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Life Cycle of Hepatitis D Virus (HDV) and HDV-Like Agents

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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 (31 March 2024) | Viewed by 3994

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Special Issue Editors

Dr. Zhenfeng Zhang

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Guest Editor

School of Public Health and Emergency Management, Southern University of Science and Technology, Shenzhen 518055, China
Interests: hepatitis D virus; virus–host interaction; interferon response

Prof. Dr. Stephan Urban

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Guest Editor

Department of Infectious Diseases, Molecular Virology (Translational Virology), Heidelberg University, 69120 Heidelberg, Germany
Interests: hepatitis B and hepatitis D virus–host interactions
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

As the smallest human virus, hepatitis D virus (HDV) represents the prototype of a large family of pathogenic agents with a unique life cycle. HDV depends on the self-assembly competent envelope proteins of its helper virus, the human hepatitis B virus (HBV), in order to exit and specifically enter hepatocytes. However, the replication of its single-stranded highly backfolded circular RNA genome is not restricted to liver cells. Recently, a number of HDV-like agents in different species were discovered without an apparent association with HBV-like helper viruses, which implies other strategies of HDV propagation. Similar to plant viroids, the circular single-stranded RNA genome of HDV explores host RNA polymerase to replicate via the amplification of the rolling circle. HDV causes the most severe form of viral hepatitis, affecting at least 12 million individuals. This burden is probably underestimated due to large gaps in reliable epidemiological data. Since the discovery the viral receptor NTCP in 2012 and the development of convenient infection models thereafter, important progress has been made regarding the virus life cycle, virus–host interaction, innate immune responses, and drug development, with the first medication (bulevirtide/Hepcludex) obtaining approval in Europe in 2020.

This Special Issue aims to collate new findings in terms of the biology of HDV and HDV-like agents. The topics to be addressed in this Issue shall cover all of the steps of the replication cycle, virus–host interaction, innate and adaptive immune responses, virus evolution, the pathogenesis of infection, epidemiology, diagnostics, and translational research with clinical implications. Both original research articles and reviews are welcome.

We look forward to receiving your contributions.

Dr. Zhenfeng Zhang
Prof. Dr. Stephan Urban
Guest Editors

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Keywords

hepatitis D virus
HDV-like agents
viral life cycle
virus–host interaction
immune responses
virus evolution
pathogenesis
epidemiology
clinical discoveries

Published Papers (4 papers)

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Research

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16 pages, 6044 KiB

Open AccessArticle

HepG2BD: A Novel and Versatile Cell Line with Inducible HDV Replication and Constitutive HBV Expression

by Matthieu Blanchet, Léna Angelo, Yasmine Tétreault, Marwa Khabir, Camille Sureau, Andrew Vaillant and Patrick Labonté

Viruses 2024, 16(4), 532; https://doi.org/10.3390/v16040532 - 29 Mar 2024

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Abstract

Individuals chronically infected with hepatitis B virus (HBV) and hepatitis Delta virus (HDV) present an increased risk of developing cirrhosis and hepatocellular carcinoma in comparison to HBV mono-infected individuals. Although HDV only replicates in individuals coinfected or superinfected with HBV, there is currently no in vitro model that can stably express both viruses simultaneously, mimicking the chronic infections seen in HBV/HDV patients. Here, we present the HepG2BD cell line as a novel in vitro culture system for long-term replication of HBV and HDV. HepG2BD cells derive from HepG2.2.15 cells in which a 2 kb HDV cDNA sequence was inserted into the adeno-associated virus safe harbor integration site 1 (AAVS1) using CRISPR-Cas9. A Tet-Off promoter was placed 5′ of the genomic HDV sequence for reliable initiation/repression of viral replication and secretion. HBV and HDV replication were then thoroughly characterized. Of note, non-dividing cells adopt a hepatocyte-like morphology associated with an increased production of both HDV and HBV virions. Finally, HDV seems to negatively interfere with HBV in this model system. Altogether, HepG2BD cells will be instrumental to evaluate, in vitro, the fundamental HBV–HDV interplay during simultaneous chronic replication as well as for antivirals screening targeting both viruses. Full article

(This article belongs to the Special Issue Life Cycle of Hepatitis D Virus (HDV) and HDV-Like Agents)

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17 pages, 3959 KiB

Open AccessArticle

Deciphering the Role of Post-Translational Modifications and Cellular Location of Hepatitis Delta Virus (HDV) Antigens in HDV-Mediated Liver Damage in Mice

by Sheila Maestro, Nahia Gomez-Echarte, Gracian Camps, Carla Usai, Cristina Olagüe, Africa Vales, Rafael Aldabe and Gloria Gonzalez-Aseguinolaza

Viruses 2024, 16(3), 379; https://doi.org/10.3390/v16030379 - 28 Feb 2024

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Abstract

Hepatitis D virus (HDV) infection represents the most severe form of chronic viral hepatitis. We have shown that the delivery of HDV replication-competent genomes to the hepatocytes using adeno-associated virus (AAV-HDV) as gene delivery vehicles offers a unique platform to investigate the molecular aspects of HDV and associated liver damage. For the purpose of this study, we generated HDV genomes modified by site-directed mutagenesis aimed to (i) prevent some post-translational modifications of HDV antigens (HDAgs) such as large-HDAg (L-HDAg) isoprenylation or short-HDAg (S-HDAg) phosphorylation; (ii) alter the localization of HDAgs within the subcellular compartments; and (iii) inhibit the right conformation of the delta ribozyme. First, the different HDV mutants were tested in vitro using plasmid-transfected Huh-7 cells and then in vivo in C57BL/6 mice using AAV vectors. We found that Ser177 phosphorylation and ribozymal activity are essential for HDV replication and HDAg expression. Mutations of the isoprenylation domain prevented the formation of infectious particles and increased cellular toxicity and liver damage. Furthermore, altering HDAg intracellular localization notably decreased viral replication, though liver damage remained unchanged versus normal HDAg distribution. In addition, a mutation in the nuclear export signal impaired the formation of infectious viral particles. These findings contribute valuable insights into the intricate mechanisms of HDV biology and have implications for therapeutic considerations. Full article

(This article belongs to the Special Issue Life Cycle of Hepatitis D Virus (HDV) and HDV-Like Agents)

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12 pages, 2196 KiB

Open AccessArticle

Phylogenetic and Phylodynamic Analysis of Delta Strains Circulating in Italy

by Leonidas Salichos, Claudia Minosse, Ubaldo Visco-Comandini, Chiara Taibi, Verdiana Zulian, Gianpiero D’Offizi, Nayan Pallothu, Fiona McPhee and Anna Rosa Garbuglia

Viruses 2023, 15(9), 1791; https://doi.org/10.3390/v15091791 - 23 Aug 2023

Viewed by 890

Abstract

The hepatitis delta virus (HDV) exhibits high genetic and evolutionary variability and is classified into eight genotypes (HDV-1 to -8). HDV-1 is the most widespread genotype worldwide and includes several subtypes. It predominates mainly in Europe, the Middle East, North America, and Northern Africa, and is associated with both severe and mild forms of liver disease. In this study, we performed phylogenetic and phylodynamic analyses of HDV strains circulating in Regione Lazio, Italy, to understand when these strains were introduced into the Lazio region and to define their genetic variability in Italy. Fifty HDV RNA positive patient samples were amplified using a nested RT-PCR approach targeting the HDV R0 region and sequenced. A phylogenetic tree of patient-derived sequences and reference sequences representing HDV-1 to -8 was constructed using the GTRGAMMA model in RAxML v8. The results indicated that HDV-1 was the predominant genotype with HDV-1d being the most frequently inferred subtype. HDV-1 sequences clustering with subtypes 1b and 1e were also identified. A phylodynamic analysis of HDV-1 sequences employing a Bayesian birth-death model inferred a clock rate of 3.04 × 10⁻⁴ substitutions per site per million years, with a 95% Highest Posterior Density (HPD) interval of 3.45 × 10⁻⁵ to 5.72 × 10⁻⁴. A Bayesian birth-death analysis with tree calibration based on a sample dating approach indicated multiple original sources of infection (from the late 1950s to late 1980s). Overall, these results suggest that HDV sequences from the native Italian and non-Italian patients analyzed in this study represent multiple lineages introduced across a wide period. A common ancestral origin should be excluded. Full article

(This article belongs to the Special Issue Life Cycle of Hepatitis D Virus (HDV) and HDV-Like Agents)

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13 pages, 2420 KiB

Open AccessSystematic Review

Diagnostic Efficacy of Serological Antibody Detection Tests for Hepatitis Delta Virus: A Systematic Review and Meta-Analysis

by Zhenzhen Pan, Sisi Chen, Ling Xu, Yao Gao, Yaling Cao, Zihao Fan, Yuan Tian, Xiangying Zhang, Zhongping Duan and Feng Ren

Viruses 2023, 15(12), 2345; https://doi.org/10.3390/v15122345 - 29 Nov 2023

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Abstract

Background and Aims Coinfection of hepatitis delta virus (HDV) with hepatitis B virus (HBV) causes the most severe form of viral hepatitis, and the global prevalence of HDV infection is underestimated. Although serological testing of anti-HDV antibodies is widely used in the diagnosis of HDV, its diagnostic efficacy remains unclear. This study aimed to evaluate the diagnostic efficacy of HDV serological tests, the results of which may assist in the diagnosis of HDV. Methods Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. The PubMed, Web of Science and Cochrane Library databases were searched from the beginning to 31 May 2023. Study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. STATA SE was used for the meta-analysis of the sensitivity, specificity, positive likelihood ratio and negative likelihood ratio. Results Among a total of 1376 initially identified studies, only 12 articles met the final inclusion criteria. The pooled sensitivity and specificity were 1.00 (95% CI: 0.00–1.00) and 0.71 (95% CI: 0.50–0.78) for HDV total antibodies, 0.96 (95% CI: 0.83–0.99) and 0.98 (95% CI: 0.82–1.00) for anti-HDV IgM and 0.95 (95% CI: 0.86–0.98) and 0.96 (95% CI: 0.67–1.00) for anti-HDV IgG. The pooled sensitivity and specificity for HDV serological tests were 0.99 (95% CI: 0.96–1.00) and 0.90 (95% CI: 0.79–0.96). Conclusions This meta-analysis suggests that serological tests have high diagnostic performance in detecting antibodies against HDV, especially in HDV IgM and IgG. However, this conclusion is based on studies of a limited number and quality, and the development of new diagnostic tools with higher precision and reliability is still necessary. Full article

(This article belongs to the Special Issue Life Cycle of Hepatitis D Virus (HDV) and HDV-Like Agents)

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