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1
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Cardoso MF, Machado MV. The Changing Face of Hepatitis Delta Virus Associated Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:3723. [PMID: 39594679 PMCID: PMC11591730 DOI: 10.3390/cancers16223723] [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: 07/23/2024] [Revised: 09/22/2024] [Accepted: 11/01/2024] [Indexed: 11/28/2024] Open
Abstract
Hepatitis delta virus (HDV) infection requires the presence of hepatitis B virus (HBV), and chronic HBV-HDV coinfection is considered the most severe form of viral hepatitis. When compared with HBV mono-infection, HBV-HDV coinfection is associated with higher rates of liver cirrhosis and hepatocellular carcinoma (HCC). In this review, we aim to elucidate the complex relationship between HDV infection and the development of HCC. The exact mechanisms underlying the carcinogenic potential of HDV remain to be fully elucidated. Evidence suggests that HDV has both indirect and direct oncogenic effects. Indirect effects promote accelerated progression to liver cirrhosis, which results in a different tumor microenvironment. Direct oncogenic effects are suggested by a distinct molecular signature. The recent epidemiological data regarding HBV-HDV coinfection should make us reconsider the HCC screening strategy, with special focus in younger non-cirrhotic patients. Finally, treating HCC in patients with chronic HDV poses unique challenges due to the complex interplay between HBV and HDV and the severity of liver disease. An in-depth understanding of the epidemiology and pathophysiology of HDV infection and carcinogenesis is essential to improve disease management in this high-risk population.
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Affiliation(s)
- Mariana Ferreira Cardoso
- Gastroenterology Department, Hospital Prof. Doutor Fernando Fonseca, 2720-276 Amadora, Portugal;
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
| | - Mariana Verdelho Machado
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
- Gastroenterology Department, Hospital de Vila Franca de Xira, 2600-009 Vila Franca de Xira, Portugal
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2
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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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3
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Papatheodoridi A, Papatheodoridis G. Hepatocellular carcinoma: The virus or the liver? Liver Int 2023; 43 Suppl 1:22-30. [PMID: 35319167 DOI: 10.1111/liv.15253] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/28/2022] [Accepted: 03/19/2022] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) represents a major public health problem being one of the most common causes of cancer-related deaths worldwide. Hepatitis B (HBV) and C viruses have been classified as oncoviruses and are responsible for the majority of HCC cases, while the role of hepatitis D virus (HDV) in liver carcinogenesis has not been elucidated. HDV/HBV coinfection is related to more severe liver damage than HBV mono-infection and recent studies suggest that HDV/HBV patients are at increased risk of developing HCC compared to HBV mono-infected patients. HBV is known to promote hepatocarcinogenesis via DNA integration into host DNA, disruption of molecular pathways by regulatory HBV x (HBx) protein and excessive oxidative stress. Recently, several molecular mechanisms have been proposed to clarify the pathogenesis of HDV-related HCC including activation of signalling pathways by specific HDV antigens, epigenetic dysregulation and altered gene expression. Alongside, ongoing chronic inflammation and impaired immune responses have also been suggested to facilitate carcinogenesis. Finally, cellular senescence seems to play an important role in chronic viral infection and inflammation leading to hepatocarcinogenesis. In this review, we summarize the current literature on the impact of HDV in HCC development and discuss the potential interplay between HBV, HDV and neighbouring liver tissue in liver carcinogenesis.
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Affiliation(s)
- Alkistis Papatheodoridi
- Department of Clinical Therapeutics, Medical School of National and Kapodistrian University of Athens, "Alexandra" General Hospital of Athens, Athens, Greece
| | - George Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens School of Health Sciences, General Hospital of Athens "Laiko", Athens, Greece
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Costante F, Stella L, Santopaolo F, Gasbarrini A, Pompili M, Asselah T, Ponziani FR. Molecular and Clinical Features of Hepatocellular Carcinoma in Patients with HBV-HDV Infection. J Hepatocell Carcinoma 2023; 10:713-724. [PMID: 37128594 PMCID: PMC10148646 DOI: 10.2147/jhc.s384751] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 04/06/2023] [Indexed: 05/03/2023] Open
Abstract
Hepatitis D virus (HDV) infection affects more than 10 million people worldwide, with an estimated prevalence of nearly 4.5% among HBsAg-positive individuals. Epidemiological studies have shown a significant increase in the prevalence of hepatocellular carcinoma (HCC) in patients with chronic HDV infection compared to those with chronic hepatitis B virus (HBV) mono-infection. Despite the clinical findings, data on molecular oncogenic mechanisms are limited and fragmentary. Moreover, the role of HDV in promoting the development of HCC has so far been controversial, because it is difficult to weigh the respective contributions of the two viruses. In this review, we focused on the direct oncogenic action of HDV, its role in modifying the tumor microenvironment, and the genetic signature of HDV-related HCC, comparing these features with HBV-related HCC.
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Affiliation(s)
- Federico Costante
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Leonardo Stella
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
| | - Tarik Asselah
- Service d’Hépatologie, Hôpital Beaujon UMR 1149 Inserm - Université de Paris, Clichy, France
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, 00168, Italy
- Department of Translational Medicine and Surgery, Catholic University, Rome, 00168, Italy
- Correspondence: Francesca Romana Ponziani; Federico Costante, Internal Medicine and Gastroenterology - Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Francesco Vito 1, Rome, 00168, Italy, Tel +390630156264, Email ;
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5
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Identification of G protein-coupled receptor 55 (GPR55) as a target of curcumin. NPJ Sci Food 2022; 6:4. [PMID: 35031622 PMCID: PMC8760322 DOI: 10.1038/s41538-021-00119-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 12/13/2021] [Indexed: 12/22/2022] Open
Abstract
The identification of molecular targets of bioactive food components is important to understand the mechanistic aspect of their physiological functions. Here, we have developed a screening system that enables us to determine the activation of G protein-coupled receptors (GPCRs) by food components and have identified GPR55 as a target for curcumin. Curcumin activated GPR55 and induced serum-response element- and serum-response factor-mediated transcription, which were inhibited by Rho kinase and GPR55 antagonists. Both the methoxy group and the heptadienone moiety of curcumin were required for GPR55 activation. The F1905.47 residue of GPR55 was important for the interaction with curcumin. The curcumin-induced secretion of glucagon-like peptide-1 in GLUTag cells was inhibited by a GPR55 antagonist. These results indicate that expression screening is a useful system to identify GPCRs as targets of food components and strongly suggest that curcumin activates GPR55 as an agonist, which is involved in the physiological function of curcumin.
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Abstract
Hepatitis D virus (HDV) is a small, defective RNA virus that depends on hepatitis B virus (HBV) for virion assembly and transmission. It replicates within the nucleus of hepatocytes and interacts with several cellular proteins. Chronic hepatitis D is a severe and progressive disease, leading to cirrhosis in up to 80% of cases. A high proportion of patients die of liver decompensation or hepatocellular carcinoma (HCC), but the lack of large prospective studies has made it difficult to precisely define the rate of these long-term complications. In particular, the question of whether HDV is an oncogenic virus has been a matter of debate. Studies conducted over the past decade provided evidence that HDV is associated with a significantly higher risk of developing HCC compared to HBV monoinfection. However, the mechanisms whereby HDV promotes liver cancer remain elusive. Recent data have demonstrated that the molecular profile of HCC-HDV is unique and distinct from that of HBV-HCC, with an enrichment of upregulated genes involved in cell-cycle/DNA replication, and DNA damage and repair, which point to genome instability as an important mechanism of HDV hepatocarcinogenesis. These data suggest that HBV and HDV promote carcinogenesis by distinct molecular mechanisms despite the obligatory dependence of HDV on HBV.
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HDV Pathogenesis: Unravelling Ariadne's Thread. Viruses 2021; 13:v13050778. [PMID: 33924806 PMCID: PMC8145675 DOI: 10.3390/v13050778] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 12/22/2022] Open
Abstract
Hepatitis Delta virus (HDV) lies in between satellite viruses and viroids, as its unique molecular characteristics and life cycle cannot categorize it according to the standard taxonomy norms for viruses. Being a satellite virus of hepatitis B virus (HBV), HDV requires HBV envelope glycoproteins for its infection cycle and its transmission. HDV pathogenesis varies and depends on the mode of HDV and HBV infection; a simultaneous HDV and HBV infection will lead to an acute hepatitis that will resolve spontaneously in the majority of patients, whereas an HDV super-infection of a chronic HBV carrier will mainly result in the establishment of a chronic HDV infection that may progress towards cirrhosis, liver decompensation, and hepatocellular carcinoma (HCC). With this review, we aim to unravel Ariadne’s thread into the labyrinth of acute and chronic HDV infection pathogenesis and will provide insights into the complexity of this exciting topic by detailing the different players and mechanisms that shape the clinical outcome.
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Fan HX, Feng YJ, Zhao XP, He YZ, Tang H. MiR-185-5p suppresses HBV gene expression by targeting ELK1 in hepatoma carcinoma cells. Life Sci 2018; 213:9-17. [PMID: 30308183 DOI: 10.1016/j.lfs.2018.10.016] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 10/05/2018] [Accepted: 10/08/2018] [Indexed: 12/12/2022]
Abstract
AIMS To investigate the role and underlying mechanism of miR-185-5p in hepatitis B virus (HBV) expression and replication. MAIN METHODS The relative levels of hepatitis B surface antigen and hepatitis B e antigen were detected by enzyme-linked immunosorbent assay (ELISA). The HBV DNA copies in the cultures medium were measured by RT-qPCR. The HBV large surface antigen promoter (S1p) activity was analyzed by luciferase reporter assay. The target relationship between miR-185-5p and ELK1 was identified by bioinformatics analysis and EGFP fluorescent reporter assay. The ELK1 expression was determined by RT-qPCR and Western blot. KEY FINDINGS miR-185-5p significantly decreased HBV large surface antigen promoter activity and subsequently the production of HBV proteins and HBV DNA copies in vitro. Further, we identified the ETS transcription factor ELK1 is a target of miR-185-5p. Overexpression and knockdown experiments showed overexpression of ELK1 stimulated HBV large surface antigen promoter activity and promoted the production of HBV proteins and HBV DNA copies, whereas knockdown of ELK1 has the opposite effects. Moreover, the rescue of ELK1 expression reversed the suppression of miR-185-5p on HBV replication and gene expression. Further mechanistic study showed that the ETS binding sites within the HBV large surface antigen promoter are required for the repression effect of miR-185-5p on HBV. SIGNIFICANCE There are few reports about the interaction between miRNAs and the transcription from HBV S1p, we found that miR-185-5p decreases HBV S1p activity by targeting ELK1, which may provide a promising therapeutic strategy for HBV infection.
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Affiliation(s)
- Hong-Xia Fan
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Yu-Jie Feng
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Xiao-Pei Zhao
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Yu-Ze He
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China
| | - Hua Tang
- Tianjin Life Science Research Center and Department of Pathogen Biology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
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9
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Sureau C, Negro F. The hepatitis delta virus: Replication and pathogenesis. J Hepatol 2016; 64:S102-S116. [PMID: 27084031 DOI: 10.1016/j.jhep.2016.02.013] [Citation(s) in RCA: 196] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 02/01/2016] [Accepted: 02/10/2016] [Indexed: 02/06/2023]
Abstract
Hepatitis delta virus (HDV) is a defective virus and a satellite of the hepatitis B virus (HBV). Its RNA genome is unique among animal viruses, but it shares common features with some plant viroids, including a replication mechanism that uses a host RNA polymerase. In infected cells, HDV genome replication and formation of a nucleocapsid-like ribonucleoprotein (RNP) are independent of HBV. But the RNP cannot exit, and therefore propagate, in the absence of HBV, as the latter supplies the propagation mechanism, from coating the HDV RNP with the HBV envelope proteins for cell egress to delivery of the HDV virions to the human hepatocyte target. HDV is therefore an obligate satellite of HBV; it infects humans either concomitantly with HBV or after HBV infection. HDV affects an estimated 15 to 20 million individuals worldwide, and the clinical significance of HDV infection is more severe forms of viral hepatitis--acute or chronic--, and a higher risk of developing cirrhosis and hepatocellular carcinoma in comparison to HBV monoinfection. This review covers molecular aspects of HDV replication cycle, including its interaction with the helper HBV and the pathogenesis of infection in humans.
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Affiliation(s)
- Camille Sureau
- Molecular Virology laboratory, Institut National de la Transfusion Sanguine (INTS), CNRS INSERM U1134, Paris, France.
| | - Francesco Negro
- Division of Gastroenterology and Hepatology, University Hospitals, Geneva, Switzerland; Division of Clinical Pathology, University Hospitals, Geneva, Switzerland.
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10
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Shirvani-Dastgerdi E, Pourkarim MR, Herbers U, Amini-Bavil-Olyaee S, Yagmur E, Alavian SM, Trautwein C, Tacke F. Hepatitis delta virus facilitates the selection of hepatitis B virus mutants in vivo and functionally impacts on their replicative capacity in vitro. Clin Microbiol Infect 2015; 22:98.e1-98.e6. [PMID: 26433026 DOI: 10.1016/j.cmi.2015.09.020] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 09/07/2015] [Accepted: 09/19/2015] [Indexed: 02/06/2023]
Abstract
To identify molecular interactions between hepatitis B virus (HBV) and hepatitis delta virus (HDV), HBV sequences were analysed in HBV/HDV-infected patients. Characteristic amino acid substitutions were found in cytosolic domains of hepatitis B surface antigen (HBsAg), in contrast to HBV-mono-infected controls. The functional impact of HDV on the replication of wild-type and mutant HBV was assessed in vitro. HDV co-transfection significantly reduced the replication of HBV strains containing precore or basal core promoter mutations, and HBV polymerase or surface antigen mutants affected HDV replication in vitro. Conclusively, our study revealed distinct HBsAg mutational patterns in HBV/HDV-infected patients and novel functional interactions between HBV and HDV.
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Affiliation(s)
| | - M R Pourkarim
- Department of Microbiology and Immunology, Laboratory of Clinical and Epidemiological Virology, Rega Institute for Medical Research, KU Leuven, Belgium; Blood Transfusion Research Centre, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - U Herbers
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany
| | - S Amini-Bavil-Olyaee
- Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Harlyne J. Norris Cancer Research Tower, Los Angeles, CA, USA
| | - E Yagmur
- Medical Care Centre, Dr Stein and Colleagues, Mönchengladbach, Germany
| | - S M Alavian
- Baqiyatallah Research Centre for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - C Trautwein
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany
| | - F Tacke
- Department of Medicine III, RWTH-University Hospital Aachen, Aachen, Germany.
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11
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Alfaiate D, Dény P, Durantel D. Hepatitis delta virus: From biological and medical aspects to current and investigational therapeutic options. Antiviral Res 2015; 122:112-29. [PMID: 26275800 DOI: 10.1016/j.antiviral.2015.08.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 08/10/2015] [Accepted: 08/11/2015] [Indexed: 12/14/2022]
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12
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Giersch K, Dandri M. Hepatitis B and Delta Virus: Advances on Studies about Interactions between the Two Viruses and the Infected Hepatocyte. J Clin Transl Hepatol 2015; 3:220-9. [PMID: 26623269 PMCID: PMC4663204 DOI: 10.14218/jcth.2015.00018] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 07/11/2015] [Accepted: 07/12/2015] [Indexed: 12/14/2022] Open
Abstract
The mechanisms determining persistence of hepatitis B virus (HBV) infection and long-term pathogenesis of HBV-associated liver disease appear to be multifactorial. Although viral replication can be efficiently suppressed by the antiviral treatments currently available, viral clearance is generally not achieved since HBV has developed unique replication strategies, enabling persistence of its genome within the infected hepatocytes. Moreover, no direct antiviral therapy exists for the more than 15 million people worldwide that are also coinfected with the hepatitis delta virus (HDV), a defective virus that needs the HBV envelope proteins for propagation. The limited availability of robust HBV and HDV infection systems has hindered the understanding of the complex network of virus-virus and virus-host interactions that are established in the course of infection and slowed down progress in drug development. Since chronic HBV/HDV coinfection leads to the most severe form of chronic viral hepatitis, elucidation of the molecular mechanisms regulating virus-host interplay and pathogenesis are urgently needed. This article summarizes the current knowledge regarding the interactions among HBV, HDV, and the infected target cell and discusses the dependence of HDV on HBV activity and possible future therapeutic approaches.
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Affiliation(s)
- Katja Giersch
- Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maura Dandri
- Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- German Center for Infection Research (DZIF), Hamburg-Lübeck-Borstel site, Germany
- Correspondence to: Maura Dandri, Department of Internal Medicine, Center for Internal Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. Tel: +49-40741052949, Fax: +49-40741057232, E-mail:
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13
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Shirvani-Dastgerdi E, Tacke F. Molecular interactions between hepatitis B virus and delta virus. World J Virol 2015; 4:36-41. [PMID: 25964870 PMCID: PMC4419120 DOI: 10.5501/wjv.v4.i2.36] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 02/12/2015] [Accepted: 03/09/2015] [Indexed: 02/05/2023] Open
Abstract
As a deficient virus due to the lack of envelope proteins, hepatitis D virus (HDV) causes chronic or fulminant “delta hepatitis” only in people with simultaneous hepatitis B virus (HBV) infection. HBV encodes three types of surface proteins known as small (S), medium (M) and large (L) envelope proteins. All three types of HBV surface antigens (HBsAgs) are present on HDV virions. The envelopment process of HDV occurs through interactions between the HDV ribonucleoprotein (RNP) complex and HBV HBsAgs. While HBsAg is the only protein required by HDV, the exact interaction sites between the S protein and pre-mature HDV are not well defined yet. In fact, these sites are distributed along the S protein with some hot spots for the envelopment process. Moreover, in most clinically studied samples, HDV infection is associated with a dramatically reduced HBV viral load, temporarily or permanently, while HBsAg resources are available for HDV packaging. Thus, beyond interacting with HBV envelope proteins, controlling mechanisms exist by which HDV inhibits HBV-DNA replication while allowing a selective transcription of HBV proteins. Here we discuss the molecular interaction sites between HBsAg and the HDV-RNP complex and address the proposed indirect mechanisms, which are employed by HBV and HDV to facilitate or inhibit each other’s viral replication. Understanding molecular interactions between HBV and HDV may help to design novel therapeutic strategies for delta hepatitis.
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14
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Aldabe R, Suárez-Amarán L, Usai C, González-Aseguinolaza G. Animal models of chronic hepatitis delta virus infection host-virus immunologic interactions. Pathogens 2015; 4:46-65. [PMID: 25686091 PMCID: PMC4384072 DOI: 10.3390/pathogens4010046] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 02/05/2015] [Indexed: 02/08/2023] Open
Abstract
Hepatitis delta virus (HDV) is a defective RNA virus that has an absolute requirement for a virus belonging to the hepadnaviridae family like hepatitis B virus (HBV) for its replication and formation of new virions. HDV infection is usually associated with a worsening of HBV-induced liver pathogenesis, which leads to more frequent cirrhosis, increased risk of hepatocellular carcinoma (HCC), and fulminant hepatitis. Importantly, no selective therapies are available for HDV infection. The mainstay of treatment for HDV infection is pegylated interferon alpha; however, response rates to this therapy are poor. A better knowledge of HDV–host cell interaction will help with the identification of novel therapeutic targets, which are urgently needed. Animal models like hepadnavirus-infected chimpanzees or the eastern woodchuck have been of great value for the characterization of HDV chronic infection. Recently, more practical animal models in which to perform a deeper study of host virus interactions and to evaluate new therapeutic strategies have been developed. Therefore, the main focus of this review is to discuss the current knowledge about HDV host interactions obtained from cell culture and animal models.
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Affiliation(s)
- Rafael Aldabe
- Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra (UNAV), Pamplona 31008, Spain.
| | - Lester Suárez-Amarán
- Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra (UNAV), Pamplona 31008, Spain
| | - Carla Usai
- Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra (UNAV), Pamplona 31008, Spain.
| | - Gloria González-Aseguinolaza
- Gene Therapy and Regulation of Gene Expression Program, Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra (UNAV), Pamplona 31008, Spain.
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15
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Huang CR, Lo SJ. Hepatitis D virus infection, replication and cross-talk with the hepatitis B virus. World J Gastroenterol 2014; 20:14589-14597. [PMID: 25356023 PMCID: PMC4209526 DOI: 10.3748/wjg.v20.i40.14589] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 05/12/2014] [Accepted: 06/23/2014] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis remains a worldwide public health problem. The hepatitis D virus (HDV) must either coinfect or superinfect with the hepatitis B virus (HBV). HDV contains a small RNA genome (approximately 1.7 kb) with a single open reading frame (ORF) and requires HBV supplying surface antigens (HBsAgs) to assemble a new HDV virion. During HDV replication, two isoforms of a delta antigen, a small delta antigen (SDAg) and a large delta antigen (LDAg), are produced from the same ORF of the HDV genome. The SDAg is required for HDV replication, whereas the interaction of LDAg with HBsAgs is crucial for packaging of HDV RNA. Various clinical outcomes of HBV/HDV dual infection have been reported, but the molecular interaction between HBV and HDV is poorly understood, especially regarding how HBV and HDV compete with HBsAgs for assembling virions. In this paper, we review the role of endoplasmic reticulum stress induced by HBsAgs and the molecular pathway involved in their promotion of LDAg nuclear export. Because the nuclear sublocalization and export of LDAg is regulated by posttranslational modifications (PTMs), including acetylation, phosphorylation, and isoprenylation, we also summarize the relationship among HBsAg-induced endoplasmic reticulum stress signaling, LDAg PTMs, and nuclear export mechanisms in this review.
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Cieśla A, Kuśmider M, Faron-Górecka A, Dziedzicka-Wasylewska M, Bociąga-Jasik M, Owczarek D, Ciećko-Michalska I, Cibor D, Mach T. Intrahepatic expression of genes related to metabotropic receptors in chronic hepatitis. World J Gastroenterol 2012; 18:4156-4161. [PMID: 22919248 PMCID: PMC3422796 DOI: 10.3748/wjg.v18.i31.4156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Revised: 04/23/2012] [Accepted: 04/27/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To screen for genes related to metabotropic receptors that might be involved in the development of chronic hepatitis. METHODS Assessment of 20 genes associated with metabotropic receptors was performed in liver specimens obtained by punch biopsy from 12 patients with autoimmune and chronic hepatitis type B and C. For this purpose, a microarray with low integrity grade and with oligonucleotide DNA probes complementary to target transcripts was used. Evaluation of gene expression was performed in relation to transcript level, correlation between samples and grouping of clinical parameters used in chronic hepatitis assessment. Clinical markers of chronic hepatitis included alanine and aspartate aminotransferase, γ-glutamyltranspeptidase, alkaline phosphatase and cholinesterase activity, levels of iron ions, total cholesterol, triglycerides, albumin, glucose, hemoglobin, platelets, histological analysis of inflammatory and necrotic status, fibrosis according to METAVIR score, steatosis, as well as anthropometric body mass index, waist/hip index, percentage of adipose tissue and liver size in ultrasound examination. Gender, age, concomitant diseases and drugs were also taken into account. Validation of oligonucleotide microarray gene expression results was done with the use of quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS The highest (0.002 < P < 0.046) expression among genes encoding main components of metabotropic receptor pathways, such as the α subunit of G-coupled protein, phosphoinositol-dependent protein kinase or arrestin was comparable to that of angiotensinogen synthesized in the liver. Carcinogenesis suppressor genes, such as chemokine ligand 4, transcription factor early growth response protein 1 and lysophosphatidic acid receptor, were characterized by the lowest expression (0.002 < P < 0.046), while the factor potentially triggering hepatic cancer, transcription factor JUN-B, had a 20-fold higher expression. The correlation between expression of genes of protein kinases PDPK1, phosphoinositide 3-kinase and protein kinase A (Spearman's coefficient range: 0.762-0.769) confirmed a functional link between these enzymes. Gender (P = 0.0046) and inflammation severity, measured by alanine aminotransferase activity (P = 0.035), were characterized by diverse metabotropic receptor gene expression patterns. The Pearson's coefficient ranging from -0.35 to 0.99 from the results of qRT-PCR and microarray indicated that qRT-PCR had certain limitations as a validation tool for oligonucleotide microarray studies. CONCLUSION A microarray-based analysis of hepatocyte metabotropic G-protein-related gene expression can reveal the molecular basis of chronic hepatitis.
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MESH Headings
- 3-Phosphoinositide-Dependent Protein Kinases
- Adult
- Arrestins/genetics
- Arrestins/metabolism
- Biopsy
- Chromogranins
- Female
- GTP-Binding Protein alpha Subunits, Gs/genetics
- GTP-Binding Protein alpha Subunits, Gs/metabolism
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/metabolism
- Hepatitis B, Chronic/pathology
- Hepatitis C, Chronic/genetics
- Hepatitis C, Chronic/metabolism
- Hepatitis C, Chronic/pathology
- Hepatocytes/metabolism
- Hepatocytes/pathology
- Humans
- Liver/metabolism
- Liver/pathology
- Male
- Middle Aged
- Oligonucleotide Array Sequence Analysis
- Protein Serine-Threonine Kinases/genetics
- Protein Serine-Threonine Kinases/metabolism
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Retrospective Studies
- Transcriptome
- beta-Arrestins
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Interaction of host cellular proteins with components of the hepatitis delta virus. Viruses 2010; 2:189-212. [PMID: 21994607 PMCID: PMC3185554 DOI: 10.3390/v2010189] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Revised: 01/13/2010] [Accepted: 01/14/2010] [Indexed: 12/18/2022] Open
Abstract
The hepatitis delta virus (HDV) is the smallest known RNA pathogen capable of propagation in the human host and causes substantial global morbidity and mortality. Due to its small size and limited protein coding capacity, HDV is exquisitely reliant upon host cellular proteins to facilitate its transcription and replication. Remarkably, HDV does not encode an RNA-dependent RNA polymerase which is traditionally required to catalyze RNA-templated RNA synthesis. Furthermore, HDV lacks enzymes responsible for post-transcriptional and -translational modification, processes which are integral to the HDV life cycle. This review summarizes the known HDV-interacting proteins and discusses their significance in HDV biology.
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Williams V, Brichler S, Radjef N, Lebon P, Goffard A, Hober D, Fagard R, Kremsdorf D, Dény P, Gordien E. Hepatitis delta virus proteins repress hepatitis B virus enhancers and activate the alpha/beta interferon-inducible MxA gene. J Gen Virol 2009; 90:2759-2767. [PMID: 19625466 DOI: 10.1099/vir.0.011239-0] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Co-infection and superinfection of hepatitis B virus (HBV) with hepatitis delta virus (HDV) leads to suppression of HBV replication both in patients and in animal and cellular models. The mechanisms behind this inhibition have not previously been explored fully. HBV replication is governed by four promoters and two enhancers, Enh1 and Enh2. Repression of these enhancers has been reported to be one of the main mechanisms of HBV inhibition. Moreover, in a previous study, it has been demonstrated that alpha interferon (IFN-alpha)-inducible MxA protein inhibits HBV replication. HDV encodes two proteins, p24 and p27. p27 was shown to activate several heterologous promoters, including HBV promoters. In an attempt to analyse the mechanisms of HBV inhibition by HDV, the question was raised whether HDV proteins could act directly by repressing HBV enhancers, and/or indirectly by activating the MxA gene. This issue was addressed in a co-transfection model in Huh-7 cells, using p24- or p27-expressing plasmids along with Enh1, Enh2, HBV and MxA promoter-luciferase constructs. Enh1 and Enh2 were strongly repressed, by 60 and 80 % and 40 and 60 %, by p24 and p27, respectively. In addition, p27 was responsible for threefold activation of the MxA promoter and potentiation of IFN-alpha on this promoter. MxA mRNA quantification and a virus yield reduction assay confirmed these results. In conclusion, this study shows that HDV proteins inhibit HBV replication by trans-repressing its enhancers and by trans-activating the IFN-alpha-inducible MxA gene.
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Affiliation(s)
- Virginie Williams
- INSERM U845, Faculté de Médecine de Necker, Université Paris 5, France
- Service de Bactériologie, Virologie, Hygiène, Associé au Centre National de Référence des Hépatites B, C et Delta, Hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Université Paris 13, Faculté de Bobigny, France
| | - Ségolène Brichler
- INSERM U845, Faculté de Médecine de Necker, Université Paris 5, France
- Service de Bactériologie, Virologie, Hygiène, Associé au Centre National de Référence des Hépatites B, C et Delta, Hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Université Paris 13, Faculté de Bobigny, France
| | - Nadjia Radjef
- Service de Bactériologie, Virologie, Hygiène, Associé au Centre National de Référence des Hépatites B, C et Delta, Hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Université Paris 13, Faculté de Bobigny, France
| | - Pierre Lebon
- Laboratoire de Virologie, Hôpital Saint Vincent de Paul, Université Paris 5, France
| | - Anne Goffard
- Service de Virologie, UPRES EA 3610 Faculté de Médecine, Université Lille 2, Centre Hospitalier Régional et Universitaire de Lille, France
| | - Didier Hober
- Service de Virologie, UPRES EA 3610 Faculté de Médecine, Université Lille 2, Centre Hospitalier Régional et Universitaire de Lille, France
| | - Remi Fagard
- Laboratoire de Biochimie, Hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Université Paris 13, Faculté de Bobigny, France
| | - Dina Kremsdorf
- INSERM U845, Faculté de Médecine de Necker, Université Paris 5, France
| | - Paul Dény
- INSERM U871, Lyon, France
- Service de Bactériologie, Virologie, Hygiène, Associé au Centre National de Référence des Hépatites B, C et Delta, Hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Université Paris 13, Faculté de Bobigny, France
| | - Emmanuel Gordien
- INSERM U845, Faculté de Médecine de Necker, Université Paris 5, France
- Service de Bactériologie, Virologie, Hygiène, Associé au Centre National de Référence des Hépatites B, C et Delta, Hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Université Paris 13, Faculté de Bobigny, France
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Transcription factor YY1 and its associated acetyltransferases CBP and p300 interact with hepatitis delta antigens and modulate hepatitis delta virus RNA replication. J Virol 2008; 82:7313-24. [PMID: 18480431 DOI: 10.1128/jvi.02581-07] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis delta virus (HDV) is a pathogenic RNA virus with a plant viroid-like genome structure. HDV encodes two isoforms of delta antigen (HDAg), the small and large forms of HDAg (SHDAg and LHDAg), which are essential for HDV RNA replication and virion assembly, respectively. Replication of HDV RNA depends on host cellular transcription machinery, and the exact molecular mechanism for HDV RNA replication is still unclear. In this study, we demonstrated that both isoforms of HDAg interact with transcription factor YY1 (Yin Yang 1) in vivo and in vitro. Their interaction domains were identified as the middle region encompassing the RNA binding domain of HDAg and the middle GA/GK-rich region and the C-terminal zinc-finger region of YY1. Results of sucrose gradient centrifugation analysis indicated the cosedimentation of the majority of SHDAg and a portion of the LHDAg with YY1 and its associated acetyltransferases CBP (CREB-binding protein) and p300 as a large nuclear complex in vivo. Furthermore, exogenous expression of YY1 or CBP/p300 in HDV RNA replication system showed an enhancement of HDV RNA replication. Interestingly, the acetyltransferase activity of p300 is important for this enhancement. Moreover, SHDAg could be acetylated in vivo, and treatment with cellular deacetylase inhibitor elevated the replication of HDV RNA and acetylation of SHDAg. All together, our results reveal that HDAg interacts with cellular transcription factor YY1 and its associated acetyltransferases CBP and p300 in a large nuclear complex, which in turn modulates the replication of HDV RNA.
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Huang C, Chang SC, Yu IC, Tsay YG, Chang MF. Large hepatitis delta antigen is a novel clathrin adaptor-like protein. J Virol 2007; 81:5985-94. [PMID: 17376909 PMCID: PMC1900268 DOI: 10.1128/jvi.02809-06] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Clathrin-mediated endocytosis is a common pathway for viral entry, but little is known about the direct association of viral protein with clathrin in the cytoplasm. In this study, a putative clathrin box known to be conserved in clathrin adaptors was identified at the C terminus of the large hepatitis delta antigen (HDAg-L). Similar to clathrin adaptors, HDAg-L directly interacted with the N terminus of the clathrin heavy chain through the clathrin box. HDAg-L is a nucleocytoplasmic shuttle protein important for the assembly of hepatitis delta virus (HDV). Here, we demonstrated that brefeldin A and wortmannin, inhibitors of clathrin-mediated exocytosis and endosomal trafficking, respectively, specifically blocked HDV assembly but had no effect on the assembly of the small surface antigen of hepatitis B virus. In addition, cytoplasm-localized HDAg-L inhibited the clathrin-mediated endocytosis of transferrin and the degradation of epidermal growth factor receptor. These results indicate that HDAg-L is a new clathrin adaptor-like protein, and it may be involved in the maturation and pathogenesis of HDV coinfection or superinfection with hepatitis B virus through interaction with clathrin.
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Affiliation(s)
- Cheng Huang
- Institute of Biochemistry and Molecular Biology, National Taiwan University College of Medicine, No. 1, Jen-Ai Road, First Section, Taipei, Taiwan
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Choi SH, Jeong SH, Hwang SB. Large hepatitis delta antigen modulates transforming growth factor-beta signaling cascades: implication of hepatitis delta virus-induced liver fibrosis. Gastroenterology 2007; 132:343-57. [PMID: 17241884 DOI: 10.1053/j.gastro.2006.10.038] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2006] [Accepted: 10/05/2006] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Transforming growth factor-beta (TGF-beta) has been implicated in the pathogenesis of liver disease. TGF-beta is involved in liver regeneration and in the fibrotic and cirrhotic transformation with hepatitis viral infection. Hepatitis delta virus (HDV) infection causes fulminant hepatitis and liver cirrhosis. To elucidate the molecular mechanism of HDV pathogenesis, we examined the effects of HDV-encoded-only protein, the small hepatitis delta antigen (SHDAg), and the large hepatitis delta antigen (LHDAg), on TGF-beta- and c-Jun-induced signaling cascades. METHODS The effects of either SHDAg or LHDAg on TGF-beta- and c-Jun-induced signaling cascades in Huh7 and Cos7 cells were investigated by luciferase reporter gene assay, immunoprecipitation assay, electrophoretic mobility shift assay, Western blot analysis, and confocal microscopy analysis. RESULTS The LHDAg, but not the SHDAg, potentiated TGF-beta- and c-Jun-induced signal activation, and the isoprenylation of LHDAg played a major role in signaling cascades. LHDAg synergistically activated hepatitis B virus X protein-mediated TGF-beta and AP-1 signaling cascades. In addition, LHDAg enhanced the protein expression level of TGF-beta-induced plasminogen activator inhibitor-1. CONCLUSIONS LHDAg may induce liver fibrosis through the regulation of TGF-beta-induced signal transductions. This regulation of TGF-beta-mediated signaling is accomplished by the isoprenylation of LHDAg, which is a novel mechanism involved in HDV pathogenesis.
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Affiliation(s)
- Soo-Ho Choi
- Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-dong, Dongan-gu, Anyang 431-060, Korea
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22
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Choi SH, Jeong SH, Hwang SB. Large hepatitis delta antigen modulates transforming growth factor-beta signaling cascades: implication of hepatitis delta virus-induced liver fibrosis. Gastroenterology 2007. [PMID: 17241884 DOI: 10.1053/j.gastro.2006.10.038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND & AIMS Transforming growth factor-beta (TGF-beta) has been implicated in the pathogenesis of liver disease. TGF-beta is involved in liver regeneration and in the fibrotic and cirrhotic transformation with hepatitis viral infection. Hepatitis delta virus (HDV) infection causes fulminant hepatitis and liver cirrhosis. To elucidate the molecular mechanism of HDV pathogenesis, we examined the effects of HDV-encoded-only protein, the small hepatitis delta antigen (SHDAg), and the large hepatitis delta antigen (LHDAg), on TGF-beta- and c-Jun-induced signaling cascades. METHODS The effects of either SHDAg or LHDAg on TGF-beta- and c-Jun-induced signaling cascades in Huh7 and Cos7 cells were investigated by luciferase reporter gene assay, immunoprecipitation assay, electrophoretic mobility shift assay, Western blot analysis, and confocal microscopy analysis. RESULTS The LHDAg, but not the SHDAg, potentiated TGF-beta- and c-Jun-induced signal activation, and the isoprenylation of LHDAg played a major role in signaling cascades. LHDAg synergistically activated hepatitis B virus X protein-mediated TGF-beta and AP-1 signaling cascades. In addition, LHDAg enhanced the protein expression level of TGF-beta-induced plasminogen activator inhibitor-1. CONCLUSIONS LHDAg may induce liver fibrosis through the regulation of TGF-beta-induced signal transductions. This regulation of TGF-beta-mediated signaling is accomplished by the isoprenylation of LHDAg, which is a novel mechanism involved in HDV pathogenesis.
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Affiliation(s)
- Soo-Ho Choi
- Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-dong, Dongan-gu, Anyang 431-060, Korea
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Misra KP, Mukherji A, Kumar V. The conserved amino-terminal region (amino acids 1–20) of the hepatitis B virus X protein shows a transrepression function. Virus Res 2004; 105:157-65. [PMID: 15351489 DOI: 10.1016/j.virusres.2004.05.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2004] [Revised: 05/28/2004] [Accepted: 05/28/2004] [Indexed: 02/08/2023]
Abstract
The X protein of hepatitis B virus or HBx is a multifunctional regulatory protein that carries the fame of a promiscuous transactivator. Although, the N-terminal 'A' region of HBx (amino acids 1-20) is the most conserved region among mammalian hepadnavirus genomes, it has been found to be dispensable for transactivation function [Proc. Natl. Acad. Sci. U.S.A. 93, 1996, 5647]. To elucidate its biological role, DNA sequence corresponding to the A region of X gene was amplified by polymerase chain reaction and cloned as a 72 base pair HBx mutant X17. In order to augment the intracellular biochemical stability of the expressed protein, the monomeric X17 was multimerized and 2-10 units long tandem repeats of the A region (X17-n) were cloned in a mammalian expression vector. Expression of the X17 constructs was confirmed by in vitro transcription and translation, as well as by RT-PCR after transfection in hepatoma cells. The function of X17 was investigated using the chloramphenicol acetyl transferase reporter constructs of viral (RSV-LTR, HIV1-LTR and HBx) and cellular gene promoters (c-Jun and epidermal growth receptor). Not only did the X17 multimers inhibit the HBx-mediated transactivation of all the reporter genes, but also their basal activities. The inhibition was dependent on the amount of X17 plasmid transfected in cells as well as on the number of repeat units present in the X17 expression vectors. Further, the X17-related inhibition of transactivation was not a cytotoxic effect. Thus, our data suggests that the N-terminal 'A' domain of HBx has a negative regulatory function.
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MESH Headings
- Animals
- Artificial Gene Fusion
- CHO Cells
- Chloramphenicol O-Acetyltransferase/genetics
- Chloramphenicol O-Acetyltransferase/metabolism
- Cloning, Molecular
- Cricetinae
- Gene Expression
- Gene Expression Regulation, Viral
- Genes, Reporter
- Genes, Viral
- Hepatitis B virus/chemistry
- Hepatitis B virus/genetics
- Hepatitis B virus/physiology
- Humans
- Promoter Regions, Genetic
- Protein Structure, Tertiary
- RNA, Messenger/analysis
- RNA, Messenger/isolation & purification
- RNA, Viral/analysis
- RNA, Viral/isolation & purification
- Recombinant Proteins/genetics
- Recombinant Proteins/metabolism
- Repressor Proteins/genetics
- Repressor Proteins/physiology
- Tandem Repeat Sequences
- Trans-Activators/chemistry
- Trans-Activators/genetics
- Trans-Activators/physiology
- Viral Regulatory and Accessory Proteins
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Affiliation(s)
- Kamana Parashar Misra
- Virology Group, International Centre for Genetic Engineering and Biotechnology, P.O. Box 10504, Aruna Asaf Ali Marg, New Delhi 110067, India
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Cheng J, Li K, Liu Y, Wang L, Lu YY, Zhong YW. Effects of HCBP6 protein on transact-ivating function of HCV core protein. Shijie Huaren Xiaohua Zazhi 2004; 12:809-812. [DOI: 10.11569/wcjd.v12.i4.809] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the inhibitory effects of HCBP6 on the transactivating effect of HCV core protein.
METHODS: The recombinant vectors expressive HCV core protein and HCBP6 protein were constructed, respectively, by routine molecular techniques. The hepatoblastoma cell line HepG2 were co-transfected. The chloramphenicol transferase (CAT) expressive levels under the SV40 early promoter were determined by an enzyme-linked immuno-sorbent assay (ELISA) kit.
RESULTS: The recombinant vectors of pcDNA3.1(-)-HCBP6 and pcDNA3.1(-)-core were constructed, and demonstrated correctly by restriction enzyme digestion and sequencing analysis. The hepatoblastoma cell line HepG2 was transfected with the vector alone or combined, respectively. The expression level of CAT indicated that the inhibitory rate was 40.4%-62.3%.
CONCLUSION: The expression of HCBP6 has inhibitory effects on the transacting activity of HCV core protein.
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