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Buti M, Wedemeyer H, Aleman S, Chulanov V, Morozov V, Sagalova O, Stepanova T, Gish RG, Lloyd A, Kaushik AM, Suri V, Manuilov D, Osinusi AO, Flaherty JF, Lampertico P. Patient-reported outcomes in chronic hepatitis delta: An exploratory analysis of the phase III MYR301 trial of bulevirtide. J Hepatol 2025; 82:28-36. [PMID: 39009085 DOI: 10.1016/j.jhep.2024.06.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 06/20/2024] [Accepted: 06/24/2024] [Indexed: 07/17/2024]
Abstract
BACKGROUND & AIMS Once-daily treatment of chronic hepatitis delta (CHD) with bulevirtide is well tolerated and associated with significant reductions in HDV RNA in the blood and in biochemical liver disease activity. This study explored the effects of 48-week bulevirtide treatment on health-related quality of life (HRQoL) in patients with CHD. METHODS In an open-label, randomised, phase III trial, 150 patients with CHD and compensated liver disease were stratified by cirrhosis status and randomised 1:1:1 to no treatment (control), bulevirtide 2 mg/day, or bulevirtide 10 mg/day for 48 weeks. HRQoL was evaluated by the following patient-reported outcome instruments at baseline, 24 weeks, and 48 weeks: EQ-5D-3L, Hepatitis Quality of Life Questionnaire, and Fatigue Severity Scale. RESULTS Patient characteristics and HRQoL scores were balanced at baseline between the treatment (2 mg, n = 49; 10 mg, n = 50) and control (n = 51) groups. Patients receiving 2 mg bulevirtide reported significant improvements compared with controls on the Hepatitis Quality of Life Questionnaire domains of role physical, hepatitis-specific limitations, and hepatitis-specific health distress. Numerically higher scores for general health, hepatitis-specific limitations, and hepatitis-specific health distress domains were reported by patients with cirrhosis who received bulevirtide vs. controls. Fatigue Severity Scale scores remained stable across treatment groups throughout. At week 48, patients in the 2 mg group showed greater mean improvement from baseline in health status compared with controls on the EQ-5D-3L visual analogue scale. CONCLUSION Patient-reported outcomes indicate that 48-week treatment with bulevirtide monotherapy may improve aspects of HRQoL in patients with CHD. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov Identifier, NCT03852719. IMPACT AND IMPLICATIONS Bulevirtide 2 mg is the only approved treatment for patients with chronic hepatitis delta (CHD) in the EU. Patients with CHD have worse quality of life scores than those with chronic hepatitis B. Bulevirtide treatment for 48 weeks reduced HDV RNA and alanine aminotransferase levels and was well tolerated among patients with CHD. For the first time, this study shows that patients who received bulevirtide therapy for 48 weeks reported improvements in physical and hepatitis-related quality of life domains compared with those who did not receive therapy (control group).
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Affiliation(s)
- Maria Buti
- Liver Unit, Hospital Universitario Vall d'Hebron, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBER-EHD) del Instituto Carlos III, Barcelona, Spain.
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology, Infectious Diseases, and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
| | - Soo Aleman
- Department of Infectious Diseases, Karolinska Universitetssjukhuset, Karolinska lnstitutet, Stockholm, Sweden
| | - Vladimir Chulanov
- Department of Infectious Diseases, Sechenov University, Moscow, Russian Federation
| | | | - Olga Sagalova
- South Ural State Medical University, Chelyabinsk, Russian Federation
| | | | - Robert G Gish
- Robert G. Gish Consultants, LLC, San Diego, CA, USA; Hepatitis B Foundation, Doylestown, PA, USA
| | | | | | | | | | | | | | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; CRC "A. M. and A. Migliavacca" Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Pinho JRR, Gomes-Gouvêa M, Carrilho FJ. Gilberta Bensabath - Centenary of the discoverer of the high prevalence of hepatitis B and Delta in the Amazon - On the path to elimination as a public health problem! Ann Hepatol 2024; 29:101575. [PMID: 39270981 DOI: 10.1016/j.aohep.2024.101575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 08/19/2024] [Accepted: 08/19/2024] [Indexed: 09/15/2024]
Affiliation(s)
- João Renato Rebello Pinho
- LIM-07, Institute of Tropical Medicine, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil.
| | - Michele Gomes-Gouvêa
- LIM-07, Institute of Tropical Medicine, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Flair José Carrilho
- LIM-07, Institute of Tropical Medicine, Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
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Wedemeyer H, Aleman S, Brunetto M, Blank A, Andreone P, Bogomolov P, Chulanov V, Mamonova N, Geyvandova N, Morozov V, Sagalova O, Stepanova T, Berger A, Ciesek S, Manuilov D, Mercier RC, Da BL, Chee GM, Li M, Flaherty JF, Lau AH, Osinusi A, Schulze Zur Wiesch J, Cornberg M, Zeuzem S, Lampertico P. Bulevirtide monotherapy in patients with chronic HDV: Efficacy and safety results through week 96 from a phase III randomized trial. J Hepatol 2024; 81:621-629. [PMID: 38734383 DOI: 10.1016/j.jhep.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/15/2024] [Accepted: 05/03/2024] [Indexed: 05/13/2024]
Abstract
BACKGROUND & AIMS Bulevirtide (BLV), a first-in-class entry inhibitor, is approved in Europe for the treatment of chronic hepatitis delta (CHD). BLV monotherapy was superior to delayed treatment at week (W) 48, the primary efficacy endpoint, in the MYR301 study (NCT03852719). Here, we assessed if continued BLV therapy until W96 would improve virologic and biochemical response rates, particularly among patients who did not achieve virologic response at W24. METHODS In this ongoing, open-label, randomized phase III study, patients with CHD (N = 150) were randomized (1:1:1) to treatment with BLV 2 mg/day (n = 49) or 10 mg/day (n = 50), each for 144 weeks, or to delayed treatment for 48 weeks followed by BLV 10 mg/day for 96 weeks (n = 51). Combined response was defined as undetectable hepatitis delta virus (HDV) RNA or a decrease in HDV RNA by ≥2 log10 IU/ml from baseline and alanine aminotransferase (ALT) normalization. Other endpoints included virologic response, ALT normalization, and change in HDV RNA. RESULTS Of 150 patients, 143 (95%) completed 96 weeks of the study. Efficacy responses were maintained and/or improved between W48 and W96, with similar combined, virologic, and biochemical response rates between BLV 2 and 10 mg. Of the patients with a suboptimal early virologic response at W24, 43% of non-responders and 82% of partial responders achieved virologic response at W96. Biochemical improvement often occurred independently of virologic response. Adverse events were mostly mild, with no serious adverse events related to BLV. CONCLUSIONS Virologic and biochemical responses were maintained and/or increased with longer term BLV therapy, including in those with suboptimal early virologic response. BLV monotherapy for CHD was safe and well tolerated through W96. IMPACT AND IMPLICATIONS In July 2023, bulevirtide was fully approved for the treatment of chronic hepatitis delta (CHD) in Europe based on clinical study results from up to 48 weeks of treatment. Understanding the efficacy and safety of bulevirtide over the longer term is important for healthcare providers. In this analysis, we demonstrate that bulevirtide monotherapy for 96 weeks in patients with CHD was associated with continued improvements in combined, virologic, and biochemical responses as well as liver stiffness from week 48 at both the 2 mg and 10 mg doses. Patients with suboptimal virologic responses to bulevirtide at week 24 also benefited from continued therapy, with the majority achieving virologic response or biochemical improvement by week 96. CLINICAL TRIALS GOV IDENTIFIER NCT03852719.
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Affiliation(s)
- Heiner Wedemeyer
- Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Hannover, Germany.
| | - Soo Aleman
- Karolinska University Hospital/Karolinska Institute, Department of Infectious Diseases, Stockholm, Sweden
| | - Maurizia Brunetto
- University Hospital of Pisa, Hepatology Unit, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, Pisa, Italy; University of Pisa, Department of Clinical and Experimental Medicine, Pisa, Italy
| | - Antje Blank
- Heidelberg University Medical Faculty, Heidelberg University Hospital, Department of Clinical Pharmacology and Pharmacoepidemiology, Heidelberg, Germany
| | - Pietro Andreone
- University of Modena and Reggio Emilia, Internal Medicine, Baggiovara Hospital, Modena, Italy
| | - Pavel Bogomolov
- State Budgetary Institution of Health Care of Moscow Region, Moscow Regional Research Clinical Institute Named After M.F. Vladimirsky, Moscow, Russian Federation
| | - Vladimir Chulanov
- FSBI National Research Medical Center for Phthisiopulmonology and Infectious Diseases of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
| | - Nina Mamonova
- FSBI National Research Medical Center for Phthisiopulmonology and Infectious Diseases of the Ministry of Health of the Russian Federation, Moscow, Russian Federation
| | | | | | - Olga Sagalova
- Federal State-Funded Institution of Higher Education, South Ural State Medical University of Ministry of Health of the Russian Federation, Chelyabinsk, Russian Federation
| | | | - Annemarie Berger
- Institute for Medical Virology, German Centre for Infection Research, External Partner Site Frankfurt, University Hospital, Goethe University, Frankfurt am Main, Germany
| | - Sandra Ciesek
- Institute for Medical Virology, German Centre for Infection Research, External Partner Site Frankfurt, University Hospital, Goethe University, Frankfurt am Main, Germany
| | | | | | - Ben L Da
- Gilead Sciences, Foster City, CA, United States
| | | | - Mingyang Li
- Gilead Sciences, Foster City, CA, United States
| | | | | | - Anu Osinusi
- Gilead Sciences, Foster City, CA, United States
| | - Julian Schulze Zur Wiesch
- Universitätsklinikum Hamburg-Eppendorf, Medizinische Klinik Studienambulanz Hepatologie, Hamburg, Germany
| | - Markus Cornberg
- Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie, Infektiologie und Endokrinologie, Hannover, Germany
| | - Stefan Zeuzem
- University Hospital Frankfurt, Department of Medicine, Frankfurt am Main, Germany
| | - Pietro Lampertico
- Division of Gastroenterology and Hepatology, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; CRC A. M. and A. Migliavacca Center for Liver Disease, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
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Lee CC, Lau YC, Liang YK, Hsian YH, Lin CH, Wu HY, Tan DJY, Yeh YM, Chao M. vHDvDB 2.0: Database and Group Comparison Server for Hepatitis Delta Virus. Viruses 2024; 16:1254. [PMID: 39205227 PMCID: PMC11359145 DOI: 10.3390/v16081254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 07/26/2024] [Accepted: 08/02/2024] [Indexed: 09/04/2024] Open
Abstract
The hepatitis delta virus (HDV) is a unique pathogen with significant global health implications, affecting individuals who are coinfected with the hepatitis B virus (HBV). HDV infection has profound clinical consequences, manifesting either as coinfection with HBV, resulting in acute hepatitis and potential liver failure, or as superinfection in chronic HBV cases, substantially increasing the risk of cirrhosis and hepatocellular carcinoma. Given the complex dynamics of HDV infection and the urgent need for advanced research tools, this article introduces vHDvDB 2.0, a comprehensive HDV full-length sequence database. This innovative platform integrates data preprocessing, secondary structure prediction, and epidemiological research tools. The primary goal of vHDvDB 2.0 is to consolidate HDV sequence data into a user-friendly repository, thereby facilitating access for researchers and enhancing the broader scientific understanding of HDV. The significance of this database lies in its potential to streamline HDV research by providing a centralized resource for analyzing viral sequences and exploring genotype-specific characteristics. It will also enable more in-depth research within the HDV sequence domains.
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Affiliation(s)
- Chi-Ching Lee
- Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan 33302, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan
- Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Yiu Chung Lau
- Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan 33302, Taiwan
| | - You-Kai Liang
- Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yun-Hsuan Hsian
- Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan 33302, Taiwan
| | - Chun-Hsiang Lin
- Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan 33302, Taiwan
| | - Hsin-Ying Wu
- Department of Computer Science and Information Engineering, Chang Gung University, Taoyuan 33302, Taiwan
| | - Deborah Jing Yi Tan
- Department of Microbiology and Immunology and Division of Microbiology, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Yuan-Ming Yeh
- Genomic Medicine Core Laboratory, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
| | - Mei Chao
- Department of Microbiology and Immunology and Division of Microbiology, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Liver Research Center, Department of Hepato-Gastroenterology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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Su CW, Ochirkhuree B, Namdag B, Badamnachin B, Ganbold S, Gidaagaya S, Ganbold A, Yang SS, Duger D, Wu JC. Risk factors associated with hepatitis D virus infection and preventive strategies in Mongolia. J Chin Med Assoc 2024; 87:480-487. [PMID: 38417133 DOI: 10.1097/jcma.0000000000001073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/01/2024] Open
Abstract
BACKGROUND Hepatitis D virus (HDV) infection is highly prevalent in Mongolia. We aimed to identify the risk factors associated with HDV infection, propose preventive strategies, and evaluate the outcomes of a 3-year collaborative project between Taiwan and Mongolia. METHODS In 2016 and 2018, we conducted onsite visits to Mongolia. Mongolian investigators collected questionnaires focusing on risk factors, demographic characteristics, and serum samples for acute HDV infections. Furthermore, 19 Mongolian seed teachers participated in a 1-week workshop on infection control in Taiwan. Subsequently, these seed teachers trained more than 400 medical personnel in Mongolia. To assess secular changes in acute HDV infection, we reviewed the registration data from the National Center for Communicable Disease (NCCD) in Mongolia between 2011 and 2021. RESULTS Among the 194 Mongolian patients, 108 had dual infection with hepatitis B virus (HBV) and HDV, while 86 had acute hepatitis B (AHB). Patients with HBV/HDV dual infections were older (28.6 vs 25.5 years, p = 0.030) and had lower rates of positive hepatitis B e antigen in their sera, lower rates of serum HBV DNA exceeding 2000 IU/mL, and higher rates of having received dental treatment (59.4% vs 40.5%, p = 0.014) and injection therapy (64.2% vs 44.0%, p = 0.009) compared with those with AHB. Analysis of NCCD data revealed that new HDV infection cases were more prevalent between 2011 and 2015 (111.20 ± 29.79 cases/y) and decreased to 54.67 ± 27.34 cases/y between 2016 and 2021 ( p = 0.010). CONCLUSION Dental treatment and injections were associated with a higher risk of acute HDV infections in Mongolia. Through collaborative efforts, the incidence rate of HDV infection has declined in recent years.
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Affiliation(s)
- Chien-Wei Su
- Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Division of Holistic and Multidisciplinary Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Internal Medicine, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Bayarmaa Ochirkhuree
- Gastroenterology Center, First Central Hospital of Mongolia, Ulaanbaatar, Mongolia
| | - Bira Namdag
- Department of Gastroenterology, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Batsukh Badamnachin
- Emergency Department, National Center for Communicable Disease, Ulaanbaatar, Mongolia
| | - Sarangua Ganbold
- Hepatology Laboratory, National Center for Communicable Diseases, Ulaanbaatar, Mongolia
| | - Sarantuya Gidaagaya
- Department of Gastroenterology, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Anar Ganbold
- Gastroenterology Center, First Central Hospital of Mongolia, Ulaanbaatar, Mongolia
| | - Sien-Sing Yang
- Liver Unit, Cathay General Hospital, Taipei, Taiwan, ROC
| | - Davaadorj Duger
- Department of Gastroenterology, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Jaw-Ching Wu
- Institute of Clinical Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Cancer Progression Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Translational Division, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
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De Meyer A, Meuleman P. Preclinical animal models to evaluate therapeutic antiviral antibodies. Antiviral Res 2024; 225:105843. [PMID: 38548022 DOI: 10.1016/j.antiviral.2024.105843] [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: 01/29/2024] [Accepted: 02/25/2024] [Indexed: 04/05/2024]
Abstract
Despite the availability of effective preventative vaccines and potent small-molecule antiviral drugs, effective non-toxic prophylactic and therapeutic measures are still lacking for many viruses. The use of monoclonal and polyclonal antibodies in an antiviral context could fill this gap and provide effective virus-specific medical interventions. In order to develop these therapeutic antibodies, preclinical animal models are of utmost importance. Due to the variability in viral pathogenesis, immunity and overall characteristics, the most representative animal model for human viral infection differs between virus species. Therefore, throughout the years researchers sought to find the ideal preclinical animal model for each virus. The most used animal models in preclinical research include rodents (mice, ferrets, …) and non-human primates (macaques, chimpanzee, ….). Currently, antibodies are tested for antiviral efficacy against a variety of viruses including different hepatitis viruses, human immunodeficiency virus (HIV), influenza viruses, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and rabies virus. This review provides an overview of the current knowledge about the preclinical animal models that are used for the evaluation of therapeutic antibodies for the abovementioned viruses.
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Affiliation(s)
- Amse De Meyer
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium.
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Gidaagaya S, Rokuhara A, Sugiyama M, Dorj S, Barsuren B, Namdag B, Munkhbat B, Oka S, Mizokami M. Prevalence, characteristics, and virologic correlations of hepatitis delta (D) among patients with hepatitis B surface antigen in Mongolia. Glob Health Med 2024; 6:101-107. [PMID: 38690137 PMCID: PMC11043131 DOI: 10.35772/ghm.2023.01080] [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: 07/18/2023] [Revised: 12/01/2023] [Accepted: 12/26/2023] [Indexed: 05/02/2024]
Abstract
Clinical and biochemical features of hepatitis delta virus (HDV) infections in Mongolia remain largely unknown. We aimed to investigate the clinical characteristics of HDV patients in Mongolia using several markers. The 143 hepatitis B surface antigen (HBsAg)-positive patients were divided into 122 HDV-positive and 21 HDV-negative patients by HDV RNA positivity. Subgroup analysis was performed between hepatitis B e antigen (HBeAg)-positive and -negative HDV-positive patients. Liver function, quantitative HBsAg (qHBsAg), anti-HDV Immunoglobulin (Ig) M, Mac-2 binding protein glycosylation isomer (M2BPGi), hepatitis B virus (HBV) DNA level, and HDV RNA level were tested. HDV RNA was positive in 85.3% (122/143) of patients showing anti-HDV IgG. Liver disease activity was higher in HDV-positive patients than in HDV-negative patients. The HDV-positive group included a higher proportion of patients with high qHBsAg and M2BPGi levels (p < 0.001). The positivity rate for anti-HDV IgM was significantly higher in the HDV-positive group (p < 0.001). HDV RNA levels showed an inverse correlation with qHBsAg levels in HBeAg-positive-HDV-positive patients (r = -0.49, p = 0.034), and a positive correlation with qHBsAg levels in HBeAg-negative patients (r = 0.35, p < 0.001). Hepatitis B virus (HBV) DNA and HDV RNA levels did not show any correlation. M2BPGi levels likewise did not correlate with HDV RNA levels. A high positivity rate for HDV RNA was observed for HBV patients in Mongolia using the highly sensitive HDV RNA assay. The positivity rate for anti-HDV IgM was high in HDV RNA-positive patients. Severity of liver disease and M2BPGi levels were both high in the HDV RNA-positive group.
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Affiliation(s)
- Sarantuya Gidaagaya
- Department of Gastroenterology and Hepatology, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Akinori Rokuhara
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Masaya Sugiyama
- Department of Viral Pathogenesis and Controls, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Sumiya Dorj
- Laboratory Department, Intermed Hospital, Ulaanbaatar, Mongolia
| | - Batnasan Barsuren
- Department of Molecular Biology, Bonavita Clinical Laboratory, Ulaanbaatar, Mongolia
| | - Bira Namdag
- Department of Gastroenterology and Hepatology, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
| | - Batmunkh Munkhbat
- Department of Graduate Education, Graduate School, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia
- Department of Public Health and Office of Medical Education, School of Medicine, International University of Health and Welfare, Japan
| | - Shinichi Oka
- AIDS Clinical Center, National Center for Global Health and Medicine, Toyama, Tokyo, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
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Thiyagarajah K, Basic M, Hildt E. Cellular Factors Involved in the Hepatitis D Virus Life Cycle. Viruses 2023; 15:1687. [PMID: 37632029 PMCID: PMC10459925 DOI: 10.3390/v15081687] [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: 06/30/2023] [Revised: 07/30/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023] Open
Abstract
Hepatitis D virus (HDV) is a defective RNA virus with a negative-strand RNA genome encompassing less than 1700 nucleotides. The HDV genome encodes only for one protein, the hepatitis delta antigen (HDAg), which exists in two forms acting as nucleoproteins. HDV depends on the envelope proteins of the hepatitis B virus as a helper virus for packaging its ribonucleoprotein complex (RNP). HDV is considered the causative agent for the most severe form of viral hepatitis leading to liver fibrosis/cirrhosis and hepatocellular carcinoma. Many steps of the life cycle of HDV are still enigmatic. This review gives an overview of the complete life cycle of HDV and identifies gaps in knowledge. The focus is on the description of cellular factors being involved in the life cycle of HDV and the deregulation of cellular pathways by HDV with respect to their relevance for viral replication, morphogenesis and HDV-associated pathogenesis. Moreover, recent progress in antiviral strategies targeting cellular structures is summarized in this article.
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Affiliation(s)
| | | | - Eberhard Hildt
- Paul-Ehrlich-Institute, Department of Virology, D-63225 Langen, Germany; (K.T.); (M.B.)
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Blaney H, Khalid M, Heller T, Koh C. Epidemiology, presentation, and therapeutic approaches for hepatitis D infections. Expert Rev Anti Infect Ther 2023; 21:127-142. [PMID: 36519386 PMCID: PMC9905306 DOI: 10.1080/14787210.2023.2159379] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Chronic Hepatitis D virus (HDV) infection remains an important global public health problem, with a changing epidemiological landscape over the past decade along with widespread implementation of hepatitis B vaccination and human migration. The landscape of HDV treatments has been changing, with therapies that have been under development for the last decade now in late stage clinical trials. The anticipated availability of these new therapies will hopefully replace the current therapies which are minimally effective. AREAS COVERED This narrative review discusses the clinical course, screening and diagnosis, transmission risk factors, epidemiology, current and investigational therapies, and liver transplantation in HDV. Literature review was performed using PubMed and ClinicalTrials.gov and includes relevant articles from 1977 to 2022. EXPERT OPINION HDV infection is an important global public health issue with a true prevalence that is still unknown. The distribution of HDV infection has changed globally with the availability of HBV vaccination and patterns of human migration. As HDV infection is associated with accelerated disease courses and poor outcomes, the global community needs to agree upon a uniform HDV screening strategy to understand the truth of global prevalence such that new therapies can target appropriate individuals as they become available in the future.
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Affiliation(s)
- Hanna Blaney
- Digestive Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Mian Khalid
- Digestive Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Lucifora J, Alfaiate D, Pons C, Michelet M, Ramirez R, Fusil F, Amirache F, Rossi A, Legrand AF, Charles E, Vegna S, Farhat R, Rivoire M, Passot G, Gadot N, Testoni B, Bach C, Baumert TF, Hyrina A, Beran RK, Zoulim F, Boonstra A, Büning H, Verrier ER, Cosset FL, Fletcher SP, Salvetti A, Durantel D. Hepatitis D virus interferes with hepatitis B virus RNA production via interferon-dependent and -independent mechanisms. J Hepatol 2023; 78:958-970. [PMID: 36702177 DOI: 10.1016/j.jhep.2023.01.005] [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: 01/31/2022] [Revised: 01/10/2023] [Accepted: 01/10/2023] [Indexed: 01/25/2023]
Abstract
BACKGROUND & AIMS Chronic coinfection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. Herein, we aimed to elucidate the molecular mechanisms underlying the widely reported observation that HDV interferes with HBV in most coinfected patients. METHODS Patient liver tissues, primary human hepatocytes, HepaRG cells and human liver chimeric mice were used to analyze the effect of HDV on HBV using virological and RNA-sequencing analyses, as well as RNA synthesis, stability and association assays. RESULTS Transcriptomic analyses in cell culture and mouse models of coinfection enabled us to define an HDV-induced signature, mainly composed of interferon (IFN)-stimulated genes (ISGs). We also provide evidence that ISGs are upregulated in chronically HDV/HBV-coinfected patients but not in cells that only express HDV antigen (HDAg). Inhibition of the hepatocyte IFN response partially rescued the levels of HBV parameters. We observed less HBV RNA synthesis upon HDV infection or HDV protein expression. Additionally, HDV infection or expression of HDAg alone specifically accelerated the decay of HBV RNA, and HDAg was associated with HBV RNAs. On the contrary, HDAg expression did not affect other viruses such as HCV or SARS-CoV-2. CONCLUSIONS Our data indicate that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms. Specifically, we uncover a new viral interference mechanism in which proteins of a satellite virus affect the RNA production of its helper virus. Exploiting these findings could pave the way to the development of new therapeutic strategies against HBV. IMPACT AND IMPLICATIONS Although the molecular mechanisms remained unexplored, it has long been known that despite its dependency, HDV decreases HBV viremia in patients. Herein, using in vitro and in vivo models, we showed that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms affecting HBV RNA metabolism, and we defined the HDV-induced modulation signature. The mechanisms we uncovered could pave the way for the development of new therapeutic strategies against HBV by mimicking and/or increasing the effect of HDAg on HBV RNA. Additionally, the HDV-induced modulation signature could potentially be correlated with responsiveness to IFN-α treatment, thereby helping to guide management of HBV/HDV-coinfected patients.
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Affiliation(s)
- Julie Lucifora
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France.
| | - Dulce Alfaiate
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; Service des Maladies Infectieuses et Tropicales, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, Lyon, France
| | - Caroline Pons
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Maud Michelet
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | | | - Floriane Fusil
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
| | - Fouzia Amirache
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
| | - Axel Rossi
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Anne-Flore Legrand
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
| | - Emilie Charles
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
| | - Serena Vegna
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Rayan Farhat
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | | | - Guillaume Passot
- Service de chirurgie générale et Oncologique, Hôpital Lyon Sud, Hospices Civils de Lyon Et CICLY, EA3738, Université Lyon 1, France
| | - Nicolas Gadot
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Barbara Testoni
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - Charlotte Bach
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, Strasbourg, France
| | - Thomas F Baumert
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, Strasbourg, France; Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France
| | | | | | - Fabien Zoulim
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France; Department of Hepatology, Croix-Rousse Hospital, Hospices Civils de Lyon, Lyon, France
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Gravendijkwal 230, Rotterdam, the Netherlands
| | - Hildegard Büning
- Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany
| | - Eloi R Verrier
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, Strasbourg, France
| | - François-Loïc Cosset
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France
| | | | - Anna Salvetti
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
| | - David Durantel
- CIRI, Centre International de Recherche en Infectiologie, Univ Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, F-69007, Lyon, France; INSERM, U1052, Cancer Research Center of Lyon (CRCL), University of Lyon (UCBL1), CNRS UMR_5286, Centre Léon Bérard, Lyon, France
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11
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Koffas A, Mak LY, Kennedy PTF. Hepatitis delta virus: Disease assessment and stratification. J Viral Hepat 2022; 30 Suppl 1:11-20. [PMID: 36458851 DOI: 10.1111/jvh.13777] [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: 10/27/2022] [Accepted: 11/26/2022] [Indexed: 12/09/2022]
Abstract
Hepatitis D virus (HDV) causes one of the most severe forms of hepatitis in people with chronic hepatitis B (CHB) infection. Timely and accurate assessment of hepatitis delta virus (HDV) and disease stratification is mandatory for thorough pre-therapeutic evaluation for prioritizing treatment and outcome prediction. Viral biomarkers associated with HDV and hepatitis B virus (HBV) are crucial to aid in diagnosis, and monitoring of serum viral nucleic acids for both viruses is recommended. Liver biopsy remains the gold standard for staging of liver fibrosis and grading of histological activity and should remain central for diagnostic purposes, but is also of importance for research to enhance our understanding of HDV. The emergence of novel non-invasive tests for the assessment of liver fibrosis in HDV patients coupled with the well-recognized potential complications of liver biopsy has resulted in reduced utility of liver biopsy in clinical practice. Preliminary data suggest that these emerging non-invasive modalities appear to be reliable, and their use is supported, similar to other viral hepatitis. Nevertheless, further validation is required before their widespread adoption into clinical practice.
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Affiliation(s)
- Apostolos Koffas
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Lung-Yi Mak
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.,Department of Medicine, Queen Mary Hospital, School of Clinical Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Patrick T F Kennedy
- Barts Liver Centre, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
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12
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Kim GW, Moon JS, Gudima SO, Siddiqui A. N 6-Methyladenine Modification of Hepatitis Delta Virus Regulates Its Virion Assembly by Recruiting YTHDF1. J Virol 2022; 96:e0112422. [PMID: 36102650 PMCID: PMC9555152 DOI: 10.1128/jvi.01124-22] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 08/22/2022] [Indexed: 11/20/2022] Open
Abstract
Hepatitis delta virus (HDV) is a defective satellite virus that uses hepatitis B virus (HBV) envelope proteins to form its virions and infect hepatocytes via the HBV receptors. Concomitant HDV/HBV infection continues to be a major health problem, with at least 25 million people chronically infected worldwide. N6-methyladenine (m6A) modification of cellular and viral RNAs is the most prevalent internal modification that occurs cotranscriptionally, and this modification regulates various biological processes. We have previously described a wider range of functional roles of m6A methylation of HBV RNAs, including its imminent regulatory role in the encapsidation of pregenomic RNA. In this study, we present evidence that m6A methylation also plays an important role in the HDV life cycle. Using the methylated RNA immunoprecipitation (MeRIP) assay, we identified that the intracellular HDV genome and antigenome are m6A methylated in HDV- and HBV-coinfected primary human hepatocytes and HepG2 cell expressing sodium taurocholate cotransporting polypeptide (NTCP), while the extracellular HDV genome is not m6A methylated. We observed that HDV genome and delta antigen levels are significantly decreased in the absence of METTL3/14, while the extracellular HDV genome levels are increased by depletion of METTL3/14. Importantly, YTHDF1, an m6A reader protein, interacts with the m6A-methylated HDV genome and inhibits the interaction between the HDV genome and antigens. Thus, m6A of the HDV genome negatively regulates virion production by inhibiting the interaction of the HDV genome with delta antigens through the recruitment of YTHDF1. This is the first study that provides insight into the functional roles of m6A in the HDV life cycle. IMPORTANCE The functional roles of N6-methyladenine (m6A) modifications in the HBV life cycle have been recently highlighted. Here, we investigated the functional role of m6A modification in the HDV life cycle. HDV is a subviral agent of HBV, as it uses HBV envelope proteins to form its virions. We found that m6A methylation also occurs in the intracellular HDV genome and antigenome but not in the extracellular HDV genome. The m6A modification of the HDV genome recruits m6A reader protein (YTHDF1) onto the viral genome. The association of YTHDF1 with the HDV genome abrogates the interaction of delta antigens with the HDV genome and inhibits virion assembly. This study describes the unique effects of m6A on regulation of the HDV life cycle.
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Affiliation(s)
- Geon-Woo Kim
- Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego, La Jolla, California, USA
- Department of Microbiology and Molecular Biology, Chungnam National University, Yuseong-gu, Daejeon, Republic of Korea
| | - Jae-Su Moon
- Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - Severin O. Gudima
- Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Aleem Siddiqui
- Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California, San Diego, La Jolla, California, USA
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13
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Yang Y, Delcourte L, Fogeron ML, Böckmann A, Lecoq L. 1H, 15N and 13C backbone and side chain solution NMR assignments of the truncated small hepatitis delta antigen Δ60-S-HDAg. BIOMOLECULAR NMR ASSIGNMENTS 2022; 16:311-316. [PMID: 35749039 DOI: 10.1007/s12104-022-10096-1] [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: 04/22/2022] [Accepted: 05/30/2022] [Indexed: 06/15/2023]
Abstract
Hepatitis D virus (HDV) is a defective virus that relies on hepatitis B virus envelope proteins to complete its replication cycle. The HDV genome contains two isoforms of hepatitis delta antigen: the small and the large hepatitis delta antigens (S- and L-HDAg). Here we report the 1H, 13C and 15 N backbone and side chain resonance assignments of an N-terminally truncated form of S-HDAg (SΔ60), which lacks the 1-60 oligomerization domain. We derived secondary structures based on NMR chemical shifts, which will be used in further structural and functional studies. We show that SΔ60 is partially disordered, and that the central structured part contains two well-defined α-helices of 22 and 17 residues, respectively. A temperature titration allowed to identify the residues involved in hydrogen bonds.
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Affiliation(s)
- Yang Yang
- Molecular Microbiology and Structural Biochemistry (MMSB), UMR 5086, CNRS, Université de Lyon, Labex Ecofect, 7 passage du Vercors, 69367, Lyon, France
| | - Loïc Delcourte
- Molecular Microbiology and Structural Biochemistry (MMSB), UMR 5086, CNRS, Université de Lyon, Labex Ecofect, 7 passage du Vercors, 69367, Lyon, France
| | - Marie-Laure Fogeron
- Molecular Microbiology and Structural Biochemistry (MMSB), UMR 5086, CNRS, Université de Lyon, Labex Ecofect, 7 passage du Vercors, 69367, Lyon, France
| | - Anja Böckmann
- Molecular Microbiology and Structural Biochemistry (MMSB), UMR 5086, CNRS, Université de Lyon, Labex Ecofect, 7 passage du Vercors, 69367, Lyon, France.
| | - Lauriane Lecoq
- Molecular Microbiology and Structural Biochemistry (MMSB), UMR 5086, CNRS, Université de Lyon, Labex Ecofect, 7 passage du Vercors, 69367, Lyon, France.
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14
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Asif B, Koh C. Hepatitis D virus (HDV): investigational therapeutic agents in clinical trials. Expert Opin Investig Drugs 2022; 31:905-920. [PMID: 34482769 PMCID: PMC11391510 DOI: 10.1080/13543784.2021.1977795] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 09/03/2021] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Chronic Hepatitis D virus (HDV) infection is a global disease leading to rapidly progressive liver disease with increased liver-related mortality and hepatocellular carcinoma. Therapies are minimally effective; however, an increased understanding of the HDV lifecycle has provided new potential drug targets. Thus, there is a growing number of investigational therapeutics under exploration for HDV with the potential for successful viral eradication. AREAS COVERED This review discusses the clinical impact of HDV infection and offers an in-depth look at the HDV life cycle. The authors examine current and new drug targets and the investigational therapies in clinical trials. The search strategy was based on PubMed database and clinicaltrials.gov which highlight the most up-to-date aspects of investigational therapies for chronic HDV infection.
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Affiliation(s)
- Bilal Asif
- Digestive Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, USA
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, USA
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15
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Burm R, Maravelia P, Ahlen G, Ciesek S, Caro Perez N, Pasetto A, Urban S, Van Houtte F, Verhoye L, Wedemeyer H, Johansson M, Frelin L, Sällberg M, Meuleman P. Novel prime-boost immune-based therapy inhibiting both hepatitis B and D virus infections. Gut 2022; 72:1186-1195. [PMID: 35977815 PMCID: PMC10176361 DOI: 10.1136/gutjnl-2022-327216] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 07/29/2022] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Chronic HBV/HDV infections are a major cause of liver cancer. Current treatments can only rarely eliminate HBV and HDV. Our previously developed preS1-HDAg immunotherapy could induce neutralising antibodies to HBV in vivo and raise HBV/HDV-specific T-cells. Here, we further investigate if a heterologous prime-boost strategy can circumvent T-cell tolerance and preclude HDV superinfection in vivo. DESIGN A DNA prime-protein boost strategy was evaluated for immunogenicity in mice and rabbits. Its ability to circumvent T-cell tolerance was assessed in immunocompetent hepatitis B surface antigen (HBsAg)-transgenic mice. Neutralisation of HBV and HDV was evaluated both in vitro and in immunodeficient human-liver chimeric mice upon adoptive transfer. RESULTS The prime-boost strategy elicits robust HBV/HDV-specific T-cells and preS1-antibodies that can effectively prevent HBV and HDV (co-)infection in vitro and in vivo. In a mouse model representing the chronic HBsAg carrier state, active immunisation primes high levels of preS1-antibodies and HDAg-specific T-cells. Moreover, transfer of vaccine-induced antibodies completely protects HBV-infected human-liver chimeric mice from HDV superinfection. CONCLUSION The herein described preS1-HDAg immunotherapy is shown to be immunogenic and vaccine-induced antibodies are highly effective at preventing HBV and HDV (super)infection both in vitro and in vivo. Our vaccine can complement current and future therapies for the control of chronic HBV and HDV infection.
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Affiliation(s)
- Rani Burm
- Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Panagiota Maravelia
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Gustaf Ahlen
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Sandra Ciesek
- Institute for Medical Virology, University Hospital, Goethe University, Frankfurt am Main, Germany.,Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany.,German Center for Infection Research, DZIF, External partner site, Frankfurt am Main, Germany
| | - Noelia Caro Perez
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Anna Pasetto
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Freya Van Houtte
- Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Lieven Verhoye
- Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Magnus Johansson
- School of Medical Sciences, Inflammatory Response and Infection Susceptibility Centre (iRiSC), Faculty of Medicine and Health, Örebro University, Orebro, Sweden
| | - Lars Frelin
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Matti Sällberg
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases (LLID), Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
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16
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Michelet M, Alfaiate D, Chardès B, Pons C, Faure-Dupuy S, Engleitner T, Farhat R, Riedl T, Legrand AF, Rad R, Rivoire M, Zoulim F, Heikenwälder M, Salvetti A, Durantel D, Lucifora J. Inducers of the NF-κB pathways impair hepatitis delta virus replication and strongly decrease progeny infectivity in vitro. JHEP Rep 2022; 4:100415. [PMID: 35141510 PMCID: PMC8792426 DOI: 10.1016/j.jhepr.2021.100415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 11/03/2021] [Accepted: 12/02/2021] [Indexed: 10/26/2022] Open
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17
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Szirovicza L, Hetzel U, Kipar A, Hepojoki J. Short '1.2× Genome' Infectious Clone Initiates Kolmiovirid Replication in Boa constrictor Cells. Viruses 2022; 14:107. [PMID: 35062311 PMCID: PMC8778117 DOI: 10.3390/v14010107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/21/2021] [Accepted: 01/04/2022] [Indexed: 11/29/2022] Open
Abstract
Human hepatitis D virus (HDV) depends on hepatitis B virus co-infection and its glycoproteins for infectious particle formation. HDV was the sole known deltavirus for decades and believed to be a human-only pathogen. However, since 2018, several groups reported finding HDV-like agents from various hosts but without co-infecting hepadnaviruses. In vitro systems enabling helper virus-independent replication are key for studying the newly discovered deltaviruses. Others and we have successfully used constructs containing multimers of the deltavirus genome for the replication of various deltaviruses via transfection in cell culture. Here, we report the establishment of deltavirus infectious clones with 1.2× genome inserts bearing two copies of the genomic and antigenomic ribozymes. We used Swiss snake colony virus 1 as the model to compare the ability of the previously reported "2× genome" and the "1.2× genome" infectious clones to initiate replication in cell culture. Using immunofluorescence, qRT-PCR, immuno- and northern blotting, we found the 2× and 1.2× genome clones to similarly initiate deltavirus replication in vitro and both induced a persistent infection of snake cells. The 1.2× genome constructs enable easier introduction of modifications required for studying deltavirus replication and cellular interactions.
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Affiliation(s)
- Leonora Szirovicza
- Medicum, Department of Virology, University of Helsinki, 00290 Helsinki, Finland;
| | - Udo Hetzel
- Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zürich, 8057 Zürich, Switzerland; (U.H.); (A.K.)
- Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, 00790 Helsinki, Finland
| | - Anja Kipar
- Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zürich, 8057 Zürich, Switzerland; (U.H.); (A.K.)
- Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, 00790 Helsinki, Finland
| | - Jussi Hepojoki
- Medicum, Department of Virology, University of Helsinki, 00290 Helsinki, Finland;
- Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zürich, 8057 Zürich, Switzerland; (U.H.); (A.K.)
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18
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Zakh R, Churkin A, Bietsch W, Lachiany M, Cotler SJ, Ploss A, Dahari H, Barash D. A Mathematical Model for early HBV and -HDV Kinetics during Anti-HDV Treatment. MATHEMATICS (BASEL, SWITZERLAND) 2021; 9:3323. [PMID: 35282153 PMCID: PMC8916717 DOI: 10.3390/math9243323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Hepatitis delta virus (HDV) is an infectious subviral agent that can only propagate in people infected with hepatitis B virus (HBV). HDV/HBV infection is considered to be the most severe form of chronic viral hepatitis. In this contribution, a mathematical model for the interplay between HDV and HBV under anti-HDV treatment is presented. Previous models were not designed to account for the observation that HBV rises when HDV declines with HDV-specific therapy. In the simple model presented here, HDV and HBV kinetics are coupled, giving rise to an improved viral kinetic model that simulates the early interplay of HDV and HBV during anti-HDV therapy.
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Affiliation(s)
- Rami Zakh
- Department of Computer Science, Ben-Gurion University, Beer-Sheva 8410501, Israel
| | - Alexander Churkin
- Department of Software Engineering, Sami Shamoon College of Engineering, Beer-Sheva 8410501, Israel
| | - William Bietsch
- Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
| | | | - Scott J. Cotler
- Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
| | - Harel Dahari
- Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA
| | - Danny Barash
- Department of Computer Science, Ben-Gurion University, Beer-Sheva 8410501, Israel
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19
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Heuschkel MJ, Baumert TF, Verrier ER. Cell Culture Models for the Study of Hepatitis D Virus Entry and Infection. Viruses 2021; 13:v13081532. [PMID: 34452397 PMCID: PMC8402901 DOI: 10.3390/v13081532] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/29/2022] Open
Abstract
Chronic hepatitis D is one of the most severe and aggressive forms of chronic viral hepatitis with a high risk of developing hepatocellular carcinoma (HCC). It results from the co-infection of the liver with the hepatitis B virus (HBV) and its satellite, the hepatitis D virus (HDV). Although current therapies can control HBV infection, no treatment that efficiently eliminates HDV is available and novel therapeutic strategies are needed. Although the HDV cycle is well described, the lack of simple experimental models has restricted the study of host–virus interactions, even if they represent relevant therapeutic targets. In the last few years, the discovery of the sodium taurocholate co-transporting polypeptide (NTCP) as a key cellular entry factor for HBV and HDV has allowed the development of new cell culture models susceptible to HBV and HDV infection. In this review, we summarize the main in vitro model systems used for the study of HDV entry and infection, discuss their benefits and limitations and highlight perspectives for future developments.
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Affiliation(s)
- Margaux J. Heuschkel
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, 67000 Strasbourg, France; (M.J.H.); (T.F.B.)
| | - Thomas F. Baumert
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, 67000 Strasbourg, France; (M.J.H.); (T.F.B.)
- Institut Hospitalo-Universitaire, Pôle Hépato-Digestif, Nouvel Hôpital Civil, 1 Place de L’Hôpital, 67000 Strasbourg, France
| | - Eloi R. Verrier
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, 67000 Strasbourg, France; (M.J.H.); (T.F.B.)
- Correspondence: ; Tel.: +33-3-68-85-37-06
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20
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Pérez-Vargas J, Pereira de Oliveira R, Jacquet S, Pontier D, Cosset FL, Freitas N. HDV-Like Viruses. Viruses 2021; 13:1207. [PMID: 34201626 PMCID: PMC8310214 DOI: 10.3390/v13071207] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 06/11/2021] [Accepted: 06/16/2021] [Indexed: 02/07/2023] Open
Abstract
Hepatitis delta virus (HDV) is a defective human virus that lacks the ability to produce its own envelope proteins and is thus dependent on the presence of a helper virus, which provides its surface proteins to produce infectious particles. Hepatitis B virus (HBV) was so far thought to be the only helper virus described to be associated with HDV. However, recent studies showed that divergent HDV-like viruses could be detected in fishes, birds, amphibians, and invertebrates, without evidence of any HBV-like agent supporting infection. Another recent study demonstrated that HDV can be transmitted and propagated in experimental infections ex vivo and in vivo by different enveloped viruses unrelated to HBV, including hepatitis C virus (HCV) and flaviviruses such as Dengue and West Nile virus. All this new evidence, in addition to the identification of novel virus species within a large range of hosts in absence of HBV, suggests that deltaviruses may take advantage of a large spectrum of helper viruses and raises questions about HDV origins and evolution.
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Affiliation(s)
- Jimena Pérez-Vargas
- CIRI—Centre International de Recherche en Infectiologie, Université de Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, 46 allée d’Italie, F-69007 Lyon, France; (J.P.-V.); (R.P.d.O.); (N.F.)
| | - Rémi Pereira de Oliveira
- CIRI—Centre International de Recherche en Infectiologie, Université de Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, 46 allée d’Italie, F-69007 Lyon, France; (J.P.-V.); (R.P.d.O.); (N.F.)
| | - Stéphanie Jacquet
- LBBE UMR5558 CNRS—Centre National de la Recherche Scientifique, Université de Lyon 1—48 bd du 11 Novembre 1918, 69100 Villeurbanne, France; (S.J.); (D.P.)
| | - Dominique Pontier
- LBBE UMR5558 CNRS—Centre National de la Recherche Scientifique, Université de Lyon 1—48 bd du 11 Novembre 1918, 69100 Villeurbanne, France; (S.J.); (D.P.)
| | - François-Loïc Cosset
- CIRI—Centre International de Recherche en Infectiologie, Université de Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, 46 allée d’Italie, F-69007 Lyon, France; (J.P.-V.); (R.P.d.O.); (N.F.)
| | - Natalia Freitas
- CIRI—Centre International de Recherche en Infectiologie, Université de Lyon, Université Claude Bernard Lyon 1, Inserm, U1111, CNRS, UMR5308, ENS Lyon, 46 allée d’Italie, F-69007 Lyon, France; (J.P.-V.); (R.P.d.O.); (N.F.)
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21
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Netter HJ, Barrios MH, Littlejohn M, Yuen LKW. Hepatitis Delta Virus (HDV) and Delta-Like Agents: Insights Into Their Origin. Front Microbiol 2021; 12:652962. [PMID: 34234753 PMCID: PMC8256844 DOI: 10.3389/fmicb.2021.652962] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 05/12/2021] [Indexed: 01/05/2023] Open
Abstract
Hepatitis delta virus (HDV) is a human pathogen, and the only known species in the genus Deltavirus. HDV is a satellite virus and depends on the hepatitis B virus (HBV) for packaging, release, and transmission. Extracellular HDV virions contain the genomic HDV RNA, a single-stranded negative-sense and covalently closed circular RNA molecule, which is associated with the HDV-encoded delta antigen forming a ribonucleoprotein complex, and enveloped by the HBV surface antigens. Replication occurs in the nucleus and is mediated by host enzymes and assisted by cis-acting ribozymes allowing the formation of monomer length molecules which are ligated by host ligases to form unbranched rod-like circles. Recently, meta-transcriptomic studies investigating various vertebrate and invertebrate samples identified RNA species with similarities to HDV RNA. The delta-like agents may be representatives of novel subviral agents or satellite viruses which share with HDV, the self-complementarity of the circular RNA genome, the ability to encode a protein, and the presence of ribozyme sequences. The widespread distribution of delta-like agents across different taxa with considerable phylogenetic distances may be instrumental in comprehending their evolutionary history by elucidating the transition from transcriptome to cellular circular RNAs to infectious subviral agents.
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Affiliation(s)
- Hans J Netter
- Victorian Infectious Diseases Reference Laboratory (VIDRL), Melbourne Health, The Peter Doherty Institute, Melbourne, VIC, Australia.,School of Science, Royal Melbourne Institute of Technology (RMIT) University, Melbourne, VIC, Australia
| | - Marilou H Barrios
- Victorian Infectious Diseases Reference Laboratory (VIDRL), Melbourne Health, The Peter Doherty Institute, Melbourne, VIC, Australia.,The Peter Doherty Institute, University of Melbourne, Melbourne, VIC, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory (VIDRL), Melbourne Health, The Peter Doherty Institute, Melbourne, VIC, Australia
| | - Lilly K W Yuen
- Victorian Infectious Diseases Reference Laboratory (VIDRL), Melbourne Health, The Peter Doherty Institute, Melbourne, VIC, Australia
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22
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Rizzetto M, Stroffolini T. Forty-Five Years after the Discovery of the Hepatitis D Virus: Where Do We Stand? Viruses 2021; 13:555. [PMID: 33810224 PMCID: PMC8066537 DOI: 10.3390/v13040555] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 03/19/2021] [Accepted: 03/23/2021] [Indexed: 12/16/2022] Open
Abstract
The discovery of the Australia Antigen in the mid-1960s led, in a few years, to the identification of the virus of Hepatitis B [...].
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Affiliation(s)
- Mario Rizzetto
- Department of Medical Sciences, University of Turin, 10126 Turin, Italy
| | - Tommaso Stroffolini
- Department of Tropical and Infectious Diseases, Policlinico Umberto I, University of Rome, 00161 Rome, Italy;
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23
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Bove G, Mehnert AK, Dao Thi VL. iPSCs for modeling hepatotropic pathogen infections. IPSCS FOR STUDYING INFECTIOUS DISEASES 2021:149-213. [DOI: 10.1016/b978-0-12-823808-0.00013-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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24
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Kumar P, Freeland C, Bodor S, Farrell S, Cohen C, Frasso R. Needs of Individuals Living With Hepatitis Delta Virus and Their Caregivers, 2016-2019. Prev Chronic Dis 2020; 17:E159. [PMID: 33337297 PMCID: PMC7769086 DOI: 10.5888/pcd17.200324] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Introduction Hepatitis delta virus (HDV) is a serious coinfection of the hepatitis B virus (HBV) that is estimated to affect between 48 to 72 million people worldwide. Data are limited on the informational needs of people living with HDV. The Hepatitis B Foundation, a US-based nonprofit organization that provides support to people living with HBV and HDV, receives emails (queries) as part of a helpline, a service to provide information, resources, and support to people affected by HBV and HDV. Methods Query content was analyzed to assess the impact of HDV at the individual level. A total of 65 HDV-related queries from 17 countries were received from October 2016 to January 2019, and all were analyzed for this study. Results Thematic analysis of queries indicated 4 dominant themes. Three were related to a need for information about 1) the disease and prevention of it, 2) disease symptoms and outcomes, and 3) treatment options. The fourth theme was related to barriers and quality of life. Individuals requested information on treatment options, medication access, diagnostic test interpretation, and clinical trials. Conclusion Our study highlights the needs and lived experience of patients with HDV and summarizes critical information gaps. Findings can inform health care providers, public health professionals, and the pharmaceutical and biotechnology industries about the informational needs and lived experiences of individuals living with HDV and help create future HDV-related educational resources, care, and clinical trials.
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Affiliation(s)
- Priyanka Kumar
- Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania.,Jefferson College of Population Health, Philadelphia, Pennsylvania.,101 The City Drive S, Suite 400, Orange, CA 92868.
| | - Catherine Freeland
- Jefferson College of Population Health, Philadelphia, Pennsylvania.,Hepatitis B Foundation, Doylestown, Pennsylvania
| | - Sierra Bodor
- Hepatitis B Foundation, Doylestown, Pennsylvania
| | - Sean Farrell
- Jefferson College of Population Health, Philadelphia, Pennsylvania.,Geisinger Commonwealth School of Medicine, Scranton, Pennsylvania
| | - Chari Cohen
- Hepatitis B Foundation, Doylestown, Pennsylvania
| | - Rosemary Frasso
- Jefferson College of Population Health, Philadelphia, Pennsylvania
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25
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Badar U, Venkataraman S, AbouHaidar M, Hefferon K. Molecular interactions of plant viral satellites. Virus Genes 2020; 57:1-22. [PMID: 33226576 DOI: 10.1007/s11262-020-01806-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 10/24/2020] [Indexed: 12/18/2022]
Abstract
Plant viral satellites fall under the category of subviral agents. Their genomes are composed of small RNA or DNA molecules a few hundred nucleotides in length and contain an assortment of highly complex and overlapping functions. Each lacks the ability to either replicate or undergo encapsidation or both in the absence of a helper virus (HV). As the number of known satellites increases steadily, our knowledge regarding their sequence conservation strategies, means of replication and specific interactions with host and helper viruses is improving. This review demonstrates that the molecular interactions of these satellites are unique and highly complex, largely influenced by the highly specific host plants and helper viruses that they associate with. Circularized forms of single-stranded RNA are of particular interest, as they have recently been found to play a variety of novel cellular functions. Linear forms of satRNA are also of great significance as they may complement the helper virus genome in exacerbating symptoms, or in certain instances, actively compete against it, thus reducing symptom severity. This review serves to describe the current literature with respect to these molecular mechanisms in detail as well as to discuss recent insights into this emerging field in terms of evolution, classification and symptom development. The review concludes with a discussion of future steps in plant viral satellite research and development.
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Affiliation(s)
- Uzma Badar
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada
| | | | - Mounir AbouHaidar
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada
| | - Kathleen Hefferon
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON, Canada.
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26
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Distinct Cytokine Profiles Correlate with Disease Severity and Outcome in Longitudinal Studies of Acute Hepatitis B Virus and Hepatitis D Virus Infection in Chimpanzees. mBio 2020; 11:mBio.02580-20. [PMID: 33203756 PMCID: PMC7683399 DOI: 10.1128/mbio.02580-20] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Historical studies conducted in chimpanzees gave us the opportunity to investigate the basis for the different severities of liver damage and disease outcome associated with infection with wild-type hepatitis B virus (HBV) versus a precore HBV mutant, HBV/hepatitis D virus (HDV) coinfection, and HDV superinfection. Weekly samples from 9 chimpanzees were studied for immune responses by measuring plasma levels of 29 cytokines in parallel with alanine aminotransferase (ALT) levels and viral kinetics. Comparison of classic acute hepatitis B (AHB) with severe or progressive AHB and HBV/HDV coinfection or superinfection identified distinct cytokine profiles. Classic AHB (mean ALT peak, 362 IU/liter) correlated with an early and significant induction of interferon alpha-2 (IFN-α2), IFN-γ, interleukin-12 p70 (IL-12 p70), and IL-17A. In contrast, these cytokines were virtually undetectable in severe AHB (mean ALT peak, 1,335 IU/liter), characterized by significant elevations of IL-10, tumor necrosis factor alpha (TNF-α), and MIP-1β. In progressive AHB (mean ALT peak, 166 IU/liter), there was a delayed and lower-magnitude induction of cytokines. The ALT peak was also delayed (mean, 23.5 weeks) compared to those of classic (13.5 weeks) and severe AHB (7.5 weeks). HBV/HDV coinfection correlated with significantly lower levels of IFN-α2, IFN-γ, and IL-17A, associated with the presence of multiple proinflammatory cytokines, including IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-15. Conversely, HDV superinfection induced the highest ALT peak (1,910 IU/liter) and was associated with a general suppression of cytokines. Our data demonstrate that the most severe liver damage, caused by an HBV precore mutant and HDV, correlated with restricted cytokine expression and lack of Th1 response, raising the question of whether these viruses are directly cytopathic.IMPORTANCE Studies performed in chimpanzees at the National Institutes of Health (NIH) demonstrated a significant difference in ALT levels during acute hepatitis of different viral etiologies, with a hierarchy in the extent of liver damage according to the infecting virus: the highest level was in HDV superinfection, followed by infection with a precore HBV mutant, HBV/HDV coinfection, and, lastly, wild-type HBV infection. Our study demonstrates that both the virus and host are important in disease pathogenesis and offers new insights into their roles. We found that distinct cytokine profiles were associated with disease severity and clinical outcome. In particular, resolution of classic acute hepatitis B (AHB) correlated with a predominant Th1 response, whereas HBV/HDV coinfection showed a predominant proinflammatory response. Severe AHB and HDV superinfection showed a restricted cytokine profile and no evidence of Th1 response. The lack of cytokines associated with adaptive T-cell responses toward the precore HBV mutant and HDV superinfection argues in favor of a direct cytopathic effect of these viruses.
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27
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Rizzetto M. The Discovery of the Hepatitis D Virus: Three Princes of Serendip and the Recognition of Autoantibodies to Liver-Kidney Microsomes. Clin Liver Dis (Hoboken) 2020; 16:1-11. [PMID: 33042522 PMCID: PMC7538916 DOI: 10.1002/cld.1033] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 08/23/2020] [Indexed: 02/04/2023] Open
Affiliation(s)
- Mario Rizzetto
- Division of GastroenterologyUniversity of TurinTurinItaly
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28
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Khuroo MS, Sofi AA. The Discovery of Hepatitis Viruses: Agents and Disease. J Clin Exp Hepatol 2020; 10:391-401. [PMID: 32655240 PMCID: PMC7335725 DOI: 10.1016/j.jceh.2020.04.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Accepted: 04/08/2020] [Indexed: 02/06/2023] Open
Abstract
Discovery of five hepatitis viruses A to E has followed distinctive definable phases. Human experiments at Willowbrook identified two forms of hepatitis namely infectious hepatitis and serum hepatitis. The discovery of Australia antigen in 1965 led to rapid scientific developments in viral hepatitis. SH antigen was detected in sera of patients with serum hepatitis and soon SH antigen and Australia antigen were found to be identical and selectively associated with serum hepatitis. In 1970, 42-nm Dane particles were detected in Australia antigen positive sera and linked to the virus of serum hepatitis. Subsequently, a new antigen-antibody system (e-antigen/antibody) was detected in such patients and associated with infectivity. Then, DNA polymerase was found in concentrated pellets containing Australia antigen. Hepatitis B virus (HBV) DNA cloning and sequencing of HBV followed these developments. In 1973, 27 nm hepatitis A virus (HAV)-like particles were visualized in stool samples obtained during acute phase of illness after inoculation of MS-1 strain in volunteers. Cloning and sequencing of HAV followed. In 1977, a new antigen-antibody system (δ antigen-antibody system) was identified by chance associated with HBV. Based on animal transmission studies, δ agent was found to be another virus called hepatitis D virus that is defective, requires the helper functions of HBV and interferes with HBV replication. The search for hepatitis C virus started when non-A, non-B hepatitis was recognised in multiply transfused patients with subsequent successful animal transmission. HCV was identified by a novel immunoscreening approach involving screening of cDNA libraries from infectious sera. The story of hepatitis E is historically linked to discovery of waterborne epidemic non-A, non-B hepatitis from Kashmir, India. Virus-like-particles of the agent were identified in stool samples of a human volunteer after a self-experimentation. HEV cDNA was detected in bile-enriched infectious samples and full-length HEV RNA genome was subsequently cloned and sequenced.
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Affiliation(s)
- Mohammad S. Khuroo
- Digestive Diseases Centre, Dr Khuroo Medical Clinic, Srinagar, Kashmir, J&K (UT), India
- Sher-I-Kashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, J&K (UT), India
| | - Ahmad A. Sofi
- Digestive Diseases Centre, Dr Khuroo Medical Clinic, Srinagar, Kashmir, J&K (UT), India
- Burn Hall School, Gupkar Road, Sonwar, Srinagar, Kashmir, J&K (UT), India
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29
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Taylor JM. Infection by Hepatitis Delta Virus. Viruses 2020; 12:v12060648. [PMID: 32560053 PMCID: PMC7354607 DOI: 10.3390/v12060648] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/10/2020] [Accepted: 06/12/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis delta virus (HDV) and hepatitis B virus (HBV) are blood-borne viruses that infect human hepatocytes and cause significant liver disease. Infections with HBV are more damaging when there is a coinfection with HDV. The genomes and modes of replication of these two viruses are fundamentally different, except for the fact that, in nature, HDV replication is dependent upon the envelope proteins of HBV to achieve assembly and release of infectious virus particles, ones that use the same host cell receptor. This review focuses on what has been found of the various ways, natural and experimental, by which HDV particles can be assembled and released. This knowledge has implications for the prevention and treatment of HDV infections, and maybe for an understanding of the origin of HDV.
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Affiliation(s)
- John M Taylor
- Fox Chase Cancer Center, Philadelphia, PA 19111, USA
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30
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Hercun J, Koh C, Heller T. Hepatitis Delta: Prevalence, Natural History, and Treatment Options. Gastroenterol Clin North Am 2020; 49:239-252. [PMID: 32389361 DOI: 10.1016/j.gtc.2020.01.004] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2023]
Abstract
Half a century after its discovery, hepatitis delta remains a pertinent global health issue with a major clinical impact in endemic regions and an underestimated prevalence worldwide. Hepatitis delta virus infection follows a challenging clinical course and is responsible for significant liver-related morbidity. Although the only currently available treatment (pegylated interferon) does not provide consistent results, emerging therapeutic options are promising. This article explores the epidemiology, natural history, as well as current and potential therapeutic options for hepatitis delta virus infection.
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Affiliation(s)
- Julian Hercun
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Room 4-5722, Bethesda, MD 20892, USA.
| | - Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Room 4-5722, Bethesda, MD 20892, USA
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, Room 4-5722, Bethesda, MD 20892, USA
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31
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Lucifora J, Delphin M. Current knowledge on Hepatitis Delta Virus replication. Antiviral Res 2020; 179:104812. [PMID: 32360949 DOI: 10.1016/j.antiviral.2020.104812] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 04/20/2020] [Accepted: 04/25/2020] [Indexed: 12/14/2022]
Abstract
Hepatitis B Virus (HBV) that infects liver parenchymal cells is responsible for severe liver diseases and co-infection with Hepatitis Delta Virus (HDV) leads to the most aggressive form of viral hepatitis. Even tough being different for their viral genome (relaxed circular partially double stranded DNA for HBV and circular RNA for HDV), HBV and HDV are both maintained as episomes in the nucleus of infected cells and use the cellular machinery for the transcription of their viral RNAs. We propose here an update on the current knowledge on HDV replication cycle that may eventually help to identify new antiviral targets.
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Affiliation(s)
- Julie Lucifora
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, France.
| | - Marion Delphin
- INSERM, U1052, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL1), CNRS UMR_5286, France
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32
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Cagliani R, Forni D, Sironi M. Mode and tempo of human hepatitis virus evolution. Comput Struct Biotechnol J 2019; 17:1384-1395. [PMID: 31768229 PMCID: PMC6872792 DOI: 10.1016/j.csbj.2019.09.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/19/2019] [Accepted: 09/21/2019] [Indexed: 02/07/2023] Open
Abstract
Human viral hepatitis, a major cause of morbidity and mortality worldwide, is caused by highly diverse viruses with different genetic, ecological, and pathogenetic features. Technological advances that allow throughput sequencing of viral genomes, as well as the development of computational tools to analyze such genome data, have largely expanded our knowledge on the host range and evolutionary history of human hepatitis viruses. Thus, with the exclusion of hepatitis D virus, close or distant relatives of these human pathogens were identified in a number of domestic and wild mammals. Also, sequences of human viral strains isolated from different geographic locations and over different time-spans have allowed the application of phylogeographic and molecular dating approaches to large viral phylogenies. In this review, we summarize the most recent insights into our understanding of the evolutionary events and ecological contexts that determined the origin and spread of human hepatitis viruses.
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Affiliation(s)
- Rachele Cagliani
- Bioinformatics, Scientific Institute, IRCCS E. MEDEA, 23842 Bosisio Parini, Lecco, Italy
| | - Diego Forni
- Bioinformatics, Scientific Institute, IRCCS E. MEDEA, 23842 Bosisio Parini, Lecco, Italy
| | - Manuela Sironi
- Bioinformatics, Scientific Institute, IRCCS E. MEDEA, 23842 Bosisio Parini, Lecco, Italy
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33
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Coppola N, Alessio L, Onorato L, Sagnelli C, Sagnelli E, Pisaturo M. HDV infection in immigrant populations. J Med Virol 2019; 91:2049-2058. [PMID: 31429940 DOI: 10.1002/jmv.25570] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 08/10/2019] [Indexed: 12/16/2022]
Abstract
AIMS Little data have been published so far on the epidemiological aspects of hepatitis D virus (HDV) infection in immigrant populations and even poorer is the information on the virological, phylogenetic, and clinical aspects of this infection in these populations. This review article, aimed primarily at physicians caring for immigrants, summarizes the information available on HDV infection and analyzes data on this topic concerning the immigrant populations. METHODS AND RESULTS The prevalence of HDV infection in HBsAg-positive immigrants varies according to the country of origin. For example, in immigrants from sub-Saharan Africa, this prevalence is higher in those born in Equatorial Guinea (24.4%) than those from other African countries (10.3%). The epidemiological impact of HDV infection linked to migratory flows is a function of the different endemicity between countries of origin and countries in which a new existence has been established. This impact is high when immigrants from areas endemic to HDV infection (eg, Equatorial Guinea) settle in areas of low endemicity (eg, Germany or England, with a prevalence of around 4%), while the impact is lesser or nonexistent if the migratory flows are directed toward countries with intermediate endemicity (eg, Italy and Greece, with a prevalence of around 10%). CONCLUSION This impact of immigration on HDV epidemiology can be strong when HDV endemicity is high in the country of origin and low in the host country and slight when immigrants move to high or medium endemic countries.
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Affiliation(s)
- Nicola Coppola
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy.,Infectious Disease Unit, AORN Caserta, Caserta, Italy
| | | | - Lorenzo Onorato
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Caterina Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy.,Infectious Disease Unit, AORN Caserta, Caserta, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
| | - Mariantonietta Pisaturo
- Department of Mental Health and Public Medicine, Section of Infectious Diseases, University of Campania Luigi Vanvitelli, Naples, Italy
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34
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Abstract
Chronic hepatitis D (CHD) results from an infection with the hepatitis B virus and hepatitis D virus (HDV). CHD is the most severe form of human viral hepatitis. Current treatment options consist of interferon alfa, which is effective only in a minority of patients. Study of HDV molecular virology has resulted in new approaches entering clinical trials, with phase-3 studies the most advanced. These include the entry inhibitor bulevirtide, the nucleic acid polymer REP 2139-Ca, the farnesyltransferase inhibitor lonafarnib, and pegylated interferon lambda. This article summarizes the available data on these emerging therapeutics.
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Affiliation(s)
- Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Ben L. Da
- Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Jeffrey S. Glenn
- Departments of Medicine and Microbiology & Immunology, Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
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35
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Rasche A, Sander AL, Corman VM, Drexler JF. Evolutionary biology of human hepatitis viruses. J Hepatol 2019; 70:501-520. [PMID: 30472320 PMCID: PMC7114834 DOI: 10.1016/j.jhep.2018.11.010] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 11/09/2018] [Accepted: 11/10/2018] [Indexed: 02/06/2023]
Abstract
Hepatitis viruses are major threats to human health. During the last decade, highly diverse viruses related to human hepatitis viruses were found in animals other than primates. Herein, we describe both surprising conservation and striking differences of the unique biological properties and infection patterns of human hepatitis viruses and their animal homologues, including transmission routes, liver tropism, oncogenesis, chronicity, pathogenesis and envelopment. We discuss the potential for translation of newly discovered hepatitis viruses into preclinical animal models for drug testing, studies on pathogenesis and vaccine development. Finally, we re-evaluate the evolutionary origins of human hepatitis viruses and discuss the past and present zoonotic potential of their animal homologues.
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Affiliation(s)
- Andrea Rasche
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, 10117 Berlin, Germany,German Center for Infection Research (DZIF), Germany
| | - Anna-Lena Sander
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, 10117 Berlin, Germany
| | - Victor Max Corman
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, 10117 Berlin, Germany,German Center for Infection Research (DZIF), Germany
| | - Jan Felix Drexler
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, 10117 Berlin, Germany; German Center for Infection Research (DZIF), Germany.
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36
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Koh C, Heller T, Glenn JS. Pathogenesis of and New Therapies for Hepatitis D. Gastroenterology 2019; 156:461-476.e1. [PMID: 30342879 PMCID: PMC6340762 DOI: 10.1053/j.gastro.2018.09.058] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 09/21/2018] [Accepted: 09/25/2018] [Indexed: 12/13/2022]
Abstract
Hepatitis delta virus (HDV) infection of humans was first reported in 1977, and now it is now estimated that 15-20 million people are infected worldwide. Infection with HDV can be an acute or chronic process that occurs only in patients with an hepatitis B virus infection. Chronic HDV infection commonly results in the most rapidly progressive form of viral hepatitis; it is the chronic viral infection that is most likely to lead to cirrhosis, and it is associated with an increased risk of hepatocellular carcinoma. HDV infection is the only chronic human hepatitis virus infection without a therapy approved by the US Food and Drug Administration. Peginterferon alfa is the only recommended therapy, but it produces unsatisfactory results. We review therapeutic agents in development, designed to disrupt the HDV life cycle, that might benefit patients with this devastating disease.
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Affiliation(s)
- Christopher Koh
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
| | - Theo Heller
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Jeffrey S. Glenn
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California, USA
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37
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Biology of viral satellites and their role in pathogenesis. Curr Opin Virol 2018; 33:96-105. [DOI: 10.1016/j.coviro.2018.08.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Revised: 07/26/2018] [Accepted: 08/01/2018] [Indexed: 12/18/2022]
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38
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Preclinical Evaluation of In Vitro and In Vivo Antiviral Activities of KCT-01, a New Herbal Formula against Hepatitis B Virus. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 2018:1073509. [PMID: 30069220 PMCID: PMC6057320 DOI: 10.1155/2018/1073509] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Accepted: 06/12/2018] [Indexed: 12/28/2022]
Abstract
Hepatitis B virus (HBV) infectious diseases currently remain incurable due to limitations of conventional antivirals such as incapability of eradicating HBV DNA, prolonged use, drug resistance, and virological relapse. KCT-01, a 30% ethanol extract consisting of Artemisia capillaris, Sanguisorba officinalis, and Curcuma longa, was newly developed. The objective of this study was to investigate pharmacological activities of KCT-01 against HBV using HepG2.2.15 cells and a hydrodynamic injection model. KCT-01 significantly lowered antigen secretion, virion production, and pgRNA synthesis in HepG2.2.15 cells without affecting cell viability. KCT-01 administration also resulted in significant decrease of serum virion production, liver covalently closed circular (ccc) DNA levels, and mRNA synthesis of cytokines in the liver of mice injected with HBV DNA hydrodynamically. Interestingly, coadministration of KCT-01 with entecavir enhanced its in vitro and in vivo antiviral activities. Moreover, safety of KCT-01 was assured up to 5000 mg/kg in rats in both single and repeated-dose preclinical studies. Taken together, our findings demonstrate that KCT-01 is capable of suppressing HBV replication and inflammatory cytokine production in in vitro and in vivo models without showing toxicity, suggesting the potential of using KCT-01 alone or in combination with entecavir as antiviral agent.
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Wang Y, Glenn JS, Winters MA, Shen LP, Choong I, Shi YL, Bi SL, Ma LY, Zeng H, Zhang FJ. A new dual-targeting real-time RT-PCR assay for hepatitis D virus RNA detection. Diagn Microbiol Infect Dis 2018; 92:112-117. [PMID: 29941366 DOI: 10.1016/j.diagmicrobio.2018.05.016] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 05/01/2018] [Accepted: 05/23/2018] [Indexed: 12/22/2022]
Abstract
In this study, a real-time reverse transcription-polymerase chain reaction (real time RT-PCR) assay targeting 2 genetic segments was established to detect HDV RNA. Utilizing the World Health Organization International Standard for Hepatitis D Virus RNA, the lower limit of detection was 575 IU/mL, and the linearity of quantification ranged from 575,000 IU/mL to 575 IU/mL. 384 HBsAg-positive samples collected from China were tested by this method and HDV antibody detection. Eleven samples were positive for anti-HDV IgG which may persist after HDV resolution, 6 samples were HDV RNA positive, and 5 samples were positive for anti-HDV IgM. This assay showed more sensitivity than the detection of anti-HDV IgM. These data demonstrate that the real-time RT-PCR assay for HDV RNA could be implemented in the clinical detection of HDV infection in chronic HBV-infected patients in China.
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Affiliation(s)
- Yan Wang
- State Key Laboratory of Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention, Beijing, P.R. China; Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Clinical Center for HIV/AIDS, Capital Medical University, Beijing, P.R. China
| | - Jeffrey S Glenn
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA
| | - Mark A Winters
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, USA
| | - Li-Ping Shen
- National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Ingrid Choong
- Eiger BioPharmaceuticals, Inc. Palo Alto, California, USA
| | - Ya-Lun Shi
- Beijing Anapure BioScientific Co. Ltd, Beijing, China
| | - Sheng-Li Bi
- National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Li-Ying Ma
- State Key Laboratory of Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Chinese Center for Disease Control and Prevention, Beijing, P.R. China
| | - Hui Zeng
- Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Fu-Jie Zhang
- Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Clinical Center for HIV/AIDS, Capital Medical University, Beijing, P.R. China.
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40
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Coller KE, Butler EK, Luk KC, Rodgers MA, Cassidy M, Gersch J, McNamara AL, Kuhns MC, Dawson GJ, Kaptue L, Bremer B, Wedemeyer H, Cloherty GA. Development and performance of prototype serologic and molecular tests for hepatitis delta infection. Sci Rep 2018; 8:2095. [PMID: 29391553 PMCID: PMC5794785 DOI: 10.1038/s41598-018-20455-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 01/18/2018] [Indexed: 12/18/2022] Open
Abstract
Worldwide, an estimated 5% of hepatitis B virus (HBV) infected people are coinfected with hepatitis delta virus (HDV). HDV infection leads to increased mortality over HBV mono-infection, yet HDV diagnostics are not widely available. Prototype molecular (RNA) and serologic (IgG) assays were developed for high-throughput testing on the Abbott m2000 and ARCHITECT systems, respectively. RNA detection was achieved through amplification of a ribozyme region target, with a limit of detection of 5 IU/ml. The prototype serology assay (IgG) was developed using peptides derived from HDV large antigen (HDAg), and linear epitopes were further identified by peptide scan. Specificity of an HBV negative population was 100% for both assays. A panel of 145 HBsAg positive samples from Cameroon with unknown HDV status was tested using both assays: 16 (11.0%) had detectable HDV RNA, and 23 (15.7%) were sero-positive including the 16 HDV RNA positive samples. Additionally, an archival serial bleed panel from an HDV superinfected chimpanzee was tested with both prototypes; data was consistent with historic testing data using a commercial total anti-Delta test. Overall, the two prototype assays provide sensitive and specific methods for HDV detection using high throughput automated platforms, allowing opportunity for improved diagnosis of HDV infected patients.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Birgit Bremer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
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Heller T, Koh C, Glenn JS. Hepatitis D. ZAKIM AND BOYER'S HEPATOLOGY 2018:501-511.e4. [DOI: 10.1016/b978-0-323-37591-7.00034-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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42
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Botelho-Souza LF, Vasconcelos MPA, Dos Santos ADO, Salcedo JMV, Vieira DS. Hepatitis delta: virological and clinical aspects. Virol J 2017; 14:177. [PMID: 28903779 PMCID: PMC5597996 DOI: 10.1186/s12985-017-0845-y] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
There are an estimated 400 million chronic carriers of HBV worldwide; between 15 and 20 million have serological evidence of exposure to HDV. Traditionally, regions with high rates of endemicity are central and northern Africa, the Amazon Basin, eastern Europe and the Mediterranean, the Middle East and parts of Asia. There are two types of HDV/HBV infection which are differentiated by the previous status infection by HBV for the individual. Individuals with acute HBV infection contaminated by HDV is an HDV/HBV co-infection, while individuals with chronic HBV infection contaminated by HDV represent an HDV/HBV super-infection. The appropriate treatment for chronic hepatitis delta is still widely discussed since it does not have an effective drug. Alpha interferon is currently the only licensed therapy for the treatment of chronic hepatitis D. The most widely used drug is pegylated interferon but only approximately 25% of patients maintain a sustained viral response after 1 year of treatment. The best marker of therapeutic success would be the clearance of HBsAg, but this data is rare in clinical practice. Therefore, the best way to predict a sustained virologic response is the maintenance of undetectable HDV RNA levels.
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Affiliation(s)
- Luan Felipo Botelho-Souza
- Laboratório de Virologia Molecular - FIOCRUZ - RONDÔNIA, Rua da Beira, 7671 - BR 364, Km 3,5 Bairro Lagoa, CEP: 76812, Porto Velho, RO, CEP: 76812-329, Brazil.
- Ambulatório de Hepatites Virais, Fundação Oswaldo Cruz Rondônia e Centro de Pesquisa em Medicina Tropical - CEPEM, Avenida Guaporé, 215, anexo Hospital CEMETRON, Agenor M de Carvalho, Porto Velho, RO, CEP: 76812-329, Brazil.
- Programa de Pós-Graduação em Biologia Experimental - PGBioExp, Rodovia Br-364, KM 9, CAMPUS UNIR, Porto Velho, RO, CEP: 76801-974, Brazil.
| | | | - Alcione de Oliveira Dos Santos
- Laboratório de Virologia Molecular - FIOCRUZ - RONDÔNIA, Rua da Beira, 7671 - BR 364, Km 3,5 Bairro Lagoa, CEP: 76812, Porto Velho, RO, CEP: 76812-329, Brazil
- Ambulatório de Hepatites Virais, Fundação Oswaldo Cruz Rondônia e Centro de Pesquisa em Medicina Tropical - CEPEM, Avenida Guaporé, 215, anexo Hospital CEMETRON, Agenor M de Carvalho, Porto Velho, RO, CEP: 76812-329, Brazil
- Programa de Pós-Graduação em Biologia Experimental - PGBioExp, Rodovia Br-364, KM 9, CAMPUS UNIR, Porto Velho, RO, CEP: 76801-974, Brazil
| | - Juan Miguel Villalobos Salcedo
- Laboratório de Virologia Molecular - FIOCRUZ - RONDÔNIA, Rua da Beira, 7671 - BR 364, Km 3,5 Bairro Lagoa, CEP: 76812, Porto Velho, RO, CEP: 76812-329, Brazil
- Ambulatório de Hepatites Virais, Fundação Oswaldo Cruz Rondônia e Centro de Pesquisa em Medicina Tropical - CEPEM, Avenida Guaporé, 215, anexo Hospital CEMETRON, Agenor M de Carvalho, Porto Velho, RO, CEP: 76812-329, Brazil
- Programa de Pós-Graduação em Biologia Experimental - PGBioExp, Rodovia Br-364, KM 9, CAMPUS UNIR, Porto Velho, RO, CEP: 76801-974, Brazil
| | - Deusilene Souza Vieira
- Laboratório de Virologia Molecular - FIOCRUZ - RONDÔNIA, Rua da Beira, 7671 - BR 364, Km 3,5 Bairro Lagoa, CEP: 76812, Porto Velho, RO, CEP: 76812-329, Brazil
- Ambulatório de Hepatites Virais, Fundação Oswaldo Cruz Rondônia e Centro de Pesquisa em Medicina Tropical - CEPEM, Avenida Guaporé, 215, anexo Hospital CEMETRON, Agenor M de Carvalho, Porto Velho, RO, CEP: 76812-329, Brazil
- Programa de Pós-Graduação em Biologia Experimental - PGBioExp, Rodovia Br-364, KM 9, CAMPUS UNIR, Porto Velho, RO, CEP: 76801-974, Brazil
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Abstract
Hepatitis D virus (HDV) infection leads to the most severe form of chronic viral hepatitis and requires the attention of a liver specialist. In this review, I will recapitulate recent advances in the management of HDV, present background information on HDV infection as well as current chronic hepatitis D treatment, briefly examine the HDV life cycle and discuss new management strategies.
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Affiliation(s)
- Cihan Yurdaydin
- Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey.,Hepatology Institute, University of Ankara, Ankara, Turkey
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44
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Lempp FA, Urban S. Hepatitis Delta Virus: Replication Strategy and Upcoming Therapeutic Options for a Neglected Human Pathogen. Viruses 2017; 9:E172. [PMID: 28677645 PMCID: PMC5537664 DOI: 10.3390/v9070172] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Revised: 06/28/2017] [Accepted: 06/29/2017] [Indexed: 12/15/2022] Open
Abstract
The human Hepatitis Delta Virus (HDV) is unique among all viral pathogens. Encoding only one protein (Hepatitis Delta Antigen; HDAg) within its viroid-like self-complementary RNA, HDV constitutes the smallest known virus in the animal kingdom. To disseminate in its host, HDV depends on a helper virus, the human Hepatitis B virus (HBV), which provides the envelope proteins required for HDV assembly. HDV affects an estimated 15-20 million out of the 240 million chronic HBV-carriers and disperses unequally in disparate geographical regions of the world. The disease it causes (chronic Hepatitis D) presents as the most severe form of viral hepatitis, leading to accelerated progression of liver dysfunction including cirrhosis and hepatocellular carcinoma and a high mortality rate. The lack of approved drugs interfering with specific steps of HDV replication poses a high burden for gaining insights into the molecular biology of the virus and, consequently, the development of specific novel medications that resiliently control HDV replication or, in the best case, functionally cure HDV infection or HBV/HDV co-infection. This review summarizes our current knowledge of HBV molecular biology, presents an update on novel cell culture and animal models to study the virus and provides updates on the clinical development of the three developmental drugs Lonafarnib, REP2139-Ca and Myrcludex B.
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Affiliation(s)
- Florian A Lempp
- Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
- German Centre for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany.
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, Heidelberg University, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.
- German Centre for Infection Research (DZIF), Partner Site Heidelberg, 69120 Heidelberg, Germany.
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45
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Abstract
Viral liver diseases are frequent comorbidities and major contributors to death in HIV-positive individuals on antiretroviral therapy. Although cure of hepatitis C and control of hepatitis B with antivirals avert liver disease progression in most HIV-coinfected patients, the lack of satisfactory treatment for hepatitis delta virus (HDV) infection remains a major threat for developing cirrhosis and liver cancer in this population. In the European Union (EU) and North America, sexual contact has replaced injection drug use that has been the major transmission route for HDV in HIV-positive persons. PegIFNα is the only approved HDV therapy; however, sustained HDV-RNA clearance is achieved by less than 25%. The recent discovery of sodium taurocholate cotransporting polypeptide as the key hepatitis B virus (HBV) and HDV cell entry receptor has opened the door to a new therapeutic era. Indeed, promising results have been released using Myrcludex-B, a sodium taurocholate cotransporting polypeptide inhibitor. More encouraging are data with new classes of HDV blockers, such as prenylation inhibitors (i.e. lonafarnib) and nucleic acid polymers. At this time, sustained suppression of HDV replication is the primary goal of HDV therapy, as it is associated with normalization of liver enzymes and histological improvement. Of note, the use of specific antivirals for HDV must be given along with anti-HBV agents to prevent HBV rebounds following removal of viral interference. The lack of persistent forms of HDV-RNA could provide a unique opportunity for curing hepatitis delta, even without eliminating HBV circular covalently closed DNA. Ultimately, suppression of HDV replication along with hepatitis B surface antigen clearance once drugs are off would be the best reflect of hepatitis delta cure.
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46
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Wyles D, Lin J. Clinical Manifestations of Acute and Chronic Hepatitis. Infect Dis (Lond) 2017. [DOI: 10.1016/b978-0-7020-6285-8.00042-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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47
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Aguilera A, Trastoy R, Barreiro P, Costa JJ, de Mendoza C, Peña JM, Soriano V. Decline and changing profile of hepatitis delta among injection drug users in Spain. Antivir Ther 2017; 23:87-90. [PMID: 28353446 DOI: 10.3851/imp3161] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/27/2017] [Indexed: 10/19/2022]
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48
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Prokaryotic Expression, Purification and Immunogenicity in Rabbits of the Small Antigen of Hepatitis Delta Virus. Int J Mol Sci 2016; 17:ijms17101721. [PMID: 27775592 PMCID: PMC5085752 DOI: 10.3390/ijms17101721] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Revised: 09/20/2016] [Accepted: 09/27/2016] [Indexed: 01/10/2023] Open
Abstract
Hepatitis delta virus (HDV) is a viroid-like blood-borne human pathogen that accompanies hepatitis B virus infection in 5% patients. HDV has been studied for four decades; however, the knowledge on its life-cycle and pathogenesis is still sparse. The studies are hampered by the absence of the commercially-available HDV-specific antibodies. Here, we describe a set of reproducible methods for the expression in E. coli of His-tagged small antigen of HDV (S-HDAg), its purification, and production of polyclonal anti-S-HDAg antibodies in rabbits. S-HDAg was cloned into a commercial vector guiding expression of the recombinant proteins with the C-terminal His-tag. We optimized S-HDAg protein purification procedure circumventing a low affinity of the His-tagged S-HDAg to the Ni-nitrilotriacetyl agarose (Ni-NTA-agarose) resin. Optimization allowed us to obtain S-HDAg with >90% purity. S-HDAg was used to immunize Shinchilla grey rabbits which received 80 μg of S-HDAg in two subcutaneous primes in the complete, followed by four 40 μg boosts in incomplete Freunds adjuvant. Rabbits were bled two weeks post each boost. Antibody titers determined by indirect ELISA exceeded 10⁷. Anti-S-HDAg antibodies detected the antigen on Western blots in the amounts of up-to 100 pg. They were also successfully used to characterize the expression of S-HDAg in the eukaryotic cells by immunofluorescent staining/confocal microscopy.
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49
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Alfaiate D, Lucifora J, Abeywickrama-Samarakoon N, Michelet M, Testoni B, Cortay JC, Sureau C, Zoulim F, Dény P, Durantel D. HDV RNA replication is associated with HBV repression and interferon-stimulated genes induction in super-infected hepatocytes. Antiviral Res 2016; 136:19-31. [PMID: 27771387 DOI: 10.1016/j.antiviral.2016.10.006] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 10/18/2016] [Indexed: 12/14/2022]
Abstract
Hepatitis D virus (HDV) super-infection of Hepatitis B virus (HBV)-infected patients is the most aggressive form of viral hepatitis. HDV infection is not susceptible to direct anti-HBV drugs, and only suboptimal antiviral responses are obtained with interferon (IFN)-alpha-based therapy. To get insights on HDV replication and interplay with HBV in physiologically relevant hepatocytes, differentiated HepaRG (dHepaRG) cells, previously infected or not with HBV, were infected with HDV, and viral markers were extensively analyzed. Innate and IFN responses to HDV were monitored by measuring pro-inflammatory and interferon-stimulated gene (ISG) expression. Both mono- and super-infected dHepaRG cells supported a strong HDV intracellular replication, which was accompanied by a strong secretion of infectious HDV virions only in the super-infection setting and despite the low number of co-infected cells. Upon HDV super-infection, HBV replication markers including HBeAg, total HBV-DNA and pregenomic RNA were significantly decreased, confirming the interference of HDV on HBV. Yet, no decrease of circular covalently closed HBV DNA (cccDNA) and HBsAg levels was evidenced. At the peak of HDV-RNA accumulation and onset of interference on HBV replication, a strong type-I IFN response was observed, with interferon stimulated genes, RSAD2 (Viperin) and IFI78 (MxA) being highly induced. We established a cellular model to characterize in more detail the direct interference of HBV and HDV, and the indirect interplay between the two viruses via innate immune responses. This model will be instrumental to assess molecular and immunological mechanisms of this viral interference.
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Affiliation(s)
- Dulce Alfaiate
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France
| | - Julie Lucifora
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France.
| | - Natali Abeywickrama-Samarakoon
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France
| | - Maud Michelet
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France
| | - Barbara Testoni
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France
| | - Jean-Claude Cortay
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France
| | - Camille Sureau
- Institut National de Transfusion Sanguine, Laboratoire de Virologie Moléculaire, 75015 Paris, France
| | - Fabien Zoulim
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France; Laboratoire d'excellence (LabEx), DEVweCAN, 69008 Lyon, France; Hospices Civils de Lyon (HCL), 69002 Lyon, France
| | - Paul Dény
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; Université Paris 13/SPC, UFR SMBH, Laboratoire de Bactériologie, Virologie - Hygiène, GHU Paris Seine Saint Denis, Assistance Publique - Hôpitaux de Paris, Bobigny, France.
| | - David Durantel
- INSERM U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), 69008 Lyon, France; University of Lyon, Université Claude-Bernard (UCBL), 69008 Lyon, France; Laboratoire d'excellence (LabEx), DEVweCAN, 69008 Lyon, France.
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50
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Lempp FA, Ni Y, Urban S. Hepatitis delta virus: insights into a peculiar pathogen and novel treatment options. Nat Rev Gastroenterol Hepatol 2016; 13:580-9. [PMID: 27534692 DOI: 10.1038/nrgastro.2016.126] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Chronic hepatitis D is the most severe form of viral hepatitis, affecting ∼20 million HBV-infected people worldwide. The causative agent, hepatitis delta virus (HDV), is a unique human pathogen: it is the smallest known virus; it depends on HBV to disseminate its viroid-like RNA; it encodes only one protein (HDAg), which has both structural and regulatory functions; and it replicates using predominantly host proteins. The failure of HBV-specific nucleoside analogues to suppress the HBV helper function, and the limitations of experimental systems to study the HDV life cycle, have impeded the development of HDV-specific drugs. Thus, the only clinical regimen for HDV is IFNα, which shows some efficacy but long-term virological responses are rare. Insights into the receptor-mediated entry of HDV, and the observation that HDV assembly requires farnesyltransferase, have enabled novel therapeutic strategies to be developed. Interference with entry, for example through blockade of the HBV-HDV-specific receptor sodium/taurocholate cotransporting polypeptide NTCP by Myrcludex B, and inhibition of assembly by blockade of farnesyltransferase using lonafarnib or nucleic acid polymers such as REP 2139-Ca, have shown promising results in phase II studies. In this Review, we summarize our knowledge of HDV epidemiology, pathogenesis and molecular biology, with a particular emphasis on possible future developments.
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Affiliation(s)
- Florian A Lempp
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany
| | - Yi Ni
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.,German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany
| | - Stephan Urban
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Im Neuenheimer Feld 345, 69120 Heidelberg, Germany.,German Center for Infection Research (DZIF), Heidelberg Partner Site, Im Neuenheimer Feld 324, 69120 Heidelberg, Germany
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