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Viruses
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Pathophysiology of Viral Hepatitis
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Pathophysiology of Viral Hepatitis

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Human Virology and Viral Diseases".

Deadline for manuscript submissions: closed (30 March 2023) | Viewed by 14334

Special Issue Editors

Dr. Xiaonan Zhang

E-Mail Website
Guest Editor
Faculty of Science and Technology, University of Canberra, Bruce Australian Capital Territory, Bruce, ACT 2617, Australia
Interests: hepatitis B virus; influenza virus; SARS-CoV-2; enteroviruses; molecular pathology
Dr. Mengji Lu

E-Mail Website
Guest Editor
Institute of Virology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany
Interests: hepatitis B virus; immune response; immune tolerance; immunotherapy; T cell therapy; innate immunity; therapeutic vaccine

Special Issue Information

Dear Colleagues,

Recent studies estimate that 844 million people globally suffer from chronic liver disease with an annual mortality of 2 million. This is on par with other major health problems such as cardiovascular disease (540 million) and diabetes (422 million). The triumph of precision medicine is exemplified by the prevention and treatment of viral hepatitis which have significantly relieved the overall disease burden. One such success story is the high curative rate for hepatitis C using direct-acting antiviral therapy. However, major obstacles in the treatment of viral hepatitis remain to be overcome. Among the viruses that cause liver diseases, HBV is responsible for the greatest burden globally, with 240 million people being chronic carriers. HBV-induced chronic liver inflammation leads to liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HBV vaccination programs have greatly lowered the seropositive rate, but simulation studies have shown the difficulty in eradicating this disease solely by vaccination by the end of this century.

Nothing would be more essential than a deepened understanding of the pathophysiology of viral hepatitis would be to develop better diagnostic tools and therapeutic solutions that offer a safe and long-lasting cure. This calls for an insightful re-analysis of the most fundamental problems in this respect, which is precisely the topic of this Special Issue. 

Dr. Xiaonan Zhang
Dr. Mengji Lu
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. 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
  • hepatitis D virus
  • hepatitis C virus
  • chronic hepatitis B
  • hepatocellular carcinoma
  • liver stem cell
  • innate immunity
  • interferon
  • cccDNA

Published Papers (7 papers)

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Research

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15 pages, 6702 KiB  
Article
Replication and Expression of the Consensus Genome of Hepatitis B Virus Genotype C from the Chinese Population
by Fenfang Liao, Junmou Xie, Rongsong Du, Wenbo Gao, Lanyin Lan, Min Wang, Xia Rong, Yongshui Fu and Hao Wang
Viruses 2023, 15(12), 2302; https://doi.org/10.3390/v15122302 - 23 Nov 2023
Viewed by 860
Abstract
Hepatitis B virus (HBV) genotype C is a prevalent HBV genotype in the Chinese population. Although genotype C shows higher sequence heterogeneity and more severe liver disease than other genotypes, its pathogenesis and immunological traits are not yet fully elucidated. In this study, [...] Read more.
Hepatitis B virus (HBV) genotype C is a prevalent HBV genotype in the Chinese population. Although genotype C shows higher sequence heterogeneity and more severe liver disease than other genotypes, its pathogenesis and immunological traits are not yet fully elucidated. In this study, we first established and chemically synthesized the consensus sequence based on representative 138 full-length HBV genotype C genomes from the Chinese population. The pHBV1.3C plasmid system, containing a 1.3-fold full-length HBV genotype C consensus sequence, was constructed for subsequent validation. Next, we performed functional assays to investigate the replicative competence of pHBV1.3C in vitro through the transient transfection of HepG2 and Huh7 cells and validated the in vivo function via a hydrodynamic injection to BALB/c recipient mice. The in vitro investigation revealed that the extracellular HBV DNA and intracellular replicative intermediate (i.e., pregenomic RNA, pgRNA) were apparently measurable at 48 h, and the HBsAg and HBcAg were still positive in hepatoma cells at 96 h. We also found that HBsAg and HBeAg accumulated at the extracellular and intracellular levels in a time-dependent manner. The in vivo validation demonstrated that pHBV1.3C plasmids induced HBV viremia, triggered morphological changes and HBsAg- or HBcAg- positivity of hepatocytes, and ultimately caused inflammatory infiltration and focal or piecemeal necrosis in the livers of the murine recipients. HBV protein (HBsAg) colocalized with CD8+ T cells or CD4+ T cells in the liver. F4/80+ Kupffer cells were abundantly recruited around the altered murine hepatocytes. Taken together, our results indicate that the synthetic consensus sequence of HBV genotype C is replication-competent in vitro and in vivo. This genotype C consensus genome supports the full HBV life cycle, which is conducive to studying its pathogenesis and immune response, screening novel antiviral agents, and further optimizing testing and therapeutics. Full article
(This article belongs to the Special Issue Pathophysiology of Viral Hepatitis)
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15 pages, 4282 KiB  
Article
Poly(I:C) Induces Distinct Liver Cell Type-Specific Responses in Hepatitis B Virus-Transgenic Mice In Vitro, but Fails to Induce These Signals In Vivo
by Stefan Schefczyk, Xufeng Luo, Yaojie Liang, Martin Trippler, Mengji Lu, Heiner Wedemeyer, Hartmut H. Schmidt and Ruth Broering
Viruses 2023, 15(5), 1203; https://doi.org/10.3390/v15051203 - 19 May 2023
Cited by 1 | Viewed by 1532
Abstract
Immunopathology in hepatitis B virus (HBV) infection is driven by innate and adaptive immunity. Whether the hepatitis B surface antigen (HBsAg) affects hepatic antiviral signalling was investigated in HBV-transgenic mouse models that either accumulate (Alb/HBs, Tg[Alb1HBV]Bri44), lack (Tg1.4HBV-s-mut3) or secrete (Tg1.4HBV-s-rec (F1, Tg1.4HBV-s-mut [...] Read more.
Immunopathology in hepatitis B virus (HBV) infection is driven by innate and adaptive immunity. Whether the hepatitis B surface antigen (HBsAg) affects hepatic antiviral signalling was investigated in HBV-transgenic mouse models that either accumulate (Alb/HBs, Tg[Alb1HBV]Bri44), lack (Tg1.4HBV-s-mut3) or secrete (Tg1.4HBV-s-rec (F1, Tg1.4HBV-s-mut × Alb/HBs) the HBsAg. Herein, the responsiveness of TLR3 and RIG-I in primary parenchymal and non-parenchymal liver cells was determined in vitro and in vivo. Cell type-specific and mouse strain-dependent interferon, cytokine and chemokine expression were observed by LEGENDplex™ and validated by quantitative PCR. In vitro, the hepatocytes, liver sinusoidal endothelial cells and Kupffer cells of Tg1.4HBV-s-rec mice showed poly(I:C) susceptibilities similar to the wild-type controls, while in the remaining leucocyte fraction the interferon, cytokine and chemokine induction was reduced. On the contrary, poly(I:C)-injected 1.4TgHBV-s-rec mice showed suppressed interferon, cytokine and chemokine levels in hepatocytes but increased levels in the leucocyte fraction. Thus, we concluded that liver cells of Tg1.4HBV-s-rec mice, which produce HBV particles and release the HBsAg, responded to exogenous TLR3/RIG-I stimuli in vitro but exhibited a tolerogenic environment in vivo. Full article
(This article belongs to the Special Issue Pathophysiology of Viral Hepatitis)
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18 pages, 7986 KiB  
Article
Canocapavir Is a Novel Capsid Assembly Modulator Inducing a Conformational Change of the Linker Region of HBV Core Protein
by Yuan Zheng, Le Yang, Lin Yu, Yuanfei Zhu, Yang Wu, Zhijun Zhang, Tian Xia and Qiang Deng
Viruses 2023, 15(5), 1195; https://doi.org/10.3390/v15051195 - 18 May 2023
Cited by 2 | Viewed by 1636
Abstract
Canocapavir is a novel antiviral agent with characteristics of core protein allosteric modulators (CpAMs) that is currently in a phase II clinical trial for treatment of hepatitis B virus (HBV) infection. Herein, we show that Canocapavir prevented the encapsidation of HBV pregenomic RNA [...] Read more.
Canocapavir is a novel antiviral agent with characteristics of core protein allosteric modulators (CpAMs) that is currently in a phase II clinical trial for treatment of hepatitis B virus (HBV) infection. Herein, we show that Canocapavir prevented the encapsidation of HBV pregenomic RNA and increased the accumulation of cytoplasmic empty capsids, presumably by targeting the hydrophobic pocket at the dimer-dimer interface of HBV core protein (HBc). Canocapavir treatment markedly reduced the egress of naked capsids, which could be reversed by Alix overexpression through a mechanism other than direct association of Alix with HBc. Moreover, Canocapavir interfered with the interaction between HBc and HBV large surface protein, resulting in diminished production of empty virions. Of particular note, Canocapavir induced a conformational change of capsids, with the C-terminus of HBc linker region fully exposed on the exterior of capsids. We posit that the allosteric effect may have great importance in the anti-HBV activity of Canocapavir, given the emerging virological significance of HBc linker region. In support of this notion, the mutation at HBc V124W typically recapitulated the conformational change of the empty capsid with aberrant cytoplasmic accumulation. Collectively, our results indicate Canocapavir as a mechanistically distinct type of CpAMs against HBV infection. Full article
(This article belongs to the Special Issue Pathophysiology of Viral Hepatitis)
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12 pages, 3207 KiB  
Article
High-Resolution Genomic Profiling of a Genotype 3b Hepatitis C Virus from a Flare of an Occult Hepatitis Patient with Acute-on-Chronic Liver Failure
by Xue Mei, Jingyi Zou, Bisheng Shi, Zhiping Qian and Zhigang Yi
Viruses 2023, 15(3), 634; https://doi.org/10.3390/v15030634 - 26 Feb 2023
Viewed by 1537
Abstract
Acute-on-chronic liver failure (ACLF) is defined as a syndrome of acutely decompensated cirrhosis in patients with chronic liver disease (CLD). Here we report an ACLF case caused by a flare of occult hepatitis C infection. This patient was infected with hepatitis C virus [...] Read more.
Acute-on-chronic liver failure (ACLF) is defined as a syndrome of acutely decompensated cirrhosis in patients with chronic liver disease (CLD). Here we report an ACLF case caused by a flare of occult hepatitis C infection. This patient was infected with hepatitis C virus (HCV) more than a decade ago and hospitalized due to alcohol-associated CLD. Upon admission, the HCV RNA in the serum was negative and the anti-HCV antibody was positive, whereas the viral RNA in the plasma dramatically increased during hospitalization, which suggests an occult hepatitis C infection. Overlapped fragments encompassing the nearly whole HCV viral genome were amplified, cloned, and sequenced. Phylogenetic analysis indicated an HCV genotype 3b strain. Sanger sequencing to 10-fold coverage of the 9.4-kb nearly whole genome reveals high diversity of viral quasispecies, an indicator of chronic infection. Inherent resistance-associated substitutions (RASs) in the NS3 and NS5A but not in the NS5B regions were identified. The patient developed liver failure and accepted liver transplantation, followed by direct-acting antiviral (DAA) treatment. The hepatitis C was cured by the DAA treatment despite the existence of RASs. Thus, care should be taken for occult hepatitis C in patients with alcoholic cirrhosis. The analysis of viral genetic diversity may help to identify an occult hepatitis C virus infection and predict the efficacy of anti-viral treatment. Full article
(This article belongs to the Special Issue Pathophysiology of Viral Hepatitis)
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Review

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14 pages, 1273 KiB  
Review
Hepatitis B Core Antibody Level: A Surrogate Marker for Host Antiviral Immunity in Chronic Hepatitis B Virus Infections
by Yang Shi, Zihan Wang, Shengxiang Ge, Ningshao Xia and Quan Yuan
Viruses 2023, 15(5), 1111; https://doi.org/10.3390/v15051111 - 3 May 2023
Cited by 3 | Viewed by 2871
Abstract
The hepatitis B virus core protein (HBcAg) is a highly immunogenic particulate antigen. Nearly all patients with persistent or resolved hepatitis B virus (HBV) infection show seropositivity for hepatitis B core antibody (anti-HBc), which appears in the early stage of infection and is [...] Read more.
The hepatitis B virus core protein (HBcAg) is a highly immunogenic particulate antigen. Nearly all patients with persistent or resolved hepatitis B virus (HBV) infection show seropositivity for hepatitis B core antibody (anti-HBc), which appears in the early stage of infection and is mostly present for life. Traditionally, the anti-HBc is regarded as an evidential serological marker of HBV infections. In the last ten years, several studies revealed the predictive value of quantitative anti-HBc (qAnti-HBc) level in the treatment response and clinical outcome of chronic HBV infections, implying new insights into this classic marker. Overall, qAnti-HBc should be regarded as an indicator of the host’s immune response specific to HBV, which correlates with HBV-related hepatitis activity and liver pathology. This review summarized the latest understanding of the clinical values of qAnti-HBc for differentiating the CHB phase, predicting treatment response, and providing disease prognosis. Moreover, we also discussed the possible mechanism of qAnti-HBc regulation during different courses of HBV infection. Full article
(This article belongs to the Special Issue Pathophysiology of Viral Hepatitis)
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11 pages, 1020 KiB  
Review
Hepatitis B Virus Capsid: The Core in Productive Entry and Covalently Closed Circular DNA Formation
by Megan A. Mendenhall, Xupeng Hong and Jianming Hu
Viruses 2023, 15(3), 642; https://doi.org/10.3390/v15030642 - 28 Feb 2023
Cited by 5 | Viewed by 2670
Abstract
Hepatitis B virus (HBV) relies on the core protein (HBc) to establish productive infection, as defined by the formation of the covalently closed circularized DNA (cccDNA), as well as to carry out almost every step of the lifecycle following cccDNA formation. Multiple copies [...] Read more.
Hepatitis B virus (HBV) relies on the core protein (HBc) to establish productive infection, as defined by the formation of the covalently closed circularized DNA (cccDNA), as well as to carry out almost every step of the lifecycle following cccDNA formation. Multiple copies of HBc form an icosahedral capsid shell that encapsidates the viral pregenomic RNA (pgRNA) and facilitates the reverse transcription of pgRNA to a relaxed circular DNA (rcDNA) within the capsid. During infection, the complete HBV virion, which contains an outer envelope layer in addition to the internal nucleocapsid containing rcDNA, enters human hepatocytes via endocytosis and traffics through the endosomal compartments and the cytosol to deliver its rcDNA to the nucleus to produce cccDNA. In addition, progeny rcDNA, newly formed in cytoplasmic nucleocapsids, is also delivered to the nucleus in the same cell to form more cccDNA in a process called intracellular cccDNA amplification or recycling. Here, we focus on recent evidence demonstrating differential effects of HBc in affecting cccDNA formation during de novo infection vs. recycling, obtained using HBc mutations and small molecule inhibitors. These results implicate a critical role of HBc in determining HBV trafficking during infection, as well as in nucleocapsid disassembly (uncoating) to release rcDNA, events essential for cccDNA formation. HBc likely functions in these processes via interactions with host factors, which contributes critically to HBV host tropism. A better understanding of the roles of HBc in HBV entry, cccDNA formation, and host species tropism should accelerate ongoing efforts to target HBc and cccDNA for the development of an HBV cure and facilitate the establishment of convenient animal models for both basic research and drug development. Full article
(This article belongs to the Special Issue Pathophysiology of Viral Hepatitis)
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9 pages, 1637 KiB  
Review
Key Factors for “Fishing” NTCP as a Functional Receptor for HBV and HDV
by Huan Yan and Chunli Wang
Viruses 2023, 15(2), 512; https://doi.org/10.3390/v15020512 - 12 Feb 2023
Viewed by 2379
Abstract
About ten years ago, Wenhui Li’s research group in China identified the sodium taurocholate co-transporting polypeptide (NTCP), a bile acid transporter predominantly expressed in the liver, as a functional receptor for hepatitis B virus (HBV) and its satellite hepatitis delta virus (HDV) through [...] Read more.
About ten years ago, Wenhui Li’s research group in China identified the sodium taurocholate co-transporting polypeptide (NTCP), a bile acid transporter predominantly expressed in the liver, as a functional receptor for hepatitis B virus (HBV) and its satellite hepatitis delta virus (HDV) through biochemical and genetic studies. This finding unraveled a longtime mystery in the HBV field and led to the establishment of efficient and easy-to-use HBV infection models, which paved the way for the in-depth study of the HBV entry mechanism and facilitated the development of therapeutics against HBV and HDV. The whole picture of the complex HBV entry process became clear upon the follow-up studies over the years, including the recent resolution found for the NTCP structure. As one of the first authors of the 2012 eLife paper on NTCP identification, here, I (H. Y.) share our experience on the bumpy and exciting journey of receptor hunting, particularly on the photo-cross-linking study and some detailed descriptions of the “fishing” process and summarize the key factors for our successful receptor identification. This review may also provide helpful insights for identifying a protein target by peptide or protein baits through cross-linking and immunoprecipitation. Full article
(This article belongs to the Special Issue Pathophysiology of Viral Hepatitis)
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