choosing to publish in the International Journal of Molecular Sciences. We are looking forward to your submissions for this highly important Special Issue.

Assoc. Prof. Tatsuo Kanda
Dr. Shingo Nakamoto
Guest Editors

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • Viral hepatitis
  • DAA
  • NASH
  • Drug-induced liver injury
  • Hepatocellular carcinoma (HCC)
  • Cirrhosis

Published Papers (7 papers)

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Editorial

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3 pages, 608 KiB  
Editorial
Hepatitis A Virus Infection and Molecular Research
by Tatsuo Kanda, Reina Sasaki-Tanaka and Shingo Nakamoto
Int. J. Mol. Sci. 2022, 23(13), 7214; https://doi.org/10.3390/ijms23137214 - 29 Jun 2022
Cited by 2 | Viewed by 1813
Abstract
Hepatitis A virus (HAV) infection is a major cause of acute viral hepatitis globally, which can occasionally lead to acute liver failure (ALF) and acute-on-chronic liver failure (ACLF), which often result in death without liver transplantation [...] Full article
(This article belongs to the Special Issue Hepatitis Virus Infection and Molecular Research 2022)
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Research

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13 pages, 3956 KiB  
Article
Evaluation of Potential Anti-Hepatitis A Virus 3C Protease Inhibitors Using Molecular Docking
by Reina Sasaki-Tanaka, Kalyan C. Nagulapalli Venkata, Hiroaki Okamoto, Mitsuhiko Moriyama and Tatsuo Kanda
Int. J. Mol. Sci. 2022, 23(11), 6044; https://doi.org/10.3390/ijms23116044 - 27 May 2022
Cited by 6 | Viewed by 2115
Abstract
Hepatitis A virus (HAV) infection is a major cause of acute hepatitis worldwide and occasionally causes acute liver failure and can lead to death in the absence of liver transplantation. Although HAV vaccination is available, the prevalence of HAV vaccination is not adequate [...] Read more.
Hepatitis A virus (HAV) infection is a major cause of acute hepatitis worldwide and occasionally causes acute liver failure and can lead to death in the absence of liver transplantation. Although HAV vaccination is available, the prevalence of HAV vaccination is not adequate in some countries. Additionally, the improvements in public health reduced our immunity to HAV infection. These situations motivated us to develop potentially new anti-HAV therapeutic options. We carried out the in silico screening of anti-HAV compounds targeting the 3C protease enzyme using the Schrodinger Modeling software from the antiviral library of 25,000 compounds to evaluate anti-HAV 3C protease inhibitors. Additionally, in vitro studies were introduced to examine the inhibitory effects of HAV subgenomic replicon replication and HAV HA11-1299 genotype IIIA replication in hepatoma cell lines using luciferase assays and real-time RT-PCR. In silico studies enabled us to identify five lead candidates with optimal binding interactions in the active site of the target HAV 3C protease using the Schrodinger Glide program. In vitro studies substantiated our hypothesis from in silico findings. One of our lead compounds, Z10325150, showed 47% inhibitory effects on HAV genotype IB subgenomic replicon replication and 36% inhibitory effects on HAV genotype IIIA HA11-1299 replication in human hepatoma cell lines, with no cytotoxic effects at concentrations of 100 μg/mL. The effects of the combination therapy of Z10325150 and RNA-dependent RNA polymerase inhibitor, favipiravir on HAV genotype IB HM175 subgenomic replicon replication and HAV genotype IIIA HA11-1299 replication showed 64% and 48% inhibitory effects of HAV subgenomic replicon and HAV replication, respectively. We identified the HAV 3C protease inhibitor Z10325150 through in silico screening and confirmed the HAV replication inhibitory activity in human hepatocytes. Z10325150 may offer the potential for a useful HAV inhibitor in severe hepatitis A. Full article
(This article belongs to the Special Issue Hepatitis Virus Infection and Molecular Research 2022)
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16 pages, 2931 KiB  
Article
Favipiravir Inhibits Hepatitis A Virus Infection in Human Hepatocytes
by Reina Sasaki-Tanaka, Toshikatsu Shibata, Hiroaki Okamoto, Mitsuhiko Moriyama and Tatsuo Kanda
Int. J. Mol. Sci. 2022, 23(5), 2631; https://doi.org/10.3390/ijms23052631 - 27 Feb 2022
Cited by 12 | Viewed by 2455
Abstract
Hepatitis A virus (HAV) is a causative agent of acute hepatitis and can occasionally induce acute liver failure. However, specific potent anti-HAV drug is not available on the market currently. Thus, we investigated several novel therapeutic drugs through a drug repositioning approach, targeting [...] Read more.
Hepatitis A virus (HAV) is a causative agent of acute hepatitis and can occasionally induce acute liver failure. However, specific potent anti-HAV drug is not available on the market currently. Thus, we investigated several novel therapeutic drugs through a drug repositioning approach, targeting ribonucleic acid (RNA)-dependent RNA polymerase and RNA-dependent deoxyribonucleic acid polymerase. In the present study, we examined the anti-HAV activity of 18 drugs by measuring the HAV subgenomic replicon and HAV HA11-1299 genotype IIIA replication in human hepatoma cell lines, using a reporter assay and real-time reverse transcription polymerase chain reaction, respectively. Mutagenesis of the HAV 5’ untranslated region was also examined by next-generation sequencing. These specific parameters were explored because lethal mutagenesis has emerged as a novel potential therapeutic approach to treat RNA virus infections. Favipiravir inhibited HAV replication in both Huh7 and PLC/PRF/5 cells, although ribavirin inhibited HAV replication in only Huh7 cells. Next-generation sequencing demonstrated that favipiravir could introduce nucleotide mutations into the HAV genome more than ribavirin. In conclusion, favipiravir could introduce nucleotide mutations into the HAV genome and work as an antiviral against HAV infection. Provided that further in vivo experiments confirm its efficacy, favipiravir would be useful for the treatment of severe HAV infection. Full article
(This article belongs to the Special Issue Hepatitis Virus Infection and Molecular Research 2022)
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18 pages, 1655 KiB  
Article
Domain 2 of Hepatitis C Virus Protein NS5A Activates Glucokinase and Induces Lipogenesis in Hepatocytes
by Laure Perrin-Cocon, Cindy Kundlacz, Clémence Jacquemin, Xavier Hanoulle, Anne Aublin-Gex, Marianne Figl, Jeremy Manteca, Patrice André, Pierre-Olivier Vidalain, Vincent Lotteau and Olivier Diaz
Int. J. Mol. Sci. 2022, 23(2), 919; https://doi.org/10.3390/ijms23020919 - 14 Jan 2022
Cited by 7 | Viewed by 2450
Abstract
Hepatitis C virus (HCV) relies on cellular lipid metabolism for its replication, and actively modulates lipogenesis and lipid trafficking in infected hepatocytes. This translates into an intracellular accumulation of triglycerides leading to liver steatosis, cirrhosis and hepatocellular carcinoma, which are hallmarks of HCV [...] Read more.
Hepatitis C virus (HCV) relies on cellular lipid metabolism for its replication, and actively modulates lipogenesis and lipid trafficking in infected hepatocytes. This translates into an intracellular accumulation of triglycerides leading to liver steatosis, cirrhosis and hepatocellular carcinoma, which are hallmarks of HCV pathogenesis. While the interaction of HCV with hepatocyte metabolic pathways is patent, how viral proteins are able to redirect central carbon metabolism towards lipogenesis is unclear. Here, we report that the HCV protein NS5A activates the glucokinase (GCK) isoenzyme of hexokinases through its D2 domain (NS5A-D2). GCK is the first rate-limiting enzyme of glycolysis in normal hepatocytes whose expression is replaced by the hexokinase 2 (HK2) isoenzyme in hepatocellular carcinoma cell lines. We took advantage of a unique cellular model specifically engineered to re-express GCK instead of HK2 in the Huh7 cell line to evaluate the consequences of NS5A-D2 expression on central carbon and lipid metabolism. NS5A-D2 increased glucose consumption but decreased glycogen storage. This was accompanied by an altered mitochondrial respiration, an accumulation of intracellular triglycerides and an increased production of very-low density lipoproteins. Altogether, our results show that NS5A-D2 can reprogram central carbon metabolism towards a more energetic and glycolytic phenotype compatible with HCV needs for replication. Full article
(This article belongs to the Special Issue Hepatitis Virus Infection and Molecular Research 2022)
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12 pages, 1425 KiB  
Article
Knockdown of Mitogen-Activated Protein Kinase Kinase 3 Negatively Regulates Hepatitis A Virus Replication
by Tatsuo Kanda, Reina Sasaki-Tanaka, Ryota Masuzaki, Naoki Matsumoto, Hiroaki Okamoto and Mitsuhiko Moriyama
Int. J. Mol. Sci. 2021, 22(14), 7420; https://doi.org/10.3390/ijms22147420 - 10 Jul 2021
Cited by 8 | Viewed by 2753
Abstract
Zinc chloride is known to be effective in combatting hepatitis A virus (HAV) infection, and zinc ions seem to be especially involved in Toll-like receptor (TLR) signaling pathways. In the present study, we examined this involvement in human hepatoma cell lines using a [...] Read more.
Zinc chloride is known to be effective in combatting hepatitis A virus (HAV) infection, and zinc ions seem to be especially involved in Toll-like receptor (TLR) signaling pathways. In the present study, we examined this involvement in human hepatoma cell lines using a human TLR signaling target RT-PCR array. We also observed that zinc chloride inhibited mitogen-activated protein kinase kinase 3 (MAP2K3) expression, which could downregulate HAV replication in human hepatocytes. It is possible that zinc chloride may inhibit HAV replication in association with its inhibition of MAP2K3. In that regard, this study set out to determine whether MAP2K3 could be considered a modulating factor in the development of the HAV pathogen-associated molecular pattern (PAMP) and its triggering of interferon-β production. Because MAP2K3 seems to play a role in antiviral immunity against HAV infection, it is a promising target for drug development. The inhibition of MAP2K3 may also prevent HAV patients from developing a severe hepatitis A infection. Full article
(This article belongs to the Special Issue Hepatitis Virus Infection and Molecular Research 2022)
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19 pages, 3185 KiB  
Article
Difluoromethylornithine (DFMO), an Inhibitor of Polyamine Biosynthesis, and Antioxidant N-Acetylcysteine Potentiate Immune Response in Mice to the Recombinant Hepatitis C Virus NS5B Protein
by Ekaterina I. Lesnova, Olga V. Masalova, Kristina Yu. Permyakova, Vyacheslav V. Kozlov, Tatyana N. Nikolaeva, Alexander V. Pronin, Vladimir T. Valuev-Elliston, Alexander V. Ivanov and Alla A. Kushch
Int. J. Mol. Sci. 2021, 22(13), 6892; https://doi.org/10.3390/ijms22136892 - 26 Jun 2021
Cited by 1 | Viewed by 3200
Abstract
Hepatitis C virus (HCV) is one of the main triggers of chronic liver disease. Despite tremendous progress in the HCV field, there is still no vaccine against this virus. Potential vaccines can be based on its recombinant proteins. To increase the humoral and, [...] Read more.
Hepatitis C virus (HCV) is one of the main triggers of chronic liver disease. Despite tremendous progress in the HCV field, there is still no vaccine against this virus. Potential vaccines can be based on its recombinant proteins. To increase the humoral and, especially, cellular immune response to them, more effective adjuvants are needed. Here, we evaluated a panel of compounds as potential adjuvants using the HCV NS5B protein as an immunogen. These compounds included inhibitors of polyamine biosynthesis and urea cycle, the mTOR pathway, antioxidants, and cellular receptors. A pronounced stimulation of cell proliferation and interferon-γ (IFN-γ) secretion in response to concanavalin A was shown for antioxidant N-acetylcysteine (NAC), polyamine biosynthesis inhibitor 2-difluoromethylornithine (DFMO), and TLR9 agonist CpG ODN 1826 (CpG). Their usage during the immunization of mice with the recombinant NS5B protein significantly increased antibody titers, enhanced lymphocyte proliferation and IFN-γ production. NAC and CpG decreased relative Treg numbers; CpG increased the number of myeloid-derived suppressor cells (MDSCs), whereas neither NAC nor DFMO affected MDSC counts. NAC and DFMO suppressed NO and interleukin 10 (IL-10) production by splenocytes, while DFMO increased the levels of IL-12. This is the first evidence of immunomodulatory activity of NAC and DFMO during prophylactic immunization against infectious diseases. Full article
(This article belongs to the Special Issue Hepatitis Virus Infection and Molecular Research 2022)
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Review

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12 pages, 697 KiB  
Review
Apolipoprotein E, a Crucial Cellular Protein in the Lifecycle of Hepatitis Viruses
by Yannick Tréguier, Anne Bull-Maurer and Philippe Roingeard
Int. J. Mol. Sci. 2022, 23(7), 3676; https://doi.org/10.3390/ijms23073676 - 27 Mar 2022
Cited by 4 | Viewed by 2838
Abstract
Apolipoprotein E (ApoE) is a multifunctional protein expressed in several tissues, including those of the liver. This lipoprotein component is responsible for maintaining lipid content homeostasis at the plasma and tissue levels by transporting lipids between the liver and peripheral tissues. The ability [...] Read more.
Apolipoprotein E (ApoE) is a multifunctional protein expressed in several tissues, including those of the liver. This lipoprotein component is responsible for maintaining lipid content homeostasis at the plasma and tissue levels by transporting lipids between the liver and peripheral tissues. The ability of ApoE to interact with host-cell surface receptors and its involvement in several cellular pathways raised questions about the hijacking of ApoE by hepatotropic viruses. Hepatitis C virus (HCV) was the first hepatitis virus reported to be dependent on ApoE for the completion of its lifecycle, with ApoE being part of the viral particle, mediating its entry into host cells and contributing to viral morphogenesis. Recent studies of the hepatitis B virus (HBV) lifecycle have revealed that this virus and its subviral envelope particles also incorporate ApoE. ApoE favors HBV entry and is crucial for the morphogenesis of infectious particles, through its interaction with HBV envelope glycoproteins. This review summarizes the data highlighting the crucial role of ApoE in the lifecycles of HBV and HCV and discusses its potential role in the lifecycle of other hepatotropic viruses. Full article
(This article belongs to the Special Issue Hepatitis Virus Infection and Molecular Research 2022)
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