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Viruses
Special Issues
HBV Transcriptional and Post-transcriptional Regulation
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HBV Transcriptional and Post-transcriptional Regulation

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 January 2024) | Viewed by 3501

Special Issue Editors

Dr. Rudolf K. Beran

E-Mail Website
Guest Editor
Gilead Sciences, Foster City, CA, USA
Interests: hepatitis B virus; hepatitis delta virus; HBx; RNA therapies; antisense oligonucleotide therapies
Dr. Simon P. Fletcher

E-Mail Website
Guest Editor
Gilead Sciences, Foster City, CA, USA
Interests: hepatitis B virus; hepatitis delta virus; herpesviruses; respiratory viruses; pandemic preparedness

Special Issue Information

Dear Colleagues,

Hepatitis B virus (HBV), a small, enveloped DNA virus from the hepadnaviridae family, contuinues to be a major public health concern, with approximately 300 million people chronically infected worldwide. Covalently closed circular HBV DNA (cccDNA) is the stable, chromatinized, episomal viral genome, which encodes two enhancers and four promoters and serves as the transcriptional template for six viral RNAs (preCore, pre-genomic (pg), preS1/S2, S, HBx). Besides these major HBV RNAs, at least 20 variants of spliced pgRNA and several HBx transcripts of varying lengths are also produced, though their functions remain mostly undefined.

HBV cccDNA exists in the nucleus as a “minichromosome” associated with histones and various other host proteins. Viral transcription is dependent on the cellular transcriptional machinery and recent studies indicate that cccDNA is controlled by host epigenetic regulatory mechanisms. For example, histone acetyltransferases, the histone-lysine N-methyltransferase SETDB1, the arginine methyltransferase PRMT1, and the structural maintenance of chromosome 5/6 complex (Smc5/6) have been reported to modulate HBV transcription. HBV RNAs are also regulated post-transcriptionally, e.g., by the TENT4-ZCCHC14 complex.

Nucleos(t)ide inhibitors of HBV replication do not directly impact cccDNA transcription or reduce HBV RNA levels. Therefore, new antiviral therapies are being developed to inhibit cccDNA transcription or to target HBV RNAs. These include HBV-targeted antisense oligonucleotides and siRNAs, as well as inhibitors of the viral HBx protein, and inhibitors of host targets such as histone modifying enzymes and TENT4A/4B. The potential of capsid assembly modulators (CAMs) to module HBV transcription also continues to be explored.

This Special Issue aims to update recent advances in the field of HBV transcriptional and post-transcriptional regulation, including furthering our understanding of:

  • Epigenetic regulation of HBV transcription;
  • Host restriction of HBV transcription;
  • HBV RNA splicing;
  • HBV RNA stabilization/degradation;
  • Advances in antiviral therapies targeting HBV transcription and HBV RNAs.

Dr. Rudolf K. Beran
Dr. Simon P. Fletcher
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

  • cccDNA
  • epigenetic regulation
  • SMC5/6 complex
  • HBx
  • RNA splicing
  • TENT4A/B (PAPD5/7)
  • interferon
  • Interferon-Stimulated Genes (ISGs)
  • antisense oligonucleotide
  • siRNA
  • CAM

Published Papers (4 papers)

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Research

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19 pages, 2046 KiB  
Article
Preclinical Antiviral and Safety Profiling of the HBV RNA Destabilizer AB-161
by Angela M. Lam, Ravi R. Dugyala, Muhammed Sheraz, Fei Liu, Emily P. Thi, Ingrid E. Graves, Andrea Cuconati, Holly Micolochick Steuer, Andrzej Ardzinski, Nathan Overholt, Jeremy D. Mason, Dimitar Gotchev, Andrew G. Cole, Troy O. Harasym and Michael J. Sofia
Viruses 2024, 16(3), 323; https://doi.org/10.3390/v16030323 - 21 Feb 2024
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Abstract
HBV RNA destabilizers are a class of small-molecule compounds that target the noncanonical poly(A) RNA polymerases PAPD5 and PAPD7, resulting in HBV RNA degradation and the suppression of viral proteins including the hepatitis B surface antigen (HBsAg). AB-161 is a next-generation HBV RNA [...] Read more.
HBV RNA destabilizers are a class of small-molecule compounds that target the noncanonical poly(A) RNA polymerases PAPD5 and PAPD7, resulting in HBV RNA degradation and the suppression of viral proteins including the hepatitis B surface antigen (HBsAg). AB-161 is a next-generation HBV RNA destabilizer with potent antiviral activity, inhibiting HBsAg expressed from cccDNA and integrated HBV DNA in HBV cell-based models. AB-161 exhibits broad HBV genotype coverage, maintains activity against variants resistant to nucleoside analogs, and shows additive effects on HBV replication when combined with other classes of HBV inhibitors. In AAV-HBV-transduced mice, the dose-dependent reduction of HBsAg correlated with concentrations of AB-161 in the liver reaching above its effective concentration mediating 90% inhibition (EC90), compared to concentrations in plasma which were substantially below its EC90, indicating that high liver exposure drives antiviral activities. In preclinical 13-week safety studies, minor non-adverse delays in sensory nerve conductance velocity were noted in the high-dose groups in rats and dogs. However, all nerve conduction metrics remained within physiologically normal ranges, with no neurobehavioral or histopathological findings. Despite the improved neurotoxicity profile, microscopic findings associated with male reproductive toxicity were detected in dogs, which subsequently led to the discontinuation of AB-161’s clinical development. Full article
(This article belongs to the Special Issue HBV Transcriptional and Post-transcriptional Regulation)
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Review

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15 pages, 1122 KiB  
Review
Co-Transcriptional Regulation of HBV Replication: RNA Quality Also Matters
by Guillaume Giraud, Khadija El Achi, Fabien Zoulim and Barbara Testoni
Viruses 2024, 16(4), 615; https://doi.org/10.3390/v16040615 - 16 Apr 2024
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Abstract
Chronic hepatitis B (CHB) virus infection is a major public health burden and the leading cause of hepatocellular carcinoma. Despite the efficacy of current treatments, hepatitis B virus (HBV) cannot be fully eradicated due to the persistence of its minichromosome, or covalently closed [...] Read more.
Chronic hepatitis B (CHB) virus infection is a major public health burden and the leading cause of hepatocellular carcinoma. Despite the efficacy of current treatments, hepatitis B virus (HBV) cannot be fully eradicated due to the persistence of its minichromosome, or covalently closed circular DNA (cccDNA). The HBV community is investing large human and financial resources to develop new therapeutic strategies that either silence or ideally degrade cccDNA, to cure HBV completely or functionally. cccDNA transcription is considered to be the key step for HBV replication. Transcription not only influences the levels of viral RNA produced, but also directly impacts their quality, generating multiple variants. Growing evidence advocates for the role of the co-transcriptional regulation of HBV RNAs during CHB and viral replication, paving the way for the development of novel therapies targeting these processes. This review focuses on the mechanisms controlling the different co-transcriptional processes that HBV RNAs undergo, and their contribution to both viral replication and HBV-induced liver pathogenesis. Full article
(This article belongs to the Special Issue HBV Transcriptional and Post-transcriptional Regulation)
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11 pages, 845 KiB  
Review
Mechanisms of Hepatitis B Virus cccDNA and Minichromosome Formation and HBV Gene Transcription
by Andoni Gómez-Moreno and Alexander Ploss
Viruses 2024, 16(4), 609; https://doi.org/10.3390/v16040609 - 15 Apr 2024
Viewed by 508
Abstract
Hepatitis B virus (HBV) is the etiologic agent of chronic hepatitis B, which puts at least 300 million patients at risk of developing fibrosis, cirrhosis, and hepatocellular carcinoma. HBV is a partially double-stranded DNA virus of the Hepadnaviridae family. While HBV was discovered [...] Read more.
Hepatitis B virus (HBV) is the etiologic agent of chronic hepatitis B, which puts at least 300 million patients at risk of developing fibrosis, cirrhosis, and hepatocellular carcinoma. HBV is a partially double-stranded DNA virus of the Hepadnaviridae family. While HBV was discovered more than 50 years ago, many aspects of its replicative cycle remain incompletely understood. Central to HBV persistence is the formation of covalently closed circular DNA (cccDNA) from the incoming relaxed circular DNA (rcDNA) genome. cccDNA persists as a chromatinized minichromosome and is the major template for HBV gene transcription. Here, we review how cccDNA and the viral minichromosome are formed and how viral gene transcription is regulated and highlight open questions in this area of research. Full article
(This article belongs to the Special Issue HBV Transcriptional and Post-transcriptional Regulation)
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13 pages, 1356 KiB  
Review
The Post-Transcriptional Regulatory Element of Hepatitis B Virus: From Discovery to Therapy
by Karim Mouzannar, Anne Schauer and T. Jake Liang
Viruses 2024, 16(4), 528; https://doi.org/10.3390/v16040528 - 29 Mar 2024
Viewed by 1077
Abstract
The post-transcriptional regulatory element (PRE) is present in all HBV mRNAs and plays a major role in their stability, nuclear export, and enhancement of viral gene expression. Understanding PRE’s structure, function, and mode of action is essential to leverage its potential as a [...] Read more.
The post-transcriptional regulatory element (PRE) is present in all HBV mRNAs and plays a major role in their stability, nuclear export, and enhancement of viral gene expression. Understanding PRE’s structure, function, and mode of action is essential to leverage its potential as a therapeutic target. A wide range of PRE-based reagents and tools have been developed and assessed in preclinical and clinical settings for therapeutic and biotechnology applications. This manuscript aims to provide a systematic review of the characteristics and mechanism of action of PRE, as well as elucidating its current applications in basic and clinical research. Finally, we discuss the promising opportunities that PRE may provide to antiviral development, viral biology, and potentially beyond. Full article
(This article belongs to the Special Issue HBV Transcriptional and Post-transcriptional Regulation)
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