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Kim J, Ha J, Song C, Sajjad MA, Kalsoom F, Kwon H, Park J, Park S, Kim K. Sirtuin 2 inhibitor AGK2 exerts antiviral effects by inducing epigenetic suppression of hepatitis B virus covalently closed circular DNA through recruitment of repressive histone lysine methyltransferases and reduction of cccDNA. Front Cell Infect Microbiol 2025; 15:1537929. [PMID: 40270769 PMCID: PMC12014779 DOI: 10.3389/fcimb.2025.1537929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 03/24/2025] [Indexed: 04/25/2025] Open
Abstract
Chronic hepatitis B virus (HBV) infection continues to be a global health concern because current treatments such as interferon-α and nucleos(t)ide analogs cannot fully eliminate the virus due to persistence of covalently closed circular DNA (cccDNA) and integrated HBV DNA. Earlier research suggests that AGK2, a selective SIRT2 inhibitor, suppresses HBV replication by modifying key signaling pathways. This study aimed to further explore the anti-HBV effects of AKG2, particularly its effects on the epigenetic landscape of cccDNA. HBV-transfected and -infected cells were used to assess the impact of AGK2 on viral replication. Changes in SIRT2 expression and α-tubulin acetylation (SDS-PAGE-immunoblotting), core particle formation (native agarose gel electrophoresis and immunoblotting), HBV RNA (northern blotting) and DNA (Southern blotting) synthesis, and cccDNA levels (Southern blotting) were measured. Chromatin immunoprecipitation assays were performed to examine deposition of transcriptionally repressive epigenetic markers on cccDNA. AGK2 reduced expression of SIRT2, increased acetylated α-tubulin levels, and reduced synthesis of HBV RNA and DNA. Importantly, AGK2 also reduced cccDNA levels and increased deposition of repressive histone markers H4K20me1, H3K27me3, and H3K9me3 on cccDNA, mediated by histone lysine methyltransferases such as PR-Set7, EZH2, SETDB1, and SUV39H1. Additionally, there was a reduction in recruitment of RNA polymerase II and acetylated H3 to cccDNA, indicating that AGK2 enhances transcriptional repression. AGK2 suppresses HBV replication through direct antiviral actions, and by epigenetic modulation of cccDNA, indicating that using AGK2 to target SIRT2 and associated epigenetic regulators shows promise as a functional cure for chronic hepatitis B.
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Affiliation(s)
- Jumi Kim
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Jiseon Ha
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Chanho Song
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Muhammad Azhar Sajjad
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Fadia Kalsoom
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hyeonjoong Kwon
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Jaewoo Park
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Sun Park
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
| | - Kyongmin Kim
- Department of Microbiology, Ajou University School of Medicine, Suwon, Republic of Korea
- Department of Biomedical Science, Graduate School of Ajou University, Suwon, Republic of Korea
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Farbod Y, Kankouni H, Moini M, Fung S. Hepatitis B-Induced Hepatocellular Carcinoma: Understanding Viral Carcinogenesis and Disease Management. J Clin Med 2025; 14:2505. [PMID: 40217955 PMCID: PMC11989475 DOI: 10.3390/jcm14072505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2025] [Revised: 03/30/2025] [Accepted: 04/01/2025] [Indexed: 04/14/2025] Open
Abstract
Hepatitis B virus (HBV) infection is a leading cause of chronic liver disease and liver cancer worldwide. Hepatocellular carcinoma (HCC) remains one of the major causes of cancer-related mortality globally. Effective prevention and management strategies for HBV infection are crucial in reducing liver-related complications, including HCC. HBV plays a distinct role in liver carcinogenesis, and there is growing knowledge about the factors contributing to its oncogenic potential. With advancements in HCC management, special attention must be given to the treatment of HBV infection in patients with HBV-induced HCC. In this review, we summarize current insights into the carcinogenic mechanisms of HBV and discuss the latest approaches to managing HBV-induced HCC.
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Affiliation(s)
- Yasamin Farbod
- Division of Gastroenterology and Hepatology, McGill University, Montreal, QC H3A 0G4, Canada
| | - Husain Kankouni
- Division of Gastroenterology and Hepatology, University of Toronto, Toronto, ON M5G 2C4, Canada
| | - Maryam Moini
- Division of Gastroenterology, McMaster University, Hamilton, ON L8S 2A5, Canada
| | - Scott Fung
- Department of Medicine, University of Toronto, Toronto, ON M5G 2C4, Canada
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Kumar V. HBx protein as a therapeutic target for functional cure of hepatitis B virus infection. Virology 2025; 604:110438. [PMID: 39908774 DOI: 10.1016/j.virol.2025.110438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 01/22/2025] [Accepted: 01/24/2025] [Indexed: 02/07/2025]
Abstract
Hepatitis B virus (HBV) is a major cause of acute and chronic liver disease and represents a major public health problem worldwide. Current antiviral therapies with nucleos(t)ide analogues can effectively suppressing viremia but are not curative, and have little or no impact upon the HBV cccDNA minichromosome or the portions of integrated HBV DNA. Several alternative therapeutic strategies targeted at viral components and life cycle are under intense investigation. This article highlights the reasons for considering HBx as a therapeutic target as this may allow targeting of both virus and disease. Recent studies focused at HBx have led to the identification of several new pharmacological agents and development of some novel therapeutic approaches that now deserve to be taken to the next level for better management of hepatitis B. Besides, new therapies could be combined with other established therapies, to provide a functional cure from hepatitis B infection.
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Affiliation(s)
- Vijay Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
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Tan X, Xun L, Yin Q, Chen C, Zhang T, Shen T. Epigenetic Modifications in HBV-Related Hepatocellular Carcinoma. J Viral Hepat 2025; 32:e14044. [PMID: 39868653 DOI: 10.1111/jvh.14044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 11/13/2024] [Accepted: 11/30/2024] [Indexed: 01/28/2025]
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Hepatitis B virus (HBV) is the main pathogen for HCC development. HBV covalently closed circular DNA (cccDNA) forms extra-host chromatin-like minichromosomes in the nucleus of hepatocytes with host histones, non-histones, HBV X protein (HBx) and HBV core protein (HBc). Epigenetic alterations are dynamic and reversible, which regulate gene expression without altering the DNA sequence and play a pivotal role in the regulation of HCC onset and progression. The aim of this review is to elucidate the deregulation of epigenetic mechanisms involved in the pathogenesis of HBV-related HCC (HBV-HCC), including post-translational histone and non-histone modifications, DNA hypermethylation and hypomethylation, non-coding RNA modification on HBV cccDNA minichromosomes and host factors, effecting the replication/transcription of HBV cccDNA and transcription/translation of host genes, and thus HBV-HCC progression. It is expected that the epigenetic regulation perspective provides new ways for more in-depth development of therapeutic control of HBV-HCC.
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Affiliation(s)
- Xiaoqing Tan
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
- Department of Pulmonary and Critical Care Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, Kunming, Peoples republic of China, China
| | - Linting Xun
- Department of Gastroenterology, the First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, People's Republic of China
| | - Qi Yin
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
- Faculty of Life Science and Technology, Kunming University of Science and Technology, Kunming, People's Republic of China, China
| | - Chaohui Chen
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Tao Zhang
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
- Department of Pulmonary and Critical Care Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, Kunming, Peoples republic of China, China
| | - Tao Shen
- Medical School, Kunming University of Science and Technology, Kunming, People's Republic of China
- Department of Pulmonary and Critical Care Medicine, Yunnan Provincial Key Laboratory for Clinical Virology, Institute of Basic and Clinical Medicine, The First People's Hospital of Yunnan Province, Kunming, Peoples republic of China, China
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Ringlander J, Rydell GE, Kann M. From the Cytoplasm into the Nucleus-Hepatitis B Virus Travel and Genome Repair. Microorganisms 2025; 13:157. [PMID: 39858925 PMCID: PMC11767736 DOI: 10.3390/microorganisms13010157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 01/03/2025] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
Hepatitis B virus (HBV) is a major global health concern, affecting millions of people worldwide. HBV is part of the hepadnaviridae family and one of the primary causes of acute and chronic liver infections, leading to conditions such as cirrhosis and hepatocellular carcinoma (HCC). Understanding the intracellular transport and genome repair mechanisms of HBV is crucial for developing new drugs, which-in combination with immune modulators-may contribute to potential cures. This review will explore the current knowledge of HBV intracytoplasmic and nuclear transport, as well as genome repair processes, while drawing comparisons to other viruses with nuclear replication.
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Affiliation(s)
- Johan Ringlander
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 41346 Gothenburg, Sweden; (J.R.); (G.E.R.)
- Department of Clinical Microbiology, Region Västra Götaland, Sahlgrenska University Hospital, 41346 Gothenburg, Sweden
| | - Gustaf E. Rydell
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 41346 Gothenburg, Sweden; (J.R.); (G.E.R.)
| | - Michael Kann
- Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 41346 Gothenburg, Sweden; (J.R.); (G.E.R.)
- Department of Clinical Microbiology, Region Västra Götaland, Sahlgrenska University Hospital, 41346 Gothenburg, Sweden
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Ren J, Cheng S, Ren F, Gu H, Wu D, Yao X, Tan M, Huang A, Chen J. Epigenetic regulation and its therapeutic potential in hepatitis B virus covalently closed circular DNA. Genes Dis 2025; 12:101215. [PMID: 39534573 PMCID: PMC11555349 DOI: 10.1016/j.gendis.2024.101215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 11/25/2023] [Accepted: 12/05/2023] [Indexed: 11/16/2024] Open
Abstract
Human hepatitis B virus (HBV) infection is the major cause of acute and chronic hepatitis B, liver cirrhosis, and hepatocellular carcinoma. Although the application of prophylactic vaccination programs has successfully prevented the trend of increasing HBV infection prevalence, the number of HBV-infected people remains very high. Approved therapeutic management efficiently suppresses viral replication; however, HBV infection is rarely completely resolved. The major reason for therapeutic failure is the persistence of covalently closed circular DNA (cccDNA), which forms viral minichromosomes by combining with histone and nonhistone proteins in the nucleus. Increasing evidence indicates that chromatin-modifying enzymes, viral proteins, and noncoding RNAs are essential for modulating the function of cccDNA. Therefore, a deeper understanding of the regulatory mechanism underlying cccDNA transcription will contribute to the development of a cure for chronic hepatitis B. This review summarizes the current knowledge of cccDNA biology, the regulatory mechanisms underlying cccDNA transcription, and novel anti-HBV approaches for eliminating cccDNA transcription.
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Affiliation(s)
- Jihua Ren
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China
| | - Shengtao Cheng
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China
| | - Fang Ren
- Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400000, China
| | - Huiying Gu
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China
| | - Daiqing Wu
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China
| | - Xinyan Yao
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China
| | - Ming Tan
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China
| | - Ailong Huang
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China
| | - Juan Chen
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing 400000, China
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Naully PG, Tan MI, Nugrahapraja H, Artarini AA, Aditama R, Giri-Rachman EA. Design of multi-epitope-based therapeutic vaccine candidates from HBc and HBx proteins of hepatitis B virus using reverse vaccinology and immunoinformatics approaches. PLoS One 2024; 19:e0313269. [PMID: 39642099 PMCID: PMC11623480 DOI: 10.1371/journal.pone.0313269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 10/21/2024] [Indexed: 12/08/2024] Open
Abstract
The major problem in cases of chronic hepatitis B (CHB) is the failure of the patient's immune response to eliminate the covalently closed circular DNA (cccDNA) minichromosome of hepatitis B virus (HBV). Epigenetic regulation involving the HBV core protein (HBc) and HBV X protein (HBx) influences the transcription and stability of the cccDNA minichromosome. The HBc and/or HBx-based therapeutic vaccines that have been developed cannot accommodate differences between HBV genotypes. This research aims to design a therapeutic vaccine candidate based on the multi-epitope of HBc and HBx using reverse vaccinology (RV) and immunoinformatics approach. HBc and HBx sequences from 10 HBV genotypes were obtained from the NCBI Entrez Protein database. Epitopes were predicted from consensus sequences, which consisted of 13,610 HBc sequences and 12,333 HBx sequences. The study identified four cytotoxic T lymphocyte epitopes, two helper T lymphocyte epitopes, and five linear B lymphocyte that met the inclusion criteria. The vaccine candidate designed using cholera toxin subunit B and pan HLA DR-binding epitope adjuvants was predicted to be safe, antigenic, stable, and has a global population coverage of 99.43%. Molecular docking and molecular dynamics simulations demonstrated that the vaccine candidate could stably bind to B cell receptor, cytotoxic T cell receptor, and TLR4 for 100 ns. Immune response simulation indicated that it can induce antibody production and the proliferation of B and T cells. It can be concluded that RV and immunoinformatics successfully facilitated the design of a multi-epitope therapeutic vaccine candidate for CHB.
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Affiliation(s)
- Patricia Gita Naully
- School of Life Science and Technology, Institut Teknologi Bandung, Bandung, West Java, Indonesia
- Faculty of Health Sciences and Technology, Jenderal Achmad Yani University, Cimahi, West Java, Indonesia
| | - Marselina Irasonia Tan
- School of Life Science and Technology, Institut Teknologi Bandung, Bandung, West Java, Indonesia
| | - Husna Nugrahapraja
- School of Life Science and Technology, Institut Teknologi Bandung, Bandung, West Java, Indonesia
| | | | - Reza Aditama
- Biochemistry and Biomolecular Engineering Research Division, Faculty of Mathematics and Natural Sciences, Institut Teknologi Bandung, Bandung, West Java, Indonesia
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Bächer J, Allweiss L, Dandri M. SMC5/6-Mediated Transcriptional Regulation of Hepatitis B Virus and Its Therapeutic Potential. Viruses 2024; 16:1667. [PMID: 39599784 PMCID: PMC11598903 DOI: 10.3390/v16111667] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 10/16/2024] [Accepted: 10/23/2024] [Indexed: 11/29/2024] Open
Abstract
Cells have developed various mechanisms to counteract viral infections. In an evolutionary arms race, cells mobilize cellular restriction factors to fight off viruses, targeted by viral factors to facilitate their own replication. The hepatitis B virus (HBV) is a small dsDNA virus that causes acute and chronic infections of the liver. Its genome persists in the nuclei of infected hepatocytes as a covalently closed circular DNA (cccDNA) minichromosome, thus building up an episomal persistence reservoir. The chromosomal maintenance complex SMC5/6 acts as a restriction factor hindering cccDNA transcription, whereas the viral regulatory protein HBx targets SMC5/6 for proteasomal degradation, thus relieving transcriptional suppression of the HBV minichromosome. To date, no curative therapies are available for chronic HBV carriers. Knowledge of the factors regulating the cccDNA and the development of therapies involving silencing the minichromosome or specifically interfering with the HBx-SMC5/6 axis holds promise in achieving sustained viral control. Here, we summarize the current knowledge of the mechanism of SMC5/6-mediated HBV restriction. We also give an overview of SMC5/6 cellular functions and how this compares to the restriction of other DNA viruses. We further discuss the therapeutic potential of available and investigational drugs interfering with the HBx-SMC5/6 axis.
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Affiliation(s)
- Johannes Bächer
- I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (J.B.); (L.A.)
| | - Lena Allweiss
- I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (J.B.); (L.A.)
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, Germany
| | - Maura Dandri
- I. Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany; (J.B.); (L.A.)
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems Site, Germany
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Kumar A, Combe E, Mougené L, Zoulim F, Testoni B. Applications of CRISPR/Cas as a Toolbox for Hepatitis B Virus Detection and Therapeutics. Viruses 2024; 16:1565. [PMID: 39459899 PMCID: PMC11512240 DOI: 10.3390/v16101565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 09/24/2024] [Accepted: 09/27/2024] [Indexed: 10/28/2024] Open
Abstract
Hepatitis B virus (HBV) infection remains a significant global health challenge, leading to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Covalently closed circular DNA (cccDNA) and integrated HBV DNA are pivotal in maintaining viral persistence. Recent advances in CRISPR/Cas technology offer innovative strategies to inhibit HBV by directly targeting both cccDNA and integrated HBV DNA or indirectly by degrading HBV RNAs or targeting host proteins. This review provides a comprehensive overview of the latest advancements in using CRISPR/Cas to inhibit HBV, with a special highlight on newer non-double-strand (non-DSB) break approaches. Beyond the canonical use of CRISPR/Cas for target inhibition, we discuss additional applications, including HBV diagnosis and developing models to understand cccDNA biology, highlighting the diverse use of this technology in the HBV field.
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Affiliation(s)
- Anuj Kumar
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, 69008 Lyon, France; (A.K.); (E.C.); (L.M.); (F.Z.)
- The Lyon Hepatology Institute EVEREST, 69003 Lyon, France
| | - Emmanuel Combe
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, 69008 Lyon, France; (A.K.); (E.C.); (L.M.); (F.Z.)
- The Lyon Hepatology Institute EVEREST, 69003 Lyon, France
| | - Léa Mougené
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, 69008 Lyon, France; (A.K.); (E.C.); (L.M.); (F.Z.)
- The Lyon Hepatology Institute EVEREST, 69003 Lyon, France
| | - Fabien Zoulim
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, 69008 Lyon, France; (A.K.); (E.C.); (L.M.); (F.Z.)
- The Lyon Hepatology Institute EVEREST, 69003 Lyon, France
- Hepatology Department, Hospices Civils de Lyon (HCL), Croix-Rousse Hospital, 69004 Lyon, France
- University of Lyon, UMR_S1052, UCBL, 69008 Lyon, France
| | - Barbara Testoni
- Cancer Research Center of Lyon, INSERM U1052, CNRS UMR 5286, 69008 Lyon, France; (A.K.); (E.C.); (L.M.); (F.Z.)
- The Lyon Hepatology Institute EVEREST, 69003 Lyon, France
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10
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Pondé RADA, Amorim GDSP. Elimination of the hepatitis B virus: A goal, a challenge. Med Res Rev 2024; 44:2015-2034. [PMID: 38528684 DOI: 10.1002/med.22030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 01/24/2024] [Accepted: 02/05/2024] [Indexed: 03/27/2024]
Abstract
The hepatitis B elimination is a goal proposed by the WHO to be achieved by 2030 through the adoption of synergistic measures for the prevention and chronic HBV infection treatment. Complete cure is characterized by the HBV elimination from the body and is the goal of the chronic hepatitis B treatment, which once achieved, will enable the hepatitis B elimination. This, today, has been a scientific challenge. The difficulty in achieving a complete cure is due to the indefinite maintenance of a covalently closed episomal circular DNA (cccDNA) reservoir and the maintenance and persistence of an insufficient and dysfunctional immune response in chronically infected patients. Among the measures adopted to eliminate hepatitis B, two have the potential to directly interfere with the virus cycle, but with limited effect on HBV control. These are conventional vaccines-blocking transmission and antiviral therapy-inhibiting replication. Vaccines, despite their effectiveness in protecting against horizontal transmission and preventing mother-to-child vertical transmission, have no effect on chronic infection or potential to eliminate the virus. Treatment with antivirals suppresses viral replication, but has no curative effect, as it has no action against cccDNA. Therapeutic vaccines comprise an additional approach in the chronic infection treatment, however, they have only a modest effect on the immune system, enhancing it temporarily. This manuscript aims to address (1) the cccDNA persistence in the hepatocyte nucleus and the immune response dysfunction in chronically infected individuals as two primary factors that have hampered the treatment and HBV elimination from the human body; (2) the limitations of antiviral therapy and therapeutic vaccines, as strategies to control hepatitis B; and (3) the possibly promising therapeutic approaches for the complete cure and elimination of hepatitis B.
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Affiliation(s)
- Robério Amorim de Almeida Pondé
- Secretaria de Estado da Saúde-SES, Superintendência de Vigilância em Saúde-SUVISA/GO, Gerência de Vigilância Epidemiológica de Doenças Transmissíveis-GVEDT/Coordenação de Análises e Pesquisas-CAP, Goiânia, Goiás, Brazil
- Department of Microbiology, Laboratory of Human Virology, Institute of Tropical Pathology and Public Health, Federal University of Goiás, Goiânia, Goiás, Brazil
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Naully PG, Tan MI, Agustiningsih A, Sukowati C, Giri-Rachman EA. cccDNA epigenetic regulator as target for therapeutical vaccine development against hepatitis B. Ann Hepatol 2024; 30:101533. [PMID: 39147134 DOI: 10.1016/j.aohep.2024.101533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/21/2024] [Accepted: 08/01/2024] [Indexed: 08/17/2024]
Abstract
Chronic hepatitis B virus infection (CHB) remains a global health concern, with currently available antiviral therapies demonstrating limited effectiveness in preventing hepatocellular carcinoma (HCC) development. Two primary challenges in CHB treatment include the persistence of the minichromosome, covalently closed circular DNA (cccDNA) of the hepatitis B virus (HBV), and the failure of the host immune response to eliminate cccDNA. Recent findings indicate several host and HBV proteins involved in the epigenetic regulation of cccDNA, including HBV core protein (HBc) and HBV x protein (HBx). Both proteins might contribute to the stability of the cccDNA minichromosome and interact with viral and host proteins to support transcription. One potential avenue for CHB treatment involves the utilization of therapeutic vaccines. This paper explores HBV antigens suitable for epigenetic manipulation of cccDNA, elucidates their mechanisms of action, and evaluates their potential as key components of epigenetically-driven vaccines for CHB therapy. Molecular targeted agents with therapeutic vaccines offer a promising strategy for addressing CHB by targeting the virus and enhancing the host's immunological response. Despite challenges, the development of these vaccines provides new hope for CHB patients by emphasizing the need for HBV antigens that induce effective immune responses without causing T cell exhaustion.
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Affiliation(s)
- Patricia Gita Naully
- School of Life Science and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia; Faculty of Health Sciences and Technology, Jenderal Achmad Yani University, Cimahi 40525, Indonesia
| | - Marselina Irasonia Tan
- School of Life Science and Technology, Institut Teknologi Bandung, Bandung 40132, Indonesia
| | - Agustiningsih Agustiningsih
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia
| | - Caecilia Sukowati
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia (BRIN), Jakarta Pusat 10340, Indonesia; Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, AREA Science Park, Basovizza 34049, Trieste, Italy
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Zeng Q, Ren Y, Wang Y, Yang J, Qin Y, Yang L, Zheng X, Huang A, Fan H. The nuclear matrix protein HNRNPU restricts hepatitis B virus transcription by promoting OAS3-based activation of host innate immunity. J Med Virol 2024; 96:e29805. [PMID: 39011773 DOI: 10.1002/jmv.29805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 05/24/2024] [Accepted: 07/04/2024] [Indexed: 07/17/2024]
Abstract
Heterogeneous nuclear protein U (HNRNPU) plays a pivotal role in innate immunity by facilitating chromatin opening to activate immune genes during host defense against viral infection. However, the mechanism by which HNRNPU is involved in Hepatitis B virus (HBV) transcription regulation through mediating antiviral immunity remains unknown. Our study revealed a significant decrease in HNRNPU levels during HBV transcription, which depends on HBx-DDB1-mediated degradation. Overexpression of HNRNPU suppressed HBV transcription, while its knockdown effectively promoted viral transcription, indicating HNRNPU as a novel host restriction factor for HBV transcription. Mechanistically, HNRNPU inhibits HBV transcription by activating innate immunity through primarily the positive regulation of the interferon-stimulating factor 2'-5'-oligoadenylate synthetase 3, which mediates an ribonuclease L-dependent mechanism to enhance innate immune responses. This study offers new insights into the host immune regulation of HBV transcription and proposes potential targets for therapeutic intervention against HBV infection.
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Affiliation(s)
- Qiqi Zeng
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Yi Ren
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Yanyan Wang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Jiaxin Yang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Yi Qin
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Lijuan Yang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Xinrui Zheng
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Ailong Huang
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Hui Fan
- The Key Laboratory of Molecular Biology of Infectious Diseases designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
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13
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Niu AX, Liu J, Zhu CW. Progress in research of ubiquitination modification of hepatitis B surface antigen. WORLD CHINESE JOURNAL OF DIGESTOLOGY 2024; 32:333-338. [DOI: 10.11569/wcjd.v32.i5.333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
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14
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Gómez-Moreno A, Ploss A. Mechanisms of Hepatitis B Virus cccDNA and Minichromosome Formation and HBV Gene Transcription. Viruses 2024; 16:609. [PMID: 38675950 PMCID: PMC11054251 DOI: 10.3390/v16040609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/11/2024] [Accepted: 04/13/2024] [Indexed: 04/28/2024] Open
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 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.
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Affiliation(s)
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
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15
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Wang Z, Liu N, Yang Y, Tu Z. The novel mechanism facilitating chronic hepatitis B infection: immunometabolism and epigenetic modification reprogramming. Front Immunol 2024; 15:1349867. [PMID: 38288308 PMCID: PMC10822934 DOI: 10.3389/fimmu.2024.1349867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 01/02/2024] [Indexed: 01/31/2024] Open
Abstract
Hepatitis B Virus (HBV) infections pose a global public health challenge. Despite extensive research on this disease, the intricate mechanisms underlying persistent HBV infection require further in-depth elucidation. Recent studies have revealed the pivotal roles of immunometabolism and epigenetic reprogramming in chronic HBV infection. Immunometabolism have identified as the process, which link cell metabolic status with innate immunity functions in response to HBV infection, ultimately contributing to the immune system's inability to resolve Chronic Hepatitis B (CHB). Within hepatocytes, HBV replication leads to a stable viral covalently closed circular DNA (cccDNA) minichromosome located in the nucleus, and epigenetic modifications in cccDNA enable persistence of infection. Additionally, the accumulation or depletion of metabolites not only directly affects the function and homeostasis of immune cells but also serves as a substrate for regulating epigenetic modifications, subsequently influencing the expression of antiviral immune genes and facilitating the occurrence of sustained HBV infection. The interaction between immunometabolism and epigenetic modifications has led to a new research field, known as metabolic epigenomics, which may form a mutually reinforcing relationship with CHB. Herein, we review the recent studies on immunometabolism and epigenetic reprogramming in CHB infection and discuss the potential mechanisms of persistent HBV infection. A deeper understanding of these mechanisms will offer novel insights and targets for intervention strategies against chronic HBV infection, thereby providing new hope for the treatment of related diseases.
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Affiliation(s)
- Zhengmin Wang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Nan Liu
- Institute of Epigenetic Medicine, First Hospital of Jilin University, Changchun, China
| | - Yang Yang
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Zhengkun Tu
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
- Institute of Liver Diseases, The First Hospital of Jilin University, Changchun, Jilin, China
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16
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Sartorius K, Sartorius B, Winkler C, Chuturgoon A, Shen TW, Zhao Y, An P. Serum microRNA Profiles and Pathways in Hepatitis B-Associated Hepatocellular Carcinoma: A South African Study. Int J Mol Sci 2024; 25:975. [PMID: 38256049 PMCID: PMC10815595 DOI: 10.3390/ijms25020975] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 01/24/2024] Open
Abstract
The incidence and mortality of hepatocellular carcinoma (HCC) in Sub-Saharan Africa is projected to increase sharply by 2040 against a backdrop of limited diagnostic and therapeutic options. Two large South African-based case control studies have developed a serum-based miRNome for Hepatitis B-associated hepatocellular carcinoma (HBV-HCC), as well as identifying their gene targets and pathways. Using a combination of RNA sequencing, differential analysis and filters including a unique molecular index count (UMI) ≥ 10 and log fold change (LFC) range > 2: <-0.5 (p < 0.05), 91 dysregulated miRNAs were characterized including 30 that were upregulated and 61 were downregulated. KEGG analysis, a literature review and other bioinformatic tools identified the targeted genes and HBV-HCC pathways of the top 10 most dysregulated miRNAs. The results, which are based on differentiating miRNA expression of cases versus controls, also develop a serum-based miRNA diagnostic panel that indicates 95.9% sensitivity, 91.0% specificity and a Youden Index of 0.869. In conclusion, the results develop a comprehensive African HBV-HCC miRNome that potentially can contribute to RNA-based diagnostic and therapeutic options.
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Affiliation(s)
- Kurt Sartorius
- Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg 2001, South Africa
- School of Laboratory Medicine and Molecular Sciences, University of Kwazulu-Natal, Durban 4041, South Africa;
- Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL 32224, USA
| | - Benn Sartorius
- School of Public Health, University of Queensland, Brisbane, QLD 4102, Australia
| | - Cheryl Winkler
- Centre for Cancer Research, Basic Research Laboratory, National Cancer Institute, Frederick Natifol Laboratory for Cancer Research, National Institute of Health, Frederick, MD 21701, USA
| | - Anil Chuturgoon
- School of Laboratory Medicine and Molecular Sciences, University of Kwazulu-Natal, Durban 4041, South Africa;
| | - Tsai-Wei Shen
- CCR-SF Bioinformatics Group, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Yongmei Zhao
- CCR-SF Bioinformatics Group, Frederick National Laboratory for Cancer Research, Frederick, MD 21701, USA
| | - Ping An
- Centre for Cancer Research, Basic Research Laboratory, National Cancer Institute, Frederick Natifol Laboratory for Cancer Research, National Institute of Health, Frederick, MD 21701, USA
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17
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Ming T, Yuting L, Meiling D, Shengtao C, Jihua R, Hui Z, Wanjin C, Dian L, Tingting G, Juan C, Zhenzhen Z. Chromatin binding protein HMGN1 promotes HBV cccDNA transcription and replication by regulating the phosphorylation of histone 3. Antiviral Res 2024; 221:105796. [PMID: 38181856 DOI: 10.1016/j.antiviral.2024.105796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 01/02/2024] [Accepted: 01/02/2024] [Indexed: 01/07/2024]
Abstract
BACKGROUND AND AIMS Direct elimination of cccDNA remains a formidable obstacle due to the persistent and stable presence of cccDNA in hepatocyte nuclei. The silencing of cccDNA transcription enduringly is one of alternative strategies in the treatment of hepatitis B. Protein binding to cccDNA plays an important role in its transcriptional regulation; thus, the identification of key factors involved in this process is of great importance. APPROACHES AND RESULTS In the present study, high mobility group nucleosome binding domain 1 (HMGN1) was screened out based on our biotin-avidin enrichment system. First, chromatin immunoprecipitation and fluorescent in situ hybridization assays confirmed the binding of HMGN1 with cccDNA in the nucleus. Second, functional experiments in HBV-infected cells showed that the promoting effect of HMGN1 on HBV transcription and replication depended on the functional region of the nucleosomal binding domain, while transfection of the HMGN1 mutant showed no influence on HBV compared with the vector. Third, further mechanistic exploration revealed that the silencing of HMGN1 increased the level of phosphorylase CLK2 and promoted H3 phosphorylation causing the reduced accessibility of cccDNA. Moreover, silenced HMGN1 was mimicked in HBV (r) cccDNA mouse model of HBV infection in vivo. The results showed that silencing HMGN1 inhibited HBV replication in vivo. CONCLUSIONS In summary, our study identified that a host protein can bind to cccDNA and promote its transcription, providing a candidate strategy for anti-HBV targeting to interfere with the transcriptional activity of cccDNA microchromosomes.
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Affiliation(s)
- Tan Ming
- Chongqing Key Laboratory of Child Infection and Immunity, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Department of Infectious Diseases, The Children's Hospital of Chongqing Medical University, Chongqing Medical University Chongqing, China; The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Liu Yuting
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Dong Meiling
- Department of Clinical Laboratory, Infectious Diseases Hospital of Nanchang University, Nanchang, China
| | - Cheng Shengtao
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Ren Jihua
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Zhang Hui
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Chen Wanjin
- Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Li Dian
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Gao Tingting
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China
| | - Chen Juan
- The Key Laboratory of Molecular Biology of Infectious Diseases Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, China; Key Laboratory of Laboratory Medical Diagnostics, Chinese Ministry of Education, Chongqing Medical University, Chongqing, China.
| | - Zhang Zhenzhen
- Chongqing Key Laboratory of Child Infection and Immunity, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Department of Infectious Diseases, The Children's Hospital of Chongqing Medical University, Chongqing Medical University Chongqing, China.
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18
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Kim ES, Guo H. Hepatitis B Virus Covalently Closed Circular DNA Chromatin Immunoprecipitation Assay. Methods Mol Biol 2024; 2837:23-32. [PMID: 39044072 PMCID: PMC11413761 DOI: 10.1007/978-1-0716-4027-2_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/25/2024]
Abstract
Hepatitis B virus (HBV) is an obligate human hepatotropic DNA virus causing both transient and chronic infection. The livers of chronic hepatitis B patients have a high risk of developing liver fibrosis, cirrhosis, and hepatocellular carcinoma. The nuclear episomal viral DNA intermediate, covalently closed circular DNA (cccDNA), forms a highly stable complex with host and viral proteins to serve as a transcription template and support HBV infection chronicity. Thus, characterization of the composition and dynamics of cccDNA nucleoprotein complexes providing cccDNA stability and gene regulation is of high importance for both basic and medical research. The presented method for chromatin immunoprecipitation coupled with qPCR (ChIP-qPCR) allows to assess provisional physical interaction of the protein of interest (POI) with cccDNA using POI-specific antibody, the level of enrichment of a POI on cccDNA versus control/background is characterized quantitatively using qPCR.
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Affiliation(s)
- Elena S Kim
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
| | - Haitao Guo
- Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Cancer Virology Program, UPMC Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
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19
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Thompson AJ, Jackson K, Bonanzinga S, Hall SA, Hume S, Burns GS, Sundararajan V, Ratnam D, Levy MT, Lubel J, Nicoll AJ, Strasser SI, Sievert W, Desmond PV, Ngu MC, Sinclair M, Meredith C, Matthews G, Revill PA, Littlejohn M, Bowden DS, Canchola JA, Torres J, Siew P, Lau J, La Brot B, Kuchta A, Visvanathan K. Baseline serum HBV RNA is associated with the risk of hepatitis flare after stopping nucleoside analog therapy in HBeAg-negative participants. Hepatol Commun 2023; 7:e0188. [PMID: 37459199 PMCID: PMC10351945 DOI: 10.1097/hc9.0000000000000188] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 04/11/2023] [Indexed: 07/20/2023] Open
Abstract
BACKGROUND AND AIMS HBV RNA in peripheral blood reflects HBV cccDNA transcriptional activity and may predict clinical outcomes. The prospective Melbourne HBV-STOP trial studied nucleot(s)ide analog discontinuation in HBeAg-negative non-cirrhotic participants with long-term virological suppression. Ninety-six weeks after stopping treatment, the proportion of participants with virological relapse (HBV DNA > 2000 IU/mL), biochemical relapse (ALT > 2 × ULN and HBV DNA > 2000 IU/mL), or hepatitis flare (ALT > 5 × ULN and HBV DNA > 2000 IU/mL) was 89%, 58%, and 38%, respectively. We evaluated the ability of serum HBV RNA levels to predict these outcomes. APPROACH RESULTS HBV RNA levels were measured using the Roche cobas 6800/8800 HBV RNA Investigational Assay. Sixty-five participants had baseline and longitudinal off-treatment specimens available for RNA testing. HBV RNA was detectable at baseline in 25% of participants and was associated with a higher risk of biochemical relapse (81% vs. 51%, p value 0.04) and hepatitis flare (63% vs. 31%, p value 0.04). Participants who had undetectable serum HBV RNA as well as HBsAg ≤ 100 IU/mL at baseline were less likely to experience virological relapse (4 of 9, 44%) than participants with detectable HBV RNA and HBsAg level > 100 IU/mL (15/15, 100%; p value 0.0009). Off-treatment levels of HBV RNA were correlated with HBV DNA and were associated with the risk of hepatitis flare. CONCLUSIONS Serum HBV RNA may be a useful biomarker for guiding clinical decision-making before stopping nucleot(s)ide analog therapy. Baseline HBV RNA and HBsAg levels are associated with the risk of clinical relapse, hepatitis flare, and disease remission off-treatment.
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Affiliation(s)
- Alexander J. Thompson
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
| | - Kathy Jackson
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Sara Bonanzinga
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Sam A.L. Hall
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
| | - Simon Hume
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
| | - Gareth S. Burns
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
| | - Vijaya Sundararajan
- Immunology Research Centre, Department of Medicine (St Vincent’s Hospital), The University of Melbourne, Melbourne, Victoria, Australia
- Department of Public Health, La Trobe University, Melbourne, Victoria, Australia
| | - Dilip Ratnam
- Gastroenterology & Hepatology Unit, Monash Health, Melbourne, Victoria, Australia
- Monash University, Melbourne, Victoria, Australia
| | - Miriam T. Levy
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, Australia
| | - John Lubel
- Department of Gastroenterology, Alfred Health, Melbourne, Victoria, Australia
- Central Clinical School, Monash University, The Alfred Centre, Melbourne, Victoria, Australia
| | - Amanda J. Nicoll
- Gastroenterology Department of Eastern Health, Melbourne, Victoria, Australia
| | - Simone I. Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, Australia
- University of Sydney, Sydney, Australia
| | - William Sievert
- Gastroenterology & Hepatology Unit, Monash Health, Melbourne, Victoria, Australia
- Monash University, Melbourne, Victoria, Australia
| | - Paul V. Desmond
- Department of Gastroenterology, St Vincent’s Hospital Melbourne, Melbourne, Victoria, Australia
| | - Meng C. Ngu
- Department of Gastroenterology, Concord Repatriation General Hospital, Sydney, Australia
| | - Marie Sinclair
- Department of Gastroenterology and Hepatology, Austin Health, Melbourne, Victoria, Australia
| | | | - Gail Matthews
- Department of Infectious Disease, St Vincent’s Hospital Sydney, Sydney, Australia
| | - Peter A. Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - D. Scott Bowden
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | | | - Jason Torres
- Roche Molecular Systems, Inc., Pleasanton, California, USA
| | - Philip Siew
- Roche Diagnostics, Pty Ltd, North Ryde, Australia
| | - Jasmin Lau
- Roche Molecular Systems, Inc., Pleasanton, California, USA
| | | | - Alison Kuchta
- Roche Molecular Systems, Inc., Pleasanton, California, USA
| | - Kumar Visvanathan
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital, Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
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20
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Yao Q, Peng B, Li C, Li X, Chen M, Zhou Z, Tang D, He J, Wu Y, Sun Y, Li W. SLF2 Interacts with the SMC5/6 Complex to Direct Hepatitis B Virus Episomal DNA to Promyelocytic Leukemia Bodies for Transcriptional Repression. J Virol 2023:e0032823. [PMID: 37338350 PMCID: PMC10373549 DOI: 10.1128/jvi.00328-23] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 05/23/2023] [Indexed: 06/21/2023] Open
Abstract
Hepatitis B virus (HBV) chronically infects approximately 300 million people worldwide, and permanently repressing transcription of covalently closed circular DNA (cccDNA), the episomal viral DNA reservoir, is an attractive approach toward curing HBV. However, the mechanism underlying cccDNA transcription is only partially understood. In this study, by illuminating cccDNA of wild-type HBV (HBV-WT) and transcriptionally inactive HBV that bears a deficient HBV X gene (HBV-ΔX), we found that the HBV-ΔX cccDNA more frequently colocalizes with promyelocytic leukemia (PML) bodies than that of HBV-WT cccDNA. A small interfering RNA (siRNA) screen targeting 91 PML body-related proteins identified SMC5-SMC6 localization factor 2 (SLF2) as a host restriction factor of cccDNA transcription, and subsequent studies showed that SLF2 mediates HBV cccDNA entrapment in PML bodies by interacting with the SMC5/6 complex. We further showed that the region of SLF2 comprising residues 590 to 710 interacts with and recruits the SMC5/6 complex to PML bodies, and the C-terminal domain of SLF2 containing this region is necessary for repression of cccDNA transcription. Our findings shed new light on cellular mechanisms that inhibit HBV infection and lend further support for targeting the HBx pathway to repress HBV activity. IMPORTANCE Chronic HBV infection remains a major public health problem worldwide. Current antiviral treatments rarely cure the infection, as they cannot clear the viral reservoir, cccDNA, in the nucleus. Therefore, permanently silencing HBV cccDNA transcription represents a promising approach for a cure of HBV infection. Our study provides new insights into the cellular mechanisms that restrict HBV infection, revealing the role of SLF2 in directing HBV cccDNA to PML bodies for transcriptional repression. These findings have important implications for the development of antiviral therapies against HBV.
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Affiliation(s)
- Qiyan Yao
- Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
- National Institute of Biological Sciences, Beijing, China
| | - Bo Peng
- National Institute of Biological Sciences, Beijing, China
| | - Cong Li
- National Institute of Biological Sciences, Beijing, China
| | - Xuelei Li
- National Institute of Biological Sciences, Beijing, China
- School of Life Sciences, Tsinghua University, Beijing, China
| | - Mingyi Chen
- National Institute of Biological Sciences, Beijing, China
| | - Zhongmin Zhou
- National Institute of Biological Sciences, Beijing, China
| | - Dingbin Tang
- National Institute of Biological Sciences, Beijing, China
| | - Jiabei He
- National Institute of Biological Sciences, Beijing, China
| | - Yumeng Wu
- National Institute of Biological Sciences, Beijing, China
| | - Yinyan Sun
- National Institute of Biological Sciences, Beijing, China
| | - Wenhui Li
- National Institute of Biological Sciences, Beijing, China
- Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China
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21
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Salama II, Sami SM, Salama SI, Abdel-Latif GA, Shaaban FA, Fouad WA, Abdelmohsen AM, Raslan HM. Current and novel modalities for management of chronic hepatitis B infection. World J Hepatol 2023; 15:585-608. [PMID: 37305370 PMCID: PMC10251278 DOI: 10.4254/wjh.v15.i5.585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 03/13/2023] [Accepted: 04/12/2023] [Indexed: 05/24/2023] Open
Abstract
Over 296 million people are estimated to have chronic hepatitis B viral infection (CHB), and it poses unique challenges for elimination. CHB is the result of hepatitis B virus (HBV)-specific immune tolerance and the presence of covalently closed circular DNA as mini chromosome inside the nucleus and the integrated HBV. Serum hepatitis B core-related antigen is the best surrogate marker for intrahepatic covalently closed circular DNA. Functional HBV "cure" is the durable loss of hepatitis B surface antigen (HBsAg), with or without HBsAg seroconversion and undetectable serum HBV DNA after completing a course of treatment. The currently approved therapies are nucleos(t)ide analogues, interferon-alpha, and pegylated-interferon. With these therapies, functional cure can be achieved in < 10% of CHB patients. Any variation to HBV or the host immune system that disrupts the interaction between them can lead to reactivation of HBV. Novel therapies may allow efficient control of CHB. They include direct acting antivirals and immunomodulators. Reduction of the viral antigen load is a crucial factor for success of immune-based therapies. Immunomodulatory therapy may lead to modulation of the host immune system. It may enhance/restore innate immunity against HBV (as toll-like-receptors and cytosolic retinoic acid inducible gene I agonist). Others may induce adaptive immunity as checkpoint inhibitors, therapeutic HBV vaccines including protein (HBsAg/preS and hepatitis B core antigen), monoclonal or bispecific antibodies and genetically engineered T cells to generate chimeric antigen receptor-T or T-cell receptor-T cells and HBV-specific T cells to restore T cell function to efficiently clear HBV. Combined therapy may successfully overcome immune tolerance and lead to HBV control and cure. Immunotherapeutic approaches carry the risk of overshooting immune responses causing uncontrolled liver damage. The safety of any new curative therapies should be measured in relation to the excellent safety of currently approved nucleos(t)ide analogues. Development of novel antiviral and immune modulatory therapies should be associated with new diagnostic assays used to evaluate the effectiveness or to predict response.
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Affiliation(s)
- Iman Ibrahim Salama
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt.
| | - Samia M Sami
- Department of Child Health, National Research Centre, Giza 12411, Dokki, Egypt
| | - Somaia I Salama
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Ghada A Abdel-Latif
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Fatma A Shaaban
- Department of Child Health, National Research Centre, Giza 12411, Dokki, Egypt
| | - Walaa A Fouad
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Aida M Abdelmohsen
- Department of Community Medicine Research, National Research Centre, Giza 12411, Dokki, Egypt
| | - Hala M Raslan
- Department of Internal Medicine, National Research Centre, Giza 12411, Dokki, Egypt
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22
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Kefayati F, Karimi Babaahmadi A, Mousavi T, Hodjat M, Abdollahi M. Epigenotoxicity: a danger to the future life. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART A, TOXIC/HAZARDOUS SUBSTANCES & ENVIRONMENTAL ENGINEERING 2023; 58:382-411. [PMID: 36942370 DOI: 10.1080/10934529.2023.2190713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 02/17/2023] [Accepted: 02/21/2023] [Indexed: 06/18/2023]
Abstract
Environmental toxicants can regulate gene expression in the absence of DNA mutations via epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs' (ncRNAs). Here, all three epigenetic modifications for seven important categories of diseases and the impact of eleven main environmental factors on epigenetic modifications were discussed. Epigenetic-related mechanisms are among the factors that could explain the root cause of a wide range of common diseases. Its overall impression on the development of diseases can help us diagnose and treat diseases, and besides, predict transgenerational and intergenerational effects. This comprehensive article attempted to address the relationship between environmental factors and epigenetic modifications that cause diseases in different categories. The studies main gap is that the precise role of environmentally-induced epigenetic alterations in the etiology of the disorders is unknown; thus, still more well-designed researches need to be accomplished to fill this gap. The present review aimed to first summarize the adverse effect of certain chemicals on the epigenome that may involve in the onset of particular disease based on in vitro and in vivo models. Subsequently, the possible adverse epigenetic changes that can lead to many human diseases were discussed.
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Affiliation(s)
- Farzaneh Kefayati
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Atoosa Karimi Babaahmadi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Taraneh Mousavi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahshid Hodjat
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
- Dental Research Center, Dentistry Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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García-Crespo C, Francisco-Recuero I, Gallego I, Camblor-Murube M, Soria ME, López-López A, de Ávila AI, Madejón A, García-Samaniego J, Domingo E, Sánchez-Pacheco A, Perales C. Hepatitis C virus fitness can influence the extent of infection-mediated epigenetic modifications in the host cells. Front Cell Infect Microbiol 2023; 13:1057082. [PMID: 36992689 PMCID: PMC10040758 DOI: 10.3389/fcimb.2023.1057082] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 02/28/2023] [Indexed: 03/14/2023] Open
Abstract
IntroductionCellular epigenetic modifications occur in the course of viral infections. We previously documented that hepatitis C virus (HCV) infection of human hepatoma Huh-7.5 cells results in a core protein-mediated decrease of Aurora kinase B (AURKB) activity and phosphorylation of Serine 10 in histone H3 (H3Ser10ph) levels, with an affectation of inflammatory pathways. The possible role of HCV fitness in infection-derived cellular epigenetic modifications is not known.MethodsHere we approach this question using HCV populations that display a 2.3-fold increase in general fitness (infectious progeny production), and up to 45-fold increase of the exponential phase of intracellular viral growth rate, relative to the parental HCV population.ResultsWe show that infection resulted in a HCV fitness-dependent, average decrease of the levels of H3Ser10ph, AURKB, and histone H4 tri-methylated at Lysine 20 (H4K20m3) in the infected cell population. Remarkably, the decrease of H4K20m3, which is a hallmark of cellular transformation, was significant upon infection with high fitness HCV but not upon infection with basal fitness virus.DiscussionHere we propose two mechanisms ─which are not mutually exclusive─ to explain the effect of high viral fitness: an early advance in the number of infected cells, or larger number of replicating RNA molecules per cell. The implications of introducing HCV fitness as an influence in virus-host interactions, and for the course of liver disease, are warranted. Emphasis is made in the possibility that HCV-mediated hepatocellular carcinoma may be favoured by prolonged HCV infection of a human liver, a situation in which viral fitness is likely to increase.
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Affiliation(s)
- Carlos García-Crespo
- Department of Interactions with the Environment, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Irene Francisco-Recuero
- Department de Biochemistry, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | - Isabel Gallego
- Department of Interactions with the Environment, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Marina Camblor-Murube
- Department de Biochemistry, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | - María Eugenia Soria
- Department of Interactions with the Environment, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain
| | - Ana López-López
- Department de Biochemistry, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
| | - Ana Isabel de Ávila
- Department of Interactions with the Environment, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Antonio Madejón
- Department of Interactions with the Environment, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain
- Hepatology Unit Hospital Universitario La Paz/Carlos III, Instituto de Investigación Sanitaria “La Paz”, Madrid, Spain
| | - Javier García-Samaniego
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Hepatology Unit Hospital Universitario La Paz/Carlos III, Instituto de Investigación Sanitaria “La Paz”, Madrid, Spain
| | - Esteban Domingo
- Department of Interactions with the Environment, Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Consejo Superior de Investigaciones Científicas (CSIC), Campus de Cantoblanco, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- *Correspondence: Esteban Domingo, ; Aurora Sánchez-Pacheco, ; Celia Perales,
| | - Aurora Sánchez-Pacheco
- Department de Biochemistry, UAM, Instituto de Investigaciones Biomédicas Alberto Sols, CSIC-UAM, Madrid, Spain
- *Correspondence: Esteban Domingo, ; Aurora Sánchez-Pacheco, ; Celia Perales,
| | - Celia Perales
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
- Department of Clinical Microbiology, IIS-Fundación Jiménez Díaz, UAM, Madrid, Spain
- Department of Molecular and Cell Biology, Centro Nacional de Biotecnología (CNB-CSIC), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain
- *Correspondence: Esteban Domingo, ; Aurora Sánchez-Pacheco, ; Celia Perales,
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Zhang J, Hu C, Xie X, Qi L, Li C, Li S. Immune Checkpoint Inhibitors in HBV-Caused Hepatocellular Carcinoma Therapy. Vaccines (Basel) 2023; 11:vaccines11030614. [PMID: 36992198 DOI: 10.3390/vaccines11030614] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 02/28/2023] [Accepted: 03/06/2023] [Indexed: 03/11/2023] Open
Abstract
Hepatitis B virus (HBV) infection is the main risk factor for the development of hepatocellular carcinoma (HCC), the most common type of liver cancer, with high incidence and mortality worldwide. Surgery, liver transplantation, and ablation therapies have been used to treat early HBV-caused HCC (HBV-HCC); meanwhile, in the advanced stage, chemoradiotherapy and drug-targeted therapy are regularly considered, but with limited efficacy. Recently, immunotherapies, such as tumor vaccine therapy, adoptive cell transfer therapy, and immune checkpoint inhibitor therapy, have demonstrated promising efficacy in cancer treatment. In particular, immune checkpoint inhibitors can successfully prevent tumors from achieving immune escape and promote an anti-tumor response, thereby boosting the therapeutic effect in HBV-HCC. However, the advantages of immune checkpoint inhibitors in the treatment of HBV-HCC remain to be exploited. Here, we describe the basic characteristics and development of HBV-HCC and introduce current treatment strategies for HBV-HCC. Of note, we review the principles of immune checkpoint molecules, such as programmed cell death protein 1(PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) in HBV-HCC, as well as related inhibitors being considered in the clinic. We also discuss the benefits of immune checkpoint inhibitors in the treatment of HBV-HCC and the efficacy of those inhibitors in HCC with various etiologies, aiming to provide insights into the use of immune checkpoint inhibitors for the treatment of HBV-HCC.
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Affiliation(s)
- Jin Zhang
- School of Medicine, Chongqing University, Chongqing 400044, China
| | - Changwei Hu
- School of Medicine, Chongqing University, Chongqing 400044, China
| | - Xiaoxiao Xie
- School of Medicine, Chongqing University, Chongqing 400044, China
| | - Linzhi Qi
- School of Medicine, Chongqing University, Chongqing 400044, China
| | - Chuanzhou Li
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Shangze Li
- School of Medicine, Chongqing University, Chongqing 400044, China
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Durantel D. Therapies against chronic hepatitis B infections: The times they are a-changin', but the changing is slow! Antiviral Res 2023; 210:105515. [PMID: 36603773 DOI: 10.1016/j.antiviral.2022.105515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 01/04/2023]
Abstract
PREAMBULAR NOTA BENE As a tribute to Dr Mike Bray, the following review of literature willbe mainly based on published data andconcepts, but will also contain my personal views, and in this respect could be more considered as a bioassay. Even though a cost-effective and excellent prophylactic vaccine exists since many years to protect against hepatitis B virus (HBV) infection, academic-researcher/drug-developers/stakeholders are still busy with the R&D of novel therapies that could eventually have an impact on its worldwide incidence. The Taiwanese experience have univocally demonstrated the effectiveness of constrained national HBV prophylactic vaccination programs to prevent the most dramatic HBV-induced end-stage liver disease, which is hepatocellular carcinoma; but yet the number of individuals chronically infected with the virus, for whom the existing prophylactic vaccine is no longer useful, remains high, with around 300 million individuals around the globe. In this review/bioassay, recent findings and novel concepts on prospective therapies against HBV infections will be discussed; yet it does not have the pretention to be exhaustive, as "pure immunotherapeutic concepts" will be mainly let aside (or referred to other reviews) due to a lack of expertise of this writer, but also due to the lack of, or incremental, positive results in clinical trials as-off today with these approaches.
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Affiliation(s)
- David Durantel
- Centre International de Recherche en Infectiologie (CIRI), INSERM U1111, UMR_5308 CNRS-Université de Lyon (UCBL1), ENS de Lyon, Lyon, 69007, France.
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26
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The scientific basis of combination therapy for chronic hepatitis B functional cure. Nat Rev Gastroenterol Hepatol 2023; 20:238-253. [PMID: 36631717 DOI: 10.1038/s41575-022-00724-5] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/24/2022] [Indexed: 01/13/2023]
Abstract
Functional cure of chronic hepatitis B (CHB) - or hepatitis B surface antigen (HBsAg) loss after 24 weeks off therapy - is now the goal of treatment, but is rarely achieved with current therapy. Understanding the hepatitis B virus (HBV) life cycle and immunological defects that lead to persistence can identify targets for novel therapy. Broadly, treatments fall into three categories: those that reduce viral replication, those that reduce antigen load and immunotherapies. Profound viral suppression alone does not achieve quantitative (q)HBsAg reduction or HBsAg loss. Combining nucleos(t)ide analogues and immunotherapy reduces qHBsAg levels and induces HBsAg loss in some patients, particularly those with low baseline qHBsAg levels. Even agents that are specifically designed to reduce viral antigen load might not be able to achieve sustained HBsAg loss when used alone. Thus, rationale exists for the use of combinations of all three therapy types. Monitoring during therapy is important not just to predict HBsAg loss but also to understand mechanisms of HBsAg loss using viral and immunological biomarkers, and in selected cases intrahepatic sampling. We consider various paths to functional cure of CHB and the need to individualize treatment of this heterogeneous infection until a therapeutic avenue for all patients with CHB is available.
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Bhattacharya A. Epigenetic modifications and regulations in gastrointestinal diseases. EPIGENETICS IN ORGAN SPECIFIC DISORDERS 2023:497-543. [DOI: 10.1016/b978-0-12-823931-5.00005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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28
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Yin GQ, Chen KP, Gu XC. Heterogeneity of immune control in chronic hepatitis B virus infection: Clinical implications on immunity with interferon-α treatment and retreatment. World J Gastroenterol 2022; 28:5784-5800. [PMID: 36353205 PMCID: PMC9639659 DOI: 10.3748/wjg.v28.i40.5784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 09/08/2022] [Accepted: 10/10/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health issue. Interferon-α (IFN-α) treatment has been used to treat hepatitis B for over 20 years, but fewer than 5% of Asians receiving IFN-α treatment achieve functional cure. Thus, IFN-α retreatment has been introduced to enhance antiviral function. In recent years, immune-related studies have found that the complex interactions between immune cells and cytokines could modulate immune response networks, in-cluding both innate and adaptive immunity, triggering immune responses that control HBV replication. However, heterogeneity of the immune system to control HBV infection, particularly HBV-specific CD8+ T cell heterogeneity, has consequ-ential effects on T cell-based immunotherapy for treating HBV infection. Altogether, the host’s genetic variants, negative-feedback regulators and HBV components affecting the immune system's ability to control HBV. In this study, we reviewed the literature on potential immune mechanisms affecting the immune control of HBV and the clinical effects of IFN-α treatment and retreatment.
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Affiliation(s)
- Guo-Qing Yin
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ke-Ping Chen
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Xiao-Chun Gu
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
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29
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Yang Z, Sun B, Xiang J, Wu H, Kan S, Hao M, Chang L, Liu H, Wang D, Liu W. Role of epigenetic modification in interferon treatment of hepatitis B virus infection. Front Immunol 2022; 13:1018053. [PMID: 36325353 PMCID: PMC9618964 DOI: 10.3389/fimmu.2022.1018053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Accepted: 09/27/2022] [Indexed: 11/28/2022] Open
Abstract
Human hepatitis B virus (HBV) is a small, enveloped DNA virus that causes acute and chronic hepatitis. Chronic hepatitis B (CHB) is associated with hepatocellular carcinoma pathogenesis. Interferons (IFNs) have been used for the treatment of CHB for a long time, with advantages including less treatment duration and sustained virological response. Presently, various evidence suggests that epigenetic modification of the viral covalently closed circular DNA (cccDNA) and the host genome is crucial for the regulation of viral activity. This modification includes histone acetylation, DNA methylation, N6-methyladenosine, and non-coding RNA modification. IFN treatment for CHB can stimulate multiple IFN-stimulated genes for inhibiting virus replication. IFNs can also affect the HBV life cycle through epigenetic modulation. In this review, we summarized the different mechanisms through which IFN-α inhibits HBV replication, including epigenetic regulation. Moreover, the mechanisms underlying IFN activity are discussed, which indicated its potential as a novel treatment for CHB. It is proposed that epigenetic changes such as histone acetylation, DNA methylation, m6A methylation could be the targets of IFN, which may offer a novel approach to HBV treatment.
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Affiliation(s)
- Zhijing Yang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Baozhen Sun
- Department of Hepatobiliary and Pancreas Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Jingcheng Xiang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Han Wu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Shaoning Kan
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Ming Hao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Lu Chang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Huimin Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
- *Correspondence: Dongxu Wang, ; Weiwei Liu,
| | - Weiwei Liu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, China
- *Correspondence: Dongxu Wang, ; Weiwei Liu,
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Yan LR, Liu AR, Jiang LY, Wang BG. Non-coding RNA and hepatitis B virus-related hepatocellular carcinoma: A bibliometric analysis and systematic review. Front Med (Lausanne) 2022; 9:995943. [PMID: 36203765 PMCID: PMC9530602 DOI: 10.3389/fmed.2022.995943] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 08/23/2022] [Indexed: 11/18/2022] Open
Abstract
Objectives A bibliometric analysis for non-coding RNA and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) was performed to describe international research status and visualize the research scope and emerging trends over the last two decades on this topic. Materials and methods Research data of non-coding RNA and HBV-related HCC were retrieved and extracted from the Web of Science Core Collection (WoSCC) database from 1 January 2003 to 13 June 2022 and then analyzed by means of bibliometric methods. A total of 1,036 articles published in this field were assessed for specific characteristics, including the year of publication, journal, author, institution, country/region, references, and keywords. VOSviewer was employed to perform co-authorship, co-occurrence, and co-citation analyses accompanied by constructing a visual network. Results Overall, 1,036 reports on non-coding RNA and HBV-related HCC from 2003 to 2022 were retrieved from WoSCC. The publication has gradually increased during the last two decades with 324 journals involved. Most research records (748 publications and 23,184 citations) were concentrated in China. A co-occurrence cluster analysis for the top 100 keywords was performed and four clusters were generated: (1) non-coding RNA as a molecular marker for the diagnosis and prognosis of HBV-related HCC; (2) dysregulation of non-coding RNA by hepatitis B virus X protein (HBx); (3) non-coding RNA affecting the biological behaviors of HBV-related HCC; and (4) epidemiological study for the effects of non-coding RNA on the risk of HBV-related HCC. Conclusion The publications and citations involved in non-coding RNA and HBV-related HCC have increased over the last two decades associated with many countries, institutions, and authors. Our study revealed current development trends, global cooperation models, basic knowledge, research hotspots, and emerging frontiers in this field.
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Affiliation(s)
- Li-rong Yan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang, China
| | - Ao-ran Liu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang, China
| | - Li-yue Jiang
- Tangdu Hospital of the Fourth Military Medical University, Xi’an, China
| | - Ben-gang Wang
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Key Laboratory of Cancer Etiology and Prevention, China Medical University, Liaoning Provincial Education Department, Shenyang, China
- Department of Hepatobiliary Surgery, Institute of General Surgery, The First Hospital of China Medical University, Shenyang, China
- *Correspondence: Ben-gang Wang,
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Patra SK, Szyf M. Epigenetic perspectives of COVID-19: Virus infection to disease progression and therapeutic control. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166527. [PMID: 36002132 PMCID: PMC9393109 DOI: 10.1016/j.bbadis.2022.166527] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/05/2022] [Accepted: 08/18/2022] [Indexed: 11/20/2022]
Abstract
COVID-19 has caused numerous deaths as well as imposed social isolation and upheaval world-wide. Although, the genome and the composition of the virus, the entry process and replication mechanisms are well investigated from by several laboratories across the world, there are many unknown remaining questions. For example, what are the functions of membrane lipids during entry, packaging and exit of virus particles? Also, the metabolic aspects of the infected tissue cells are poorly understood. In the course of virus replication and formation of virus particles within the host cell, the enhanced metabolic activities of the host is directly proportional to viral loads. The epigenetic landscape of the host cells is also altered, particularly the expression/repression of genes associated with cellular metabolism as well as cellular processes that are antagonistic to the virus. Metabolic pathways are enzyme driven processes and the expression profile and mechanism of regulations of the respective genes encoding those enzymes during the course of pathogen invasion might be highly informative on the course of the disease. Recently, the metabolic profile of the patients' sera have been analysed from few patients. In view of this, and to gain further insights into the roles that epigenetic mechanisms might play in this scenario in regulation of metabolic pathways during the progression of COVID-19 are discussed and summarised in this contribution for ensuring best therapy.
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Affiliation(s)
- Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology, Rourkela 769008, Odisha, India.
| | - Moshe Szyf
- Department of Pharmacology & Therapeutics, McIntyre Medical Sciences Building, McGill University, Montreal, QC H3G 1Y6, Canada
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Qu B, Nebioglu F, Leuthold MM, Ni Y, Mutz P, Beneke J, Erfle H, Vondran FW, Bartenschlager R, Urban S. Dual role of neddylation in transcription of hepatitis B virus RNAs from cccDNA and production of viral surface antigen. JHEP Rep 2022; 4:100551. [PMID: 36124123 PMCID: PMC9482114 DOI: 10.1016/j.jhepr.2022.100551] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 07/10/2022] [Accepted: 07/14/2022] [Indexed: 02/07/2023] Open
Abstract
Background & Aims HBV persistence is maintained by both an episomal covalently closed circular (ccc)DNA reservoir and genomic integration of HBV DNA fragments. While cccDNA transcription is regulated by Cullin4A-DDB1-HBx-mediated degradation of the SMC5/6 complex, HBsAg expression from integrants is largely SMC5/6 independent. Inhibiting neddylation of Cullin-RING ubiquitin ligases impairs degradation of substrates. Herein, we show that targeting neddylation pathway components by small-interfering (si)RNAs or the drug MLN4924 (pevonedistat) suppresses expression of HBV proteins from both cccDNA and integrants. Methods An siRNA screen targeting secretory pathway regulators and neddylation genes was performed. Activity of MLN4924 was assessed in infection and integration models. Trans-complementation assays were used to study HBx function in cccDNA-driven expression. Results siRNA screening uncovered neddylation pathway components (Nedd8, Ube2m) that promote HBsAg production post-transcriptionally. Likewise, MLN4924 inhibited production of HBsAg encoded by integrants and reduced intracellular HBsAg levels, independent of HBx. MLN4924 also profoundly inhibited cccDNA transcription in three infection models. Using the HBV inducible cell line HepAD38 as a model, we verified the dual action of MLN4924 on both cccDNA and integrants with sustained suppression of HBV markers during 42 days of treatment. Conclusions Neddylation is required both for transcription of a cccDNA reservoir and for the genomic integration of viral DNA. Therefore, blocking neddylation might offer an attractive approach towards functional cure of chronic hepatitis B. Lay summary Current treatments for chronic hepatitis B are rarely able to induce a functional cure. This is partly because of the presence of a pool of circular viral DNA in the host nucleus, as well as viral DNA fragments that are integrated into the host genome. Herein, we show that a host biological pathway called neddylation could play a key role in infection and viral DNA integration. Inhibiting this pathway could hold therapeutic promise for patients with chronic hepatitis B.
Neddylation plays a dual role in HBV expression from viral integrants and episomal cccDNA. Impaired neddylation suppresses production of HBsAg expressed from viral integrants. Neddylation promotes HBsAg generation from viral integrants in an HBx-independent manner. MLN4924 also inhibits the synthesis of viral transcripts from episomal cccDNA.
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Skrlec I, Talapko J. Hepatitis B and circadian rhythm of the liver. World J Gastroenterol 2022; 28:3282-3296. [PMID: 36158265 PMCID: PMC9346465 DOI: 10.3748/wjg.v28.i27.3282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/15/2022] [Accepted: 06/13/2022] [Indexed: 02/06/2023] Open
Abstract
The circadian rhythm in humans is determined by the central clock located in the hypothalamus's suprachiasmatic nucleus, and it synchronizes the peripheral clocks in other tissues. Circadian clock genes and clock-controlled genes exist in almost all cell types. They have an essential role in many physiological processes, including lipid metabolism in the liver, regulation of the immune system, and the severity of infections. In addition, circadian rhythm genes can stimulate the immune response of host cells to virus infection. Hepatitis B virus (HBV) infection is the leading cause of liver disease and liver cancer globally. HBV infection depends on the host cell, and hepatocyte circadian rhythm genes are associated with HBV replication, survival, and spread. The core circadian rhythm proteins, REV-ERB and brain and muscle ARNTL-like protein 1, have a crucial role in HBV replication in hepatocytes. In addition to influencing the virus's life cycle, the circadian rhythm also affects the pharmacokinetics and efficacy of antiviral vaccines. Therefore, it is vital to apply antiviral therapy at the appropriate time of day to reduce toxicity and improve the effectiveness of antiviral treatment. For these reasons, understanding the role of the circadian rhythm in the regulation of HBV infection and host responses to the virus provides us with a new perspective of the interplay of the circadian rhythm and anti-HBV therapy. Therefore, this review emphasizes the importance of the circadian rhythm in HBV infection and the optimization of antiviral treatment based on the circadian rhythm-dependent immune response.
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Affiliation(s)
- Ivana Skrlec
- Department of Biophysics, Biology, and Chemistry, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Osijek 31000, Croatia
| | - Jasminka Talapko
- Department of Anatomy Histology, Embryology, Pathology Anatomy and Pathology Histology, Faculty of Dental Medicine and Health, Osijek 31000, Croatia
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Sengupta I, Mondal P, Sengupta A, Mondal A, Singh V, Adhikari S, Dhang S, Roy S, Das C. Epigenetic regulation of Fructose‐1,6‐bisphosphatase 1 by host transcription factor Speckled 110
kDa
during hepatitis B virus infection. FEBS J 2022; 289:6694-6713. [DOI: 10.1111/febs.16544] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 05/09/2022] [Accepted: 06/01/2022] [Indexed: 12/17/2022]
Affiliation(s)
- Isha Sengupta
- Biophysics and Structural Genomics Division Saha Institute of Nuclear Physics Kolkata India
| | - Payel Mondal
- Biophysics and Structural Genomics Division Saha Institute of Nuclear Physics Kolkata India
- Homi Bhaba National Institute Mumbai India
| | - Amrita Sengupta
- Biophysics and Structural Genomics Division Saha Institute of Nuclear Physics Kolkata India
| | - Atanu Mondal
- Biophysics and Structural Genomics Division Saha Institute of Nuclear Physics Kolkata India
- Homi Bhaba National Institute Mumbai India
| | - Vipin Singh
- Biophysics and Structural Genomics Division Saha Institute of Nuclear Physics Kolkata India
- Homi Bhaba National Institute Mumbai India
| | - Swagata Adhikari
- Biophysics and Structural Genomics Division Saha Institute of Nuclear Physics Kolkata India
- Homi Bhaba National Institute Mumbai India
| | - Sinjini Dhang
- Structural Biology & Bio‐Informatics Division CSIR‐Indian Institute of Chemical Biology Kolkata India
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad India
| | - Siddhartha Roy
- Structural Biology & Bio‐Informatics Division CSIR‐Indian Institute of Chemical Biology Kolkata India
- Academy of Scientific and Innovative Research (AcSIR) Ghaziabad India
| | - Chandrima Das
- Biophysics and Structural Genomics Division Saha Institute of Nuclear Physics Kolkata India
- Homi Bhaba National Institute Mumbai India
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35
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Gherlan GS. Occult hepatitis B - the result of the host immune response interaction with different genomic expressions of the virus. World J Clin Cases 2022; 10:5518-5530. [PMID: 35979101 PMCID: PMC9258381 DOI: 10.12998/wjcc.v10.i17.5518] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 01/30/2022] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
With over 40 years of history, occult hepatitis B infection (OBI) continues to remain an important and challenging public health problem. Defined as the presence of replication-competent hepatitis B virus (HBV) DNA (i.e., episomal HBV covalently closed circular DNA) in the liver and/or HBV DNA in the blood of people who test negative for hepatitis B surface antigen (HBsAg) in currently available assays, OBI is currently diagnosed using polymerase chain reaction (PCR) and real-time PCR assays. However, all efforts should be made to exclude a false negative HBsAg in order to completely follow the definition of OBI. In recent years, significant advances have been made in understanding the HBV lifecycle and the molecular mechanisms that lead to the persistence of the virus in the occult form. These factors are mainly related to the host immune system and, to a smaller proportion, to the virus. Both innate and adaptive immune responses are important in HBV infection management, and epigenetic changes driven by host mechanisms (acetylation, methylation, and microRNA implication) are added to such actions. Although greater genetic variability in the S gene of HBV isolated from OBIs was found compared with overt infection, the mechanisms of OBI are not mainly viral mutations.
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Affiliation(s)
- George Sebastian Gherlan
- Department of Infectious Diseases, “Carol Davila” University of Medicine and Pharmacy, Bucharest 030303, Romania
- Department of Infectious Diseases, “Dr. Victor Babes” Hospital of Infectious and Tropical Diseases, Bucharest 030303, Romania
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36
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Boettler T, Gill US, Allweiss L, Pollicino T, Tavis JE, Zoulim F. Assessing immunological and virological responses in the liver: Implications for the cure of chronic hepatitis B virus infection. JHEP Rep 2022; 4:100480. [PMID: 35493765 PMCID: PMC9039841 DOI: 10.1016/j.jhepr.2022.100480] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 11/11/2022] Open
Abstract
Cure from chronic HBV infection is rare with current therapies. Basic research has helped to fundamentally improve our knowledge of the viral life cycle and virus-host interactions, and provided the basis for several novel drug classes that are currently being developed or are being tested in clinical trials. While these novel compounds targeting the viral life cycle or antiviral immune responses hold great promise, we are still lacking a comprehensive understanding of the immunological and virological processes that occur at the site of infection, the liver. At the International Liver Congress 2021 (ILC 2021), a research think tank on chronic HBV infection focused on mechanisms within the liver that facilitate persistent infection and looked at the research questions that need to be addressed to fill knowledge gaps and identify novel therapeutic strategies. Herein, we summarise the discussion by the think tank and identify the key basic research questions that must be addressed in order to develop more effective strategies for the functional cure of HBV infection.
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Affiliation(s)
- Tobias Boettler
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Upkar S. Gill
- Blizard Institute, Centre for Immunobiology, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Lena Allweiss
- I. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems sites, Germany
| | - Teresa Pollicino
- Department of Human Pathology, University Hospital "G. Martino" of Messina, Messina, Italy
| | - John E. Tavis
- Department of Molecular Microbiology and Immunology and Institute for Drug and Biotherapeutic Innovation, Saint Louis University, Saint Louis MO USA
| | - Fabien Zoulim
- INSERM Unit 1052 – Cancer Research Center of Lyon, Department of Hepatology Hospices Civils de Lyon, Lyon University, France
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37
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Yang L, Zou T, Chen Y, Zhao Y, Wu X, Li M, Du F, Chen Y, Xiao Z, Shen J. Hepatitis B virus X protein mediated epigenetic alterations in the pathogenesis of hepatocellular carcinoma. Hepatol Int 2022; 16:741-754. [PMID: 35648301 DOI: 10.1007/s12072-022-10351-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 04/25/2022] [Indexed: 12/13/2022]
Abstract
Chronic hepatitis B virus (HBV) infection is a worldwide health problem. Hepatitis B virus X protein (HBx), a pleiotropic regulatory protein encoded by HBV, is necessary for the transcription of HBV covalently closed circular DNA (cccDNA) minichromosomes, and affects the epigenetic regulation of host cells. The epigenetic reprogramming of HBx on host cell genome is strongly involved in HBV-related HCC carcinogenesis. Here, we review the latest findings of the epigenetic regulation induced by HBx protein in hepatocellular carcinoma (HCC), including DNA methylation, histone modification and non-coding RNA expression. The influence of HBx on the epigenetic regulation of cccDNA is also summarized. In addition, preliminary studies of targeted drugs for epigenetic changes induced by HBx are also discussed. The exploration of epigenetic markers as potential targets will help to develop new prevention and/or treatment methods for HBx-related HCC.
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Affiliation(s)
- Liqiong Yang
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Tao Zou
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Yao Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Yueshui Zhao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Xu Wu
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Mingxing Li
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Fukuan Du
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Yu Chen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China
| | - Zhangang Xiao
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China.
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China.
| | - Jing Shen
- Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, 646000, China.
- Cell Therapy and Cell Drugs of Luzhou Key Laboratory, Luzhou, 646000, China.
- South Sichuan Institute of Translational Medicine, Luzhou, 646000, China.
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38
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Lin Y, Qiu T, Wei G, Que Y, Wang W, Kong Y, Xie T, Chen X. Role of Histone Post-Translational Modifications in Inflammatory Diseases. Front Immunol 2022; 13:852272. [PMID: 35280995 PMCID: PMC8908311 DOI: 10.3389/fimmu.2022.852272] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammation is a defensive reaction for external stimuli to the human body and generally accompanied by immune responses, which is associated with multiple diseases such as atherosclerosis, type 2 diabetes, Alzheimer’s disease, psoriasis, asthma, chronic lung diseases, inflammatory bowel disease, and multiple virus-associated diseases. Epigenetic mechanisms have been demonstrated to play a key role in the regulation of inflammation. Common epigenetic regulations are DNA methylation, histone modifications, and non-coding RNA expression; among these, histone modifications embrace various post-modifications including acetylation, methylation, phosphorylation, ubiquitination, and ADP ribosylation. This review focuses on the significant role of histone modifications in the progression of inflammatory diseases, providing the potential target for clinical therapy of inflammation-associated diseases.
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Affiliation(s)
- Yingying Lin
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Ting Qiu
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Guifeng Wei
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Yueyue Que
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Wenxin Wang
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yichao Kong
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Tian Xie
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
| | - Xiabin Chen
- School of Pharmacy, Hangzhou Normal University, Hangzhou, China.,Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines, Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, China
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Wang Y, Li Y, Zai W, Hu K, Zhu Y, Deng Q, Wu M, Li Y, Chen J, Yuan Z. HBV covalently closed circular DNA minichromosomes in distinct epigenetic transcriptional states differ in their vulnerability to damage. Hepatology 2022; 75:1275-1288. [PMID: 34779008 DOI: 10.1002/hep.32245] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Revised: 10/20/2021] [Accepted: 11/10/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS HBV covalently closed circular DNA (cccDNA) is a major obstacle for a cure of chronic hepatitis B. Accumulating evidence suggests that epigenetic modifications regulate the transcriptional activity of cccDNA minichromosomes. However, it remains unclear how the epigenetic state of cccDNA affects its stability. APPROACHES AND RESULTS By using HBV infection cell models and in vitro and in vivo recombinant cccDNA (rcccDNA) and HBVcircle models, the reduction rate of HBV cccDNA and the efficacy of apolipoprotein B mRNA editing enzyme catalytic subunit 3A (APOBEC3A)-mediated and CRISPR/CRISPR-associated 9 (Cas9)-mediated cccDNA targeting were compared between cccDNAs with distinct transcriptional activities. Interferon-α treatment and hepatitis B x protein (HBx) deletion were applied as two strategies for cccDNA repression. Chromatin immunoprecipitation and micrococcal nuclease assays were performed to determine the epigenetic pattern of cccDNA. HBV cccDNA levels remained stable in nondividing hepatocytes; however, they were significantly reduced during cell division, and the reduction rate was similar between cccDNAs in transcriptionally active and transcriptionally repressed states. Strikingly, HBV rcccDNA without HBx expression exhibited a significantly longer persistence in mice. The cccDNA with low transcriptional activity exhibited an epigenetically inactive pattern and was more difficult to access by APOBEC3A and engineered CRISPR-Cas9. The epigenetic regulator activating cccDNA increased its vulnerability to APOBEC3A. CONCLUSIONS HBV cccDNA minichromosomes in distinct epigenetic transcriptional states showed a similar reduction rate during cell division but significantly differed in their accessibility and vulnerability to targeted nucleases and antiviral agents. Epigenetic sensitization of cccDNA makes it more susceptible to damage and may potentially contribute to an HBV cure.
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Affiliation(s)
- Yang Wang
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS)School of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Yumeng Li
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS)School of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Wenjing Zai
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS)School of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Kongying Hu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS)School of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Yuanfei Zhu
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS)School of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Qiang Deng
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS)School of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
- Research Unit of Cure of Chronic Hepatitis B Virus InfectionChinese Academy of Medical SciencesShanghaiChina
- Shanghai Frontiers Science Center of Pathogenic Microbes and InfectionShanghaiChina
| | - Min Wu
- Shanghai Public Health Clinical CenterFudan UniversityShanghaiChina
| | - Yaming Li
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS)School of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS)School of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
- Research Unit of Cure of Chronic Hepatitis B Virus InfectionChinese Academy of Medical SciencesShanghaiChina
- Shanghai Frontiers Science Center of Pathogenic Microbes and InfectionShanghaiChina
| | - Zhenghong Yuan
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS)School of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghaiChina
- Research Unit of Cure of Chronic Hepatitis B Virus InfectionChinese Academy of Medical SciencesShanghaiChina
- Shanghai Frontiers Science Center of Pathogenic Microbes and InfectionShanghaiChina
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40
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Murphy SA, Mapes NJ, Dua D, Kaur B. Histone modifiers at the crossroads of oncolytic and oncogenic viruses. Mol Ther 2022; 30:2153-2162. [PMID: 35143960 DOI: 10.1016/j.ymthe.2022.02.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 12/18/2021] [Accepted: 02/04/2022] [Indexed: 02/07/2023] Open
Abstract
Cancer is a disease caused by loss of regulatory processes that control cell cycle, resulting in increased proliferation. The loss of control can deregulate both tumor suppressors and oncogenes. Apart from cell intrinsic gene mutations and environmental factors, infection by cancer-causing viruses also induces changes that lead to malignant transformation. This can be caused by both expression of oncogenic viral proteins and also by changes in cellular genes and proteins that affect the epigenome. Thus, these epigenetic modifiers are good therapeutic targets, and several epigenetic inhibitors are approved for the treatment of different cancers. In addition to small molecule drugs, biological therapies such as antibodies and viral therapies are also increasingly being used to treat cancer. An HSV-1 derived oncolytic virus is currently approved by the US FDA and the European Medicines Agency. Similarly, an adenovirus-based therapeutic is approved for use in China for some cancer types. Since viruses can affect cellular epigenetics, the interaction of epigenome-targeting drugs with oncogenic and oncolytic viruses is a highly significant area of investigation. Here we will review the current knowledge about the impact of using epigenetic drugs in tumors positive for oncogenic viruses or as therapeutic combinations with oncolytic viruses.
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Affiliation(s)
- Sara A Murphy
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030;; University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030
| | - Norman John Mapes
- Center for Biomedical Engineering and Rehabilitation Sciences, Louisiana Tech University, Ruston, LA 71270
| | | | - Balveen Kaur
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030;.
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41
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Allweiss L, Giersch K, Pirosu A, Volz T, Muench RC, Beran RK, Urban S, Javanbakht H, Fletcher SP, Lütgehetmann M, Dandri M. Therapeutic shutdown of HBV transcripts promotes reappearance of the SMC5/6 complex and silencing of the viral genome in vivo. Gut 2022; 71:372-381. [PMID: 33509930 PMCID: PMC8762019 DOI: 10.1136/gutjnl-2020-322571] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 01/12/2021] [Accepted: 01/14/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Therapeutic strategies silencing and reducing the hepatitis B virus (HBV) reservoir, the covalently closed circular DNA (cccDNA), have the potential to cure chronic HBV infection. We aimed to investigate the impact of small interferring RNA (siRNA) targeting all HBV transcripts or pegylated interferon-α (peg-IFNα) on the viral regulatory HBx protein and the structural maintenance of chromosome 5/6 complex (SMC5/6), a host factor suppressing cccDNA transcription. In particular, we assessed whether interventions lowering HBV transcripts can achieve and maintain silencing of cccDNA transcription in vivo. DESIGN HBV-infected human liver chimeric mice were treated with siRNA or peg-IFNα. Virological and host changes were analysed at the end of treatment and during the rebound phase by qualitative PCR, ELISA, immunoblotting and chromatin immunoprecipitation. RNA in situ hybridisation was combined with immunofluorescence to detect SMC6 and HBV RNAs at single cell level. The entry inhibitor myrcludex-B was used during the rebound phase to avoid new infection events. RESULTS Both siRNA and peg-IFNα strongly reduced all HBV markers, including HBx levels, thus enabling the reappearance of SMC5/6 in hepatocytes that achieved HBV-RNA negativisation and SMC5/6 association with the cccDNA. Only IFN reduced cccDNA loads and enhanced IFN-stimulated genes. However, the antiviral effects did not persist off treatment and SMC5/6 was again degraded. Remarkably, the blockade of viral entry that started at the end of treatment hindered renewed degradation of SMC5/6. CONCLUSION These results reveal that therapeutics abrogating all HBV transcripts including HBx promote epigenetic suppression of the HBV minichromosome, whereas strategies protecting the human hepatocytes from reinfection are needed to maintain cccDNA silencing.
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Affiliation(s)
- Lena Allweiss
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Katja Giersch
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andrea Pirosu
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tassilo Volz
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany,German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems and Heidelberg sites, Germany
| | | | | | - Stephan Urban
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems and Heidelberg sites, Germany,Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
| | | | | | - Marc Lütgehetmann
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems and Heidelberg sites, Germany,Department of Medical Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maura Dandri
- Department of Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany .,German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel-Riems and Heidelberg sites, Germany
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42
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Medhat A, Arzumanyan A, Feitelson MA. Hepatitis B x antigen (HBx) is an important therapeutic target in the pathogenesis of hepatocellular carcinoma. Oncotarget 2021; 12:2421-2433. [PMID: 34853663 PMCID: PMC8629409 DOI: 10.18632/oncotarget.28077] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 09/04/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) is a human pathogen that has infected an estimated two billion people worldwide. Despite the availability of highly efficacious vaccines, universal screening of the blood supply for virus, and potent direct acting anti-viral drugs, there are more than 250 million carriers of HBV who are at risk for the sequential development of hepatitis, fibrosis, cirrhosis and hepatocellular carcinoma (HCC). More than 800,000 deaths per year are attributed to chronic hepatitis B. Many different therapeutic approaches have been developed to block virus replication, and although effective, none are curative. These treatments have little or no impact upon the portions of integrated HBV DNA, which often encode the virus regulatory protein, HBx. Although given little attention, HBx is an important therapeutic target because it contributes importantly to (a) HBV replication, (b) in protecting infected cells from immune mediated destruction during chronic infection, and (c) in the development of HCC. Thus, the development of therapies targeting HBx, combined with other established therapies, will provide a functional cure that will target virus replication and further reduce or eliminate both the morbidity and mortality associated with chronic liver disease and HCC. Simultaneous targeting of all these characteristics underscores the importance of developing therapies against HBx.
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Affiliation(s)
- Arvin Medhat
- Department of Molecular Cell Biology, Azad University, North Unit, Tehran, Iran
| | - Alla Arzumanyan
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Mark A Feitelson
- Department of Biology, College of Science and Technology, Temple University, Philadelphia, PA, USA
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de Almeida NAA, de Paula VS. Occult Hepatitis B virus (HBV) infection and challenges for hepatitis elimination: A literature review. J Appl Microbiol 2021; 132:1616-1635. [PMID: 34724308 DOI: 10.1111/jam.15351] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/08/2021] [Accepted: 10/11/2021] [Indexed: 12/15/2022]
Abstract
Occult hepatitis B infection (OBI) is characterized by the detection of hepatitis B virus (HBV) DNA in serum or liver but negativity for hepatitis B surface antigen. OBI, which is thought to be maintained by host, immunological, viral and/or epigenetic factors, is one of the most challenging clinical features in the study of viral hepatitis. Currently, there is no validated detection test for OBI. It is believed that OBI is widely distributed throughout the world, with a higher prevalence in populations at high-risk HBV, but the detailed worldwide prevalence patterns are unknown. We conducted a survey of recently published studies on OBI rates across all continents. High prevalence rates of OBI are observed in some specific groups, including patients with hepatitis C virus, human immunodeficiency virus co-infection or hepatocellular carcinoma. In 2016, the World Health Organization adopted strategies to eliminate viral hepatitis by 2030, but the difficulties in detecting and treating OBI currently challenge this goal. Subjects with OBI can transmit HBV, and episodes of reactivation can occur. Further studies to understanding the mechanisms that drive the development of OBI are needed and can contribute to efforts at eliminating viral hepatitis.
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Miao J, Gao P, Li Q, He K, Zhang L, Wang J, Huang L. Advances in Nanoparticle Drug Delivery Systems for Anti-Hepatitis B Virus Therapy: A Narrative Review. Int J Mol Sci 2021; 22:ijms222011227. [PMID: 34681886 PMCID: PMC8538950 DOI: 10.3390/ijms222011227] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 09/26/2021] [Accepted: 10/11/2021] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B (CHB) is an infectious viral disease that is prevalent worldwide. Traditional nucleoside analogues, as well as the novel drug targets against hepatitis B virus (HBV), are associated with certain critical factors that influence the curative effect, such as biological stability and safety, effective drug delivery, and controlled release. Nanoparticle drug delivery systems have significant advantages and have provided a basis for the development of anti-HBV strategies. In this review, we aim to review the advances in nanoparticle drug delivery systems for anti-hepatitis B virus therapy by summarizing the relevant literature. First, we focus on the characteristics of nanoparticle drug delivery systems for anti-HBV therapy. Second, we discuss the nanoparticle delivery systems for anti-HBV nucleoside drugs, gene-based drugs, and vaccines. Lastly, we provide an overview of the prospects for nanoparticle-based anti-HBV agents.
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Affiliation(s)
- Jing Miao
- Department of Pharmacy, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; (J.M.); (P.G.); (K.H.); (L.Z.)
- Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, Hangzhou 310003, China
| | - Peng Gao
- Department of Pharmacy, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; (J.M.); (P.G.); (K.H.); (L.Z.)
| | - Qian Li
- Department of Pharmacy, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China;
| | - Kaifeng He
- Department of Pharmacy, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; (J.M.); (P.G.); (K.H.); (L.Z.)
| | - Liwen Zhang
- Department of Pharmacy, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; (J.M.); (P.G.); (K.H.); (L.Z.)
| | - Junyan Wang
- Department of Pharmacy, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; (J.M.); (P.G.); (K.H.); (L.Z.)
- Correspondence: (J.W.); (L.H.)
| | - Lingfei Huang
- Department of Pharmacy, The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China; (J.M.); (P.G.); (K.H.); (L.Z.)
- Correspondence: (J.W.); (L.H.)
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Worse outcome and distinct mutational pattern in follicular lymphoma with anti-HBc positivity. Blood Adv 2021; 6:82-86. [PMID: 34649275 PMCID: PMC8753219 DOI: 10.1182/bloodadvances.2021005316] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Accepted: 09/22/2021] [Indexed: 11/20/2022] Open
Abstract
Epidemiological studies have demonstrated the association between hepatitis B virus (HBV) infection and B-cell non-Hodgkin lymphomas (NHL), mainly for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). We studied a cohort of 121 FL patients for HBV infection status, clinical features and gene mutational profile. Anti-HBc was detectable in sixteen patients (13.2%), although all had undetectable HBV DNA. Anti-HBc+ cases presented with older age at diagnosis than anti-HBc- cases (68.1 vs. 57.2 years, P=0.007) and higher β2-microglobulin (56.3% vs. 28.9%, P=0.04). All patients included in the study fulfilled criteria for treatment and received therapy with rituximab or rituximab-containing chemotherapy. There were no episodes of HBV reactivation or HBV-hepatitis during treatment and/or maintenance. Remarkably, anti-HBc+ patients had significantly lower 10-year PFS (12.9% vs 58.3%; P<0.0001) and OS (22.0% vs. 86.2%, P<0.0001), that remained at multivariate analysis. Gene mutational profiling of all cases showed that anti-HBc+ cases had higher incidence of ARID1A mutations and absence of EP300 mutations, two key epigenetic regulators in FL. Overall, our study shows that FL patients with resolved HBV infection have a worse outcome independently of other well-known clinical risk factors and a distinct gene mutational profile.
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Moon IY, Kim JW. Methylation profile of hepatitis B virus is not influenced by interferon α in human liver cancer cells. Mol Med Rep 2021; 24:715. [PMID: 34396432 PMCID: PMC8383030 DOI: 10.3892/mmr.2021.12354] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Accepted: 07/12/2021] [Indexed: 12/17/2022] Open
Abstract
Interferon (IFN) α is used for the treatment of chronic hepatitis B virus (HBV) infection, but the molecular mechanisms underlying its antiviral effect have not been fully elucidated. Epigenetic modifications regulate the transcriptional activity of covalently closed circular DNA (cccDNA) in cells with chronic HBV infection. IFN‑α has been shown to modify cccDNA‑bound histones, but it is not known whether the anti‑HBV effect of IFN‑α involves methylation of cccDNA. The present study aimed to determine whether IFN‑α induced methylation of HBV cccDNA in a cell‑based model in which HepG2 cells were directly infected with wild‑type HBV virions. Methylation status of HBV cccDNA was assessed using global DNA methylation ELISA assay, methylation‑specific PCR and bisulfite sequencing. IFN‑α suppressed HBV DNA and RNA transcripts, but methylation profiles were similar between the control and IFN‑α treated groups. Chromatin immunoprecipitation results revealed binding of DNA methyltransferases (DNMT) 3A and DNMT3B to HBV cccDNA and treatment with IFN‑α suppressed the recruitment of DNMT3B to cccDNA. Taken together, these results suggest that IFN‑α does not induce methylation of HBV cccDNA. Therefore, it was concluded that methylation is unlikely to contribute to the anti‑HBV effect of IFN‑α in HepG2 cells, and that alternative mechanisms need to be sought to enhance cccDNA methylation as a novel therapy against HBV.
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Affiliation(s)
- In Young Moon
- Department of Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea
| | - Jin-Wook Kim
- Department of Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi 13620, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea
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Lin Y, Liu Y, Xu D, Guo F, Zhang W, Zhang Y, Bai G. HBxAg promotes HBV replication and EGFR activation in human placental trophoblasts. Exp Ther Med 2021; 22:1211. [PMID: 34584556 PMCID: PMC8422389 DOI: 10.3892/etm.2021.10645] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 06/09/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a global epidemic. The main transmission route of chronic HBV infection is from mother to child, yet the mechanisms underlying HBV intrauterine infection remain unclear. In the present study, the effect and the mechanism underlying hepatitis B virus X antigen (HBxAg) on HBV replication and EGFR activation in trophoblasts was investigated. Serum samples from pregnant women with HBV infection were used to infect trophoblasts and HBxAg expression was detected using ELISA. HBV plasmids carrying either full length hepatitis B virus X (HBx) or HBx with a deletion mutation (ΔHBx) were transfected into trophoblasts and expression levels of HBV DNA, hepatitis B e-antigen and pregenomic (pg)RNA, and structural maintenance of chromosomes (Smc) 5/6 were assessed. The association between HBx and EGFR promoters was characterized using a luciferase reporter assay and EGFR/PI3K/phosphorylated (p)-AKT expression and apoptosis rate were also monitored. The results of the present study indicated that HBxAg expression increased with the increasing titre of HBV DNA (P<0.05). Compared with the wild-type group, the amount of HBV DNA in the supernatant and cells was significantly reduced (P<0.05) in the ΔHBx group and the intracellular HBeAg and pgRNA levels were also significantly decreased (P<0.05). In addition, Smc5/6 expression was also significantly decreased (P<0.05) when the intracellular HBx protein was expressed compared with mock-transfected cells. Co-transfection of HBx and EGFR promoter plasmids in JEG-3 and HTR-8 cells significantly elevated EGFR promoter driven luciferase expression relative to the control group (P<0.01). In EGFR overexpressing cells, the expression of PI3K/p-AKT was significantly increased, whereas the apoptosis rate was significantly decreased (P<0.05). These results were reversed in the EGFR-knockdown group. In conclusion, the present study demonstrated that HBx promotes HBV replication in trophoblasts via downregulation of Smc5/6, activates the EGFR promoter and inhibits trophoblast apoptosis via the PI3K/p-AKT downstream signalling pathway, thereby increasing the risk of HBV intrauterine infection.
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Affiliation(s)
- Yayun Lin
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yan Liu
- Institute of Infectious Diseases, 5th Medical Center of Chinese PLA General Hospital, Beijing 100141, P.R. China
| | - Dongping Xu
- Institute of Infectious Diseases, 5th Medical Center of Chinese PLA General Hospital, Beijing 100141, P.R. China
| | - Fanfan Guo
- College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Wentao Zhang
- College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yidan Zhang
- College of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Guiqin Bai
- Department of Gynecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Martinez MG, Boyd A, Combe E, Testoni B, Zoulim F. Covalently closed circular DNA: The ultimate therapeutic target for curing HBV infections. J Hepatol 2021; 75:706-717. [PMID: 34051332 DOI: 10.1016/j.jhep.2021.05.013] [Citation(s) in RCA: 95] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 05/03/2021] [Accepted: 05/07/2021] [Indexed: 12/16/2022]
Abstract
Current antiviral therapies, such as pegylated interferon-α and nucleos(t)ide analogues, effectively improve the quality of life of patients with chronic hepatitis B. However, they can only control the infection rather than curing infected hepatocytes. Complete HBV cure is hampered by the lack of therapies that can directly affect the viral minichromosome (in the form of covalently closed circular DNA [cccDNA]). Approaches currently under investigation in early clinical trials are aimed at achieving a functional cure, defined as the loss of HBsAg and undetectable HBV DNA levels in serum. However, achieving a complete HBV cure requires therapies that can directly target the cccDNA pool, either via degradation, lethal mutations or functional silencing. In this review, we discuss cutting-edge technologies that could lead to non-cytolytic direct cccDNA targeting and cure of infected hepatocytes.
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Affiliation(s)
| | - Anders Boyd
- Stichting HIV Monitoring, Amsterdam, the Netherlands; Department of Infectious Diseases, Research and Prevention, Public Health Service of Amsterdam, Amsterdam, the Netherlands
| | - Emmanuel Combe
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, 69008, France
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, 69008, France
| | - Fabien Zoulim
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, 69008, France; University of Lyon, Université Claude- Bernard (UCBL), 69008 Lyon, France; Hospices Civils de Lyon (HCL), 69002 Lyon, France.
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Ligat G, Verrier ER, Nassal M, Baumert TF. Hepatitis B virus-host interactions and novel targets for viral cure. Curr Opin Virol 2021; 49:41-51. [PMID: 34029994 PMCID: PMC7613419 DOI: 10.1016/j.coviro.2021.04.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023]
Abstract
Chronic infection with HBV is a major cause of advanced liver disease and hepatocellular carcinoma. Nucleos(t)ide analogues effectively control HBV replication but viral cure is rare. Hence treatment has often to be administered for an indefinite duration, increasing the risk for selection of drug resistant virus variants. PEG-interferon-α-based therapies can sometimes cure infection but suffer from a low response rate and severe side-effects. CHB is characterized by the persistence of a nuclear covalently closed circular DNA (cccDNA), which is not targeted by approved drugs. Targeting host factors which contribute to the viral life cycle provides new opportunities for the development of innovative therapeutic strategies aiming at HBV cure. An improved understanding of the host immune system has resulted in new potentially curative candidate approaches. Here, we review the recent advances in understanding HBV-host interactions and highlight how this knowledge contributes to exploiting host-targeting strategies for a viral cure.
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Affiliation(s)
- Gaëtan Ligat
- Université de Strasbourg, F-67000 Strasbourg, France; Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMRS 1110, F-67000 Strasbourg, France.
| | - Eloi R Verrier
- Université de Strasbourg, F-67000 Strasbourg, France; Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMRS 1110, F-67000 Strasbourg, France.
| | - Michael Nassal
- University Hospital Freiburg, Dept. of Internal Medicine 2/Molecular Biology, D79106 Freiburg, Germany.
| | - Thomas F Baumert
- Université de Strasbourg, F-67000 Strasbourg, France; Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMRS 1110, F-67000 Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France.
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50
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Zhang D, Zhang K, Protzer U, Zeng C. HBV Integration Induces Complex Interactions between Host and Viral Genomic Functions at the Insertion Site. J Clin Transl Hepatol 2021; 9:399-408. [PMID: 34221926 PMCID: PMC8237140 DOI: 10.14218/jcth.2021.00062] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV), one of the well-known DNA oncogenic viruses, is the leading cause of hepatocellular carcinoma (HCC). In infected hepatocytes, HBV DNA can be integrated into the host genome through an insertional mutagenesis process inducing tumorigenesis. Dissection of the genomic features surrounding integration sites will deepen our understanding of mechanisms underlying integration. Moreover, the quantity and biological activity of integration sites may reflect the DNA damage within affected cells or the potential survival benefits they may confer. The well-known human genomic features include repeat elements, particular regions (such as telomeres), and frequently interrupted genes (e.g., telomerase reverse transcriptase [i.e. TERT], lysine methyltransferase 2B [i.e. KMT2B], cyclin E1 [CCNE1], and cyclin A2 [CCNA2]). Consequently, distinct genomic features within diverse integrations differentiate their biological functions. Meanwhile, accumulating evidence has shown that viral proteins produced by integrants may cause cell damage even after the suppression of HBV replication. The integration-derived gene products can also serve as tumor markers, promoting the development of novel therapeutic strategies for HCC. Viral integrants can be single copy or multiple copies of different fragments with complicated rearrangement, which warrants elucidation of the whole viral integrant arrangement in future studies. All of these considerations underlie an urgent need to develop novel methodology and technology for sequence characterization and function evaluation of integration events in chronic hepatitis B-associated disease progression by monitoring both host genomic features and viral integrants. This endeavor may also serve as a promising solution for evaluating the risk of tumorigenesis and as a companion diagnostic for designing therapeutic strategies targeting integration-related disease complications.
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Affiliation(s)
- Dake Zhang
- Beijing Advanced Innovation Centre for Biomedical Engineering, Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Ke Zhang
- SCG Cell Therapy Pte. Ltd, Singapore
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
| | - Urlike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich, Germany
| | - Changqing Zeng
- Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
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