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Viruses
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Recent Advances in Hepatitis B Virus Research
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Recent Advances in Hepatitis B Virus Research

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

Deadline for manuscript submissions: closed (30 January 2017) | Viewed by 140620

Special Issue Editors

Prof. Dr. Ulrike Protzer

E-Mail Website
Guest Editor
Institute of Virology, TU Munich / Helmholtz Zentrum München, Trogerstr. 30, 81675 München, Germany
Interests: hepatitis B virus host interaction; novel therapeutic approaches for hepatitis B
Prof. Dr. Michael Nassal

E-Mail Website
Guest Editor
Gastroenterologie, Hepatologie, Endokrinologie und Infektiologie, Hugstetter Straße 55, 79106 Freiburg, Germany
Interests: molecular biology of hepatitis B viruses

Special Issue Information

The publication of this Special Issue publication has been partially sponsored by Gilead Sciences, Inc. Gilead Sciences, Inc. has provided an unrestricted grant. Gilead Sciences, Inc. has had no input into the development or content of these materials.

Dear Colleagues,

Hepatitis B virus has been attracting increasing research interest in the recent 2-3 years since it became obvious that it remained a major health threat despite the availability of a prophylactic vaccine. To develop new, curative therapies for patients with chronic hepatitis B, an improved understanding of the virus life cycle and in particular virus persistence is essential. Important progress in this respect that has been made after the recent discovery of the bile acid transporter NTCP as an essential receptor that allowed the generation of efficient cell culture infection models will be discussed in this special issue.

Prof. Ulrike Protzer, MD
Prof. Michael Nassal, PhD
Guest Editor

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Keywords

  • HBV
  • hepatitis B
  • uptake
  • cccDNA
  • immune control
  • hepatitis Delta virus

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Published Papers (11 papers)

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Review

870 KiB  
Review
Applicability of Metal Nanoparticles in the Detection and Monitoring of Hepatitis B Virus Infection
by Maxim Shevtsov, Lili Zhao, Ulrike Protzer and Maarten A. A. van de Klundert
Viruses 2017, 9(7), 193; https://doi.org/10.3390/v9070193 - 21 Jul 2017
Cited by 27 | Viewed by 7540
Abstract
Chronic infection with the hepatitis B virus (HBV) can lead to liver failure and can cause liver cirrhosis and hepatocellular carcinoma (HCC). Reliable means for detecting and monitoring HBV infection are essential to identify patients in need of therapy and to prevent HBV [...] Read more.
Chronic infection with the hepatitis B virus (HBV) can lead to liver failure and can cause liver cirrhosis and hepatocellular carcinoma (HCC). Reliable means for detecting and monitoring HBV infection are essential to identify patients in need of therapy and to prevent HBV transmission. Nanomaterials with defined electrical, optical, and mechanical properties have been developed to detect and quantify viral antigens. In this review, we discuss the challenges in applying nanoparticles to HBV antigen detection and in realizing the bio-analytical potential of such nanoparticles. We discuss recent developments in generating detection platforms based on gold and iron oxide nanoparticles. Such platforms increase biological material detection efficiency by the targeted capture and concentration of HBV antigens, but the unique properties of nanoparticles can also be exploited for direct, sensitive, and specific antigen detection. We discuss several studies that show that nanomaterial-based platforms enable ultrasensitive HBV antigen detection. Full article
(This article belongs to the Special Issue Recent Advances in Hepatitis B Virus Research)
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1460 KiB  
Review
Hepatitis Delta Virus: Replication Strategy and Upcoming Therapeutic Options for a Neglected Human Pathogen
by Florian A. Lempp and Stephan Urban
Viruses 2017, 9(7), 172; https://doi.org/10.3390/v9070172 - 4 Jul 2017
Cited by 31 | Viewed by 19357
Abstract
The human Hepatitis Delta Virus (HDV) is unique among all viral pathogens. Encoding only one protein (Hepatitis Delta Antigen; HDAg) within its viroid-like self-complementary RNA, HDV constitutes the smallest known virus in the animal kingdom. To disseminate in its host, HDV depends on [...] Read more.
The human Hepatitis Delta Virus (HDV) is unique among all viral pathogens. Encoding only one protein (Hepatitis Delta Antigen; HDAg) within its viroid-like self-complementary RNA, HDV constitutes the smallest known virus in the animal kingdom. To disseminate in its host, HDV depends on a helper virus, the human Hepatitis B virus (HBV), which provides the envelope proteins required for HDV assembly. HDV affects an estimated 15–20 million out of the 240 million chronic HBV-carriers and disperses unequally in disparate geographical regions of the world. The disease it causes (chronic Hepatitis D) presents as the most severe form of viral hepatitis, leading to accelerated progression of liver dysfunction including cirrhosis and hepatocellular carcinoma and a high mortality rate. The lack of approved drugs interfering with specific steps of HDV replication poses a high burden for gaining insights into the molecular biology of the virus and, consequently, the development of specific novel medications that resiliently control HDV replication or, in the best case, functionally cure HDV infection or HBV/HDV co-infection. This review summarizes our current knowledge of HBV molecular biology, presents an update on novel cell culture and animal models to study the virus and provides updates on the clinical development of the three developmental drugs Lonafarnib, REP2139-Ca and Myrcludex B. Full article
(This article belongs to the Special Issue Recent Advances in Hepatitis B Virus Research)
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Figure 1

343 KiB  
Review
The Role of cccDNA in HBV Maintenance
by Lena Allweiss and Maura Dandri
Viruses 2017, 9(6), 156; https://doi.org/10.3390/v9060156 - 21 Jun 2017
Cited by 149 | Viewed by 13099
Abstract
Chronic hepatitis B virus (HBV) infection continues to be a major health burden worldwide; it can cause various degrees of liver damage and is strongly associated with the development of liver cirrhosis and hepatocellular carcinoma. The molecular mechanisms determining HBV persistence are not [...] Read more.
Chronic hepatitis B virus (HBV) infection continues to be a major health burden worldwide; it can cause various degrees of liver damage and is strongly associated with the development of liver cirrhosis and hepatocellular carcinoma. The molecular mechanisms determining HBV persistence are not fully understood, but these appear to be multifactorial and the unique replication strategy employed by HBV enables its maintenance in infected hepatocytes. Both the stability of the HBV genome, which forms a stable minichromosome, the covalently closed circular DNA (cccDNA) in the hepatocyte nucleus, and the inability of the immune system to resolve chronic HBV infection are believed to be key mechanisms of HBV chronicity. Since a true cure of HBV requires clearance of intranuclear cccDNA from infected hepatocytes, understanding the mechanisms involved in cccDNA biogenesis, regulation and stability is mandatory to achieve HBV eradication. This review will summarize the state of knowledge on these mechanisms including the impact of current treatments on the cccDNA stability and activity. We will focus on events challenging cccDNA persistence in dividing hepatocytes. Full article
(This article belongs to the Special Issue Recent Advances in Hepatitis B Virus Research)
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3705 KiB  
Review
A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?
by Sabrina Schreiner and Michael Nassal
Viruses 2017, 9(5), 125; https://doi.org/10.3390/v9050125 - 22 May 2017
Cited by 75 | Viewed by 14696
Abstract
Chronic hepatitis B virus (HBV) infection puts more than 250 million people at a greatly increased risk to develop end-stage liver disease. Like all hepadnaviruses, HBV replicates via protein-primed reverse transcription of a pregenomic (pg) RNA, yielding an unusually structured, viral polymerase-linked relaxed-circular [...] Read more.
Chronic hepatitis B virus (HBV) infection puts more than 250 million people at a greatly increased risk to develop end-stage liver disease. Like all hepadnaviruses, HBV replicates via protein-primed reverse transcription of a pregenomic (pg) RNA, yielding an unusually structured, viral polymerase-linked relaxed-circular (RC) DNA as genome in infectious particles. Upon infection, RC-DNA is converted into nuclear covalently closed circular (ccc) DNA. Associating with cellular proteins into an episomal minichromosome, cccDNA acts as template for new viral RNAs, ensuring formation of progeny virions. Hence, cccDNA represents the viral persistence reservoir that is not directly targeted by current anti-HBV therapeutics. Eliminating cccDNA will thus be at the heart of a cure for chronic hepatitis B. The low production of HBV cccDNA in most experimental models and the associated problems in reliable cccDNA quantitation have long hampered a deeper understanding of cccDNA molecular biology. Recent advancements including cccDNA-dependent cell culture systems have begun to identify select host DNA repair enzymes that HBV usurps for RC-DNA to cccDNA conversion. While this list is bound to grow, it may represent just one facet of a broader interaction with the cellular DNA damage response (DDR), a network of pathways that sense and repair aberrant DNA structures and in the process profoundly affect the cell cycle, up to inducing cell death if repair fails. Given the divergent interactions between other viruses and the DDR it will be intriguing to see how HBV copes with this multipronged host system. Full article
(This article belongs to the Special Issue Recent Advances in Hepatitis B Virus Research)
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1024 KiB  
Review
Immune Tolerant Chronic Hepatitis B: The Unrecognized Risks
by Patrick T. F. Kennedy, Samuel Litwin, Grace E. Dolman, Antonio Bertoletti and William S. Mason
Viruses 2017, 9(5), 96; https://doi.org/10.3390/v9050096 - 29 Apr 2017
Cited by 61 | Viewed by 8027
Abstract
Chronic infection with hepatitis B virus (HBV) progresses through multiple phases, including immune tolerant, immune active, immune control, and, in a subset of patients who achieve immune control, reactivation. The first, the immune tolerant phase, is considered to be prolonged in duration but [...] Read more.
Chronic infection with hepatitis B virus (HBV) progresses through multiple phases, including immune tolerant, immune active, immune control, and, in a subset of patients who achieve immune control, reactivation. The first, the immune tolerant phase, is considered to be prolonged in duration but essentially benign in nature, lacking long-term consequences, and thus not recommended for antiviral therapy. This review challenges the notion that the immune tolerant phase is truly benign and considers the possibility that events during this phase may contribute significantly to cirrhosis, hepatocellular carcinoma (HCC), and the premature death of 25% of HBV carriers worldwide. Thus, earlier treatment than recommended by current guidelines should be considered. Low therapeutic coverage exacerbated by restrictive treatment guidelines may facilitate disease progression in many patients but also increase the risk of neonatal and horizontal transmission from untreated mothers to their children. While a prophylactic vaccine exists, there are many areas worldwide where the treatment of adults and the delivery of an effective vaccination course to newborns present difficult challenges. Full article
(This article belongs to the Special Issue Recent Advances in Hepatitis B Virus Research)
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1386 KiB  
Review
Interplay between the Hepatitis B Virus and Innate Immunity: From an Understanding to the Development of Therapeutic Concepts
by Suzanne Faure-Dupuy, Julie Lucifora and David Durantel
Viruses 2017, 9(5), 95; https://doi.org/10.3390/v9050095 - 28 Apr 2017
Cited by 47 | Viewed by 9139
Abstract
The hepatitis B virus (HBV) infects hepatocytes, which are the main cell type composing a human liver. However, the liver is enriched with immune cells, particularly innate cells (e.g., myeloid cells, natural killer and natural killer T-cells (NK/NKT), dendritic cells (DCs)), in resting [...] Read more.
The hepatitis B virus (HBV) infects hepatocytes, which are the main cell type composing a human liver. However, the liver is enriched with immune cells, particularly innate cells (e.g., myeloid cells, natural killer and natural killer T-cells (NK/NKT), dendritic cells (DCs)), in resting condition. Hence, the study of the interaction between HBV and innate immune cells is instrumental to: (1) better understand the conditions of establishment and maintenance of HBV infections in this secondary lymphoid organ; (2) define the role of these innate immune cells in treatment failure and pathogenesis; and (3) design novel immune-therapeutic concepts based on the activation/restoration of innate cell functions and/or innate effectors. This review will summarize and discuss the current knowledge we have on this interplay between HBV and liver innate immunity. Full article
(This article belongs to the Special Issue Recent Advances in Hepatitis B Virus Research)
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1893 KiB  
Review
HBV DNA Integration: Molecular Mechanisms and Clinical Implications
by Thomas Tu, Magdalena A. Budzinska, Nicholas A. Shackel and Stephan Urban
Viruses 2017, 9(4), 75; https://doi.org/10.3390/v9040075 - 10 Apr 2017
Cited by 285 | Viewed by 22861
Abstract
Chronic infection with the Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality. One peculiar observation in cells infected with HBV (or with closely‑related animal hepadnaviruses) is the presence of viral DNA integration in the host cell genome, despite [...] Read more.
Chronic infection with the Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality. One peculiar observation in cells infected with HBV (or with closely‑related animal hepadnaviruses) is the presence of viral DNA integration in the host cell genome, despite this form being a replicative dead-end for the virus. The frequent finding of somatic integration of viral DNA suggests an evolutionary benefit for the virus; however, the mechanism of integration, its functions, and the clinical implications remain unknown. Here we review the current body of knowledge of HBV DNA integration, with particular focus on the molecular mechanisms and its clinical implications (including the possible consequences of replication-independent antigen expression and its possible role in hepatocellular carcinoma). HBV DNA integration is likely to influence HBV replication, persistence, and pathogenesis, and so deserves greater attention in future studies. Full article
(This article belongs to the Special Issue Recent Advances in Hepatitis B Virus Research)
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891 KiB  
Review
Identifying and Characterizing Interplay between Hepatitis B Virus X Protein and Smc5/6
by Christine M. Livingston, Dhivya Ramakrishnan, Michel Strubin, Simon P. Fletcher and Rudolf K. Beran
Viruses 2017, 9(4), 69; https://doi.org/10.3390/v9040069 - 3 Apr 2017
Cited by 36 | Viewed by 8800
Abstract
Hepatitis B X protein (HBx) plays an essential role in the hepatitis B virus (HBV) replication cycle, but the function of HBx has been elusive until recently. It was recently shown that transcription from the HBV genome (covalently-closed circular DNA, cccDNA) is inhibited [...] Read more.
Hepatitis B X protein (HBx) plays an essential role in the hepatitis B virus (HBV) replication cycle, but the function of HBx has been elusive until recently. It was recently shown that transcription from the HBV genome (covalently-closed circular DNA, cccDNA) is inhibited by the structural maintenance of chromosome 5/6 complex (Smc5/6), and that a key function of HBx is to redirect the DNA-damage binding protein 1 (DDB1) E3 ubiquitin ligase to target this complex for degradation. By doing so, HBx alleviates transcriptional repression by Smc5/6 and stimulates HBV gene expression. In this review, we discuss in detail how the interplay between HBx and Smc5/6 was identified and characterized. We also discuss what is known regarding the repression of cccDNA transcription by Smc5/6, the timing of HBx expression, and the potential role of HBx in promoting hepatocellular carcinoma (HCC). Full article
(This article belongs to the Special Issue Recent Advances in Hepatitis B Virus Research)
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Figure 1

576 KiB  
Review
Complete and Incomplete Hepatitis B Virus Particles: Formation, Function, and Application
by Jianming Hu and Kuancheng Liu
Viruses 2017, 9(3), 56; https://doi.org/10.3390/v9030056 - 21 Mar 2017
Cited by 219 | Viewed by 15583
Abstract
Hepatitis B virus (HBV) is a para-retrovirus or retroid virus that contains a double-stranded DNA genome and replicates this DNA via reverse transcription of a RNA pregenome. Viral reverse transcription takes place within a capsid upon packaging of the RNA and the viral [...] Read more.
Hepatitis B virus (HBV) is a para-retrovirus or retroid virus that contains a double-stranded DNA genome and replicates this DNA via reverse transcription of a RNA pregenome. Viral reverse transcription takes place within a capsid upon packaging of the RNA and the viral reverse transcriptase. A major characteristic of HBV replication is the selection of capsids containing the double-stranded DNA, but not those containing the RNA or the single-stranded DNA replication intermediate, for envelopment during virion secretion. The complete HBV virion particles thus contain an outer envelope, studded with viral envelope proteins, that encloses the capsid, which, in turn, encapsidates the double-stranded DNA genome. Furthermore, HBV morphogenesis is characterized by the release of subviral particles that are several orders of magnitude more abundant than the complete virions. One class of subviral particles are the classical surface antigen particles (Australian antigen) that contain only the viral envelope proteins, whereas the more recently discovered genome-free (empty) virions contain both the envelope and capsid but no genome. In addition, recent evidence suggests that low levels of RNA-containing particles may be released, after all. We will summarize what is currently known about how the complete and incomplete HBV particles are assembled. We will discuss briefly the functions of the subviral particles, which remain largely unknown. Finally, we will explore the utility of the subviral particles, particularly, the potential of empty virions and putative RNA virions as diagnostic markers and the potential of empty virons as a vaccine candidate. Full article
(This article belongs to the Special Issue Recent Advances in Hepatitis B Virus Research)
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Figure 1

2028 KiB  
Review
Nuclear Import of Hepatitis B Virus Capsids and Genome
by Lara Gallucci and Michael Kann
Viruses 2017, 9(1), 21; https://doi.org/10.3390/v9010021 - 21 Jan 2017
Cited by 53 | Viewed by 11490
Abstract
Hepatitis B virus (HBV) is an enveloped pararetrovirus with a DNA genome, which is found in an up to 36 nm-measuring capsid. Replication of the genome occurs via an RNA intermediate, which is synthesized in the nucleus. The virus must have thus ways [...] Read more.
Hepatitis B virus (HBV) is an enveloped pararetrovirus with a DNA genome, which is found in an up to 36 nm-measuring capsid. Replication of the genome occurs via an RNA intermediate, which is synthesized in the nucleus. The virus must have thus ways of transporting its DNA genome into this compartment. This review summarizes the data on hepatitis B virus genome transport and correlates the finding to those from other viruses. Full article
(This article belongs to the Special Issue Recent Advances in Hepatitis B Virus Research)
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Figure 1

217 KiB  
Review
Control of Hepatitis B Virus by Cytokines
by Yuchen Xia and Ulrike Protzer
Viruses 2017, 9(1), 18; https://doi.org/10.3390/v9010018 - 20 Jan 2017
Cited by 99 | Viewed by 8857
Abstract
Hepatitis B virus (HBV) infection remains a major public health problem worldwide with more than 240 million individuals chronically infected. Current treatments can control HBV replication to a large extent, but cannot eliminate HBV infection. Cytokines have been shown to control HBV replication [...] Read more.
Hepatitis B virus (HBV) infection remains a major public health problem worldwide with more than 240 million individuals chronically infected. Current treatments can control HBV replication to a large extent, but cannot eliminate HBV infection. Cytokines have been shown to control HBV replication and contribute to HBV cure in different models. Cytokines play an important role in limiting acute HBV infection in patients and mediate a non-cytolytic clearance of the virus. In this review, we summarize the effects of cytokines and cytokine-induced cellular signaling pathways on different steps of the HBV life cycle, and discuss possible strategies that may contribute to the eradication of HBV through innate immune activation. Full article
(This article belongs to the Special Issue Recent Advances in Hepatitis B Virus Research)
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