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Structural Variations and Molecular Genetics of Hepatitis Virus and Related...
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Structural Variations and Molecular Genetics of Hepatitis Virus and Related Viruses

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

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 24932

Special Issue Editor

Dr. Kei Fujiwara

E-Mail Website
Guest Editor
Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
Interests: hepatitis virus; viral genome research; bioinformatics; structural variation; hepatocellular carcinoma; chronic liver disease

Special Issue Information

Dear Colleagues,

Since the great discovery of Australian antigen in 1965 by Dr. Alter and Dr. Blumberg, five hepatitis viruses (A to E) have been discovered, and enormous scientific achievements have been accomplished.

Among those hepatitis viruses, hepatitis B virus (HBV) has been investigated extensively. Starting from virological property and pathogenesis, research on the HBV genome has extended into HBV in primates, mammals, birds, reptiles and more. HBV and its related viruses infect an amazingly wide range of hosts.

Genetic alterations in hepatitis virus contain single nucleotide changes, such as core promoter and pre-core mutations in HBV, and recombinations in HBV and HCV. In addition, two patterns of structural variations (SVs) in HBV have been reported. One is complex SVs in human HBV. Complex SVs are defined by multiple breakpoints and, practically, are composed of two or more SVs, such as insertion, deletion, and duplication. The other is polymorphic SVs observed in hepadnaviruses.

In this Special Issue, we would like to explore genetic changes in hepatitis virus in-depth. Along with research articles and reviews of mutations, recombinations, and SVs in hepatitis virus, analyses on HBV integration in the host genome are welcomed, as are analyses on SVs in the host genome. This Special Issue also covers research on bioinformatical techniques for the analysis of genetic alterations in hepatitis virus and experimental data on genetic alterations in hepatitis virus.

Dr. Kei Fujiwara
Guest Editor

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Keywords

  • hepatitis virus
  • viral genome
  • structural variation
  • complex structural variation
  • structural variation polymorphisms
  • mutation
  • recombination
  • bioinformatics
  • HBV integration

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 161 KiB  
Editorial
Special Issue “Structural Variations and Molecular Genetics of Hepatitis Virus and Related Viruses”
by Kei Fujiwara
Viruses 2021, 13(8), 1456; https://doi.org/10.3390/v13081456 - 27 Jul 2021
Viewed by 2183
Abstract
In this special issue, we present collected updated data on the hepatitis viruses [...] Full article
(This article belongs to the Special Issue Structural Variations and Molecular Genetics of Hepatitis Virus and Related Viruses)

Research

Jump to: Editorial, Review

12 pages, 1784 KiB  
Article
Hepatitis C Virus Subtypes Novel 6g-Related Subtype and 6w Could Be Indigenous in Southern Taiwan with Characteristic Geographic Distribution
by Hung-Da Tung, Pei-Lun Lee, Jyh-Jou Chen, Hsing-Tao Kuo, Ming-Jen Sheu, Chun-Ta Cheng, Tang-Wei Chuang, Hsu-Ju Kao, Yu-Hsun Wu, Mai-Gio Pang, Cheng-Heng Lin, Chia-Yi Hou, Hsin-Hua Tsai, Li-Ching Wu and Chuan Lee
Viruses 2021, 13(7), 1316; https://doi.org/10.3390/v13071316 - 7 Jul 2021
Cited by 3 | Viewed by 2096
Abstract
Hepatitis C virus (HCV) genotype (GT) 6 is the most genetically diverse GT and mainly distributed in Southeast Asia and south China but not Taiwan. Earlier studies showed the major HCV GTs in Taiwan were GT 1b and 2 with very rare GT [...] Read more.
Hepatitis C virus (HCV) genotype (GT) 6 is the most genetically diverse GT and mainly distributed in Southeast Asia and south China but not Taiwan. Earlier studies showed the major HCV GTs in Taiwan were GT 1b and 2 with very rare GT 6 except in injection drug users (IDUs), and subtype 6a is the main GT 6 subtype among IDUs. Recently, we reported a much higher prevalence (18.3%) of GT 6 in Tainan City, southern Taiwan. This study was designed to clarify the subtypes of GT 6 in this endemic area. A total of 3022 (1343 men and 1679 women) HCV viremic patients were enrolled. Subtypes of GT 6 were determined by sequencing of core/E1 and nonstructural protein 5B in 322 of 518 GT 6 patients. The overall GT 6 prevalence rate was 17.1% (518/3022), with higher prevalence districts (>25%) located in northern Tainan. A novel 6g-related subtype is the most prevalent subtype (81.0%), followed by 6w (10.8%), 6a (7.5%), and 6n (0.7%). The high GT 6 prevalence in Tainan was mainly due to a novel 6g-related subtype and 6w. These two subtypes could be indigenous in Tainan with characteristic geographic distribution. Full article
(This article belongs to the Special Issue Structural Variations and Molecular Genetics of Hepatitis Virus and Related Viruses)
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16 pages, 1553 KiB  
Article
Molecular Characterization and Seroprevalence of Hepatitis E Virus in Inflammatory Bowel Disease Patients and Solid Organ Transplant Recipients
by Juozas Grigas, Maria Montoya, Evelina Simkute, Marius Buitkus, Ruta Zagrabskaite, Arnoldas Pautienius, Dainius Razukevicius, Laimas Virginijus Jonaitis, Gediminas Kiudelis, Jurgita Skieceviciene, Ruta Vaiciuniene, Asta Stankuviene, Inga Arune Bumblyte, Juozas Kupcinskas and Arunas Stankevicius
Viruses 2021, 13(4), 670; https://doi.org/10.3390/v13040670 - 13 Apr 2021
Cited by 7 | Viewed by 2765
Abstract
Seroprevalence rates and molecular characterization of hepatitis E virus (HEV) prevalent in the Lithuanian human population has not yet been evaluated. Immunosuppressed individuals have been recognized as a risk group for chronic hepatitis due to HEV genotype 3 (HEV-3) infections. The objectives of [...] Read more.
Seroprevalence rates and molecular characterization of hepatitis E virus (HEV) prevalent in the Lithuanian human population has not yet been evaluated. Immunosuppressed individuals have been recognized as a risk group for chronic hepatitis due to HEV genotype 3 (HEV-3) infections. The objectives of the present study were to determine prevalence rates of anti-HEV antibodies among inflammatory bowel disease (IBD) patients and solid organ transplant (SOT) recipients, to isolate and characterize HEV strain present in the Lithuanian human population, and to investigate its capacity to infect non-human primate (MARC-145 and Vero), swine (PK-15) and murine (Neuro-2a) cells in vitro. In the present study, the significant difference of anti-HEV IgG prevalence between healthy (3.0% (95% CI 0–6.3)) and immunosuppressed individuals (12.0% [95% CI 8.1–15.9]) was described. Moreover, our findings showed that anti-HEV IgG seropositivity can be significantly predicted by increasing age (OR = 1.032, p < 0.01), diagnosis of IBD (OR = 4.541, p < 0.01) and reception of SOT (OR = 4.042, <0.05). Locally isolated HEV strain clustered within genotype 3i subtype of genotype 3 and was capable of infecting MARC-145 cells. This study demonstrates higher HEV seroprevalence in the risk group compared to healthy control individuals without confidence interval overlap. The high level of genetic homology between human and animal strains in Lithuania and the capacity of locally isolated strains to infect cells of non-human origin suggests its potential for zoonotic transmission. Full article
(This article belongs to the Special Issue Structural Variations and Molecular Genetics of Hepatitis Virus and Related Viruses)
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16 pages, 2346 KiB  
Article
Characterization of Hepatitis B Virus Integrations Identified in Hepatocellular Carcinoma Genomes
by Pranav P. Mathkar, Xun Chen, Arvis Sulovari and Dawei Li
Viruses 2021, 13(2), 245; https://doi.org/10.3390/v13020245 - 4 Feb 2021
Cited by 6 | Viewed by 3317
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Almost half of HCC cases are associated with hepatitis B virus (HBV) infections, which often lead to HBV sequence integrations in the human genome. Accurate identification of HBV integration sites at a single [...] Read more.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality. Almost half of HCC cases are associated with hepatitis B virus (HBV) infections, which often lead to HBV sequence integrations in the human genome. Accurate identification of HBV integration sites at a single nucleotide resolution is critical for developing a better understanding of the cancer genome landscape and of the disease itself. Here, we performed further analyses and characterization of HBV integrations identified by our recently reported VIcaller platform in recurrent or known HCC genes (such as TERT, MLL4, and CCNE1) as well as non-recurrent cancer-related genes (such as CSMD2, NKD2, and RHOU). Our pathway enrichment analysis revealed multiple pathways involving the alcohol dehydrogenase 4 gene, such as the metabolism pathways of retinol, tyrosine, and fatty acid. Further analysis of the HBV integration sites revealed distinct patterns involving the integration upper breakpoints, integrated genome lengths, and integration allele fractions between tumor and normal tissues. Our analysis also implies that the VIcaller method has diagnostic potential through discovering novel clonal integrations in cancer-related genes. In conclusion, although VIcaller is a hypothesis free virome-wide approach, it can still be applied to accurately identify genome-wide integration events of a specific candidate virus and their integration allele fractions. Full article
(This article belongs to the Special Issue Structural Variations and Molecular Genetics of Hepatitis Virus and Related Viruses)
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Review

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30 pages, 1739 KiB  
Review
Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability
by Marina Campos-Valdez, Hugo C. Monroy-Ramírez, Juan Armendáriz-Borunda and Laura V. Sánchez-Orozco
Viruses 2021, 13(6), 1167; https://doi.org/10.3390/v13061167 - 18 Jun 2021
Cited by 17 | Viewed by 6461
Abstract
The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients’ responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance [...] Read more.
The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients’ responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes. Full article
(This article belongs to the Special Issue Structural Variations and Molecular Genetics of Hepatitis Virus and Related Viruses)
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13 pages, 6675 KiB  
Review
Hepatitis B Virus Pre-S Gene Deletions and Pre-S Deleted Proteins: Clinical and Molecular Implications in Hepatocellular Carcinoma
by Yueh-Te Lin, Long-Bin Jeng, Wen-Ling Chan, Ih-Jen Su and Chiao-Fang Teng
Viruses 2021, 13(5), 862; https://doi.org/10.3390/v13050862 - 8 May 2021
Cited by 14 | Viewed by 3756
Abstract
Hepatocellular carcinoma (HCC) is one of the most frequent and fatal human cancers worldwide and its development and prognosis are intimately associated with chronic infection with hepatitis B virus (HBV). The identification of genetic mutations and molecular mechanisms that mediate HBV-induced tumorigenesis therefore [...] Read more.
Hepatocellular carcinoma (HCC) is one of the most frequent and fatal human cancers worldwide and its development and prognosis are intimately associated with chronic infection with hepatitis B virus (HBV). The identification of genetic mutations and molecular mechanisms that mediate HBV-induced tumorigenesis therefore holds promise for the development of potential biomarkers and targets for HCC prevention and therapy. The presence of HBV pre-S gene deletions in the blood and the expression of pre-S deleted proteins in the liver tissues of patients with chronic hepatitis B and HBV-related HCC have emerged as valuable biomarkers for higher incidence rates of HCC development and a higher risk of HCC recurrence after curative surgical resection, respectively. Moreover, pre-S deleted proteins are regarded as important oncoproteins that activate multiple signaling pathways to induce DNA damage and promote growth and proliferation in hepatocytes, leading to HCC development. The signaling molecules dysregulated by pre-S deleted proteins have also been validated as potential targets for the prevention of HCC development. In this review, we summarize the clinical and molecular implications of HBV pre-S gene deletions and pre-S deleted proteins in HCC development and recurrence and highlight their potential applications in HCC prevention and therapy. Full article
(This article belongs to the Special Issue Structural Variations and Molecular Genetics of Hepatitis Virus and Related Viruses)
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11 pages, 3194 KiB  
Review
Novel Genetic Rearrangements in Hepatitis B Virus: Complex Structural Variations and Structural Variation Polymorphisms
by Kei Fujiwara
Viruses 2021, 13(3), 473; https://doi.org/10.3390/v13030473 - 12 Mar 2021
Cited by 1 | Viewed by 2927
Abstract
Chronic hepatitis B virus (HBV) causes serious clinical problems, such as liver cirrhosis and hepatocellular carcinoma. Current antiviral treatments suppress HBV; however, the clinical cure rate remains low. Basic research on HBV is indispensable to eradicate and cure HBV. Genetic alterations are defined [...] Read more.
Chronic hepatitis B virus (HBV) causes serious clinical problems, such as liver cirrhosis and hepatocellular carcinoma. Current antiviral treatments suppress HBV; however, the clinical cure rate remains low. Basic research on HBV is indispensable to eradicate and cure HBV. Genetic alterations are defined by nucleotide substitutions and canonical forms of structural variations (SVs), such as insertion, deletion and duplication. Additionally, genetic changes inconsistent with the canonical forms have been reported, and these have been termed complex SVs. Detailed analyses of HBV using bioinformatical applications have detected complex SVs in HBV genomes. Sequence gaps and low sequence similarity have been observed in the region containing complex SVs. Additionally, insertional motif sequences have been observed in HBV strains with complex SVs. Following the analyses of complex SVs in the HBV genome, the role of SVs in the genetic diversity of orthohepadnavirus has been investigated. SV polymorphisms have been detected in comparisons of several species of orthohepadnaviruses. As mentioned, complex SVs are composed of multiple SVs. On the contrary, SV polymorphisms are observed as insertions of different SVs. Up to a certain point, nucleotide substitutions cause genetic differences. However, at some point, the nucleotide sequences are split into several particular patterns. These SVs have been observed as polymorphic changes. Different species of orthohepadnaviruses possess SVs which are unique and specific to a certain host of the virus. Studies have shown that SVs play an important role in the HBV genome. Further studies are required to elucidate their virologic and clinical roles. Full article
(This article belongs to the Special Issue Structural Variations and Molecular Genetics of Hepatitis Virus and Related Viruses)
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