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1
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Bruni A, Castellana C, Dajti E, Barbara G, Marasco G, Maida M, Serviddio G, Facciorusso A. Epidemiological, diagnostic, therapeutic and prognostic impact of hepatitis B and D virus infection on hepatocellular carcinoma: A review of the literature. Virology 2024; 600:110273. [PMID: 39454228 DOI: 10.1016/j.virol.2024.110273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2024] [Revised: 10/17/2024] [Accepted: 10/21/2024] [Indexed: 10/28/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) accounts for >90% of primary liver cancer cases, and chronic infections with hepatitis B virus (HBV) and hepatitis D virus (HDV) are major contributors. METHODS A comprehensive literature review was conducted using the MEDLINE (PubMed) database, focusing on studies related to HBV, HDV, and HCC. RESULTS HBV contributes to HCC through mechanisms like viral integration into the host genome, chronic inflammation, and immune modulation, leading to genomic instability and altered cell signaling. HDV exacerbates HBV-induced liver damage, accelerating fibrosis and cirrhosis, and significantly increasing HCC risk. Antiviral therapies and vaccinations have majorly reduced the burden of HBV-related HCC, but HDV remains challenging to treat due to limited therapeutic options. Emerging treatments like Bulevirtide showed promising results. CONCLUSION This review highlights the critical impact of HBV and HDV co-infections on HCC development, emphasizing the need for more effective therapeutic strategies. While advances in antiviral therapies have reduced the incidence of HBV-related HCC, the high burden of HDV-related complications persists. Future research should focus on improving treatments for HDV and understanding its unique contribution to HCC pathogenesis.
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Affiliation(s)
- Angelo Bruni
- Department of Medical and Surgical Sciences, Università di Bologna, Bologna, Italy
| | - Chiara Castellana
- Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Elton Dajti
- Department of Medical and Surgical Sciences, Università di Bologna, Bologna, Italy; Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giovanni Barbara
- Department of Medical and Surgical Sciences, Università di Bologna, Bologna, Italy; Gastroenterology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Giovanni Marasco
- Department of Medical and Surgical Sciences, Università di Bologna, Bologna, Italy; Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Marcello Maida
- Department of Medicine and Surgery, University of Enna 'Kore', Enna, Italy; Gastroenterology Unit, Umberto I Hospital, Enna, Italy
| | - Gaetano Serviddio
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy
| | - Antonio Facciorusso
- Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
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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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3
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Roulot D, Layese R, Brichler S, Ganne N, Asselah T, Zoulim F, Gordien E, Nahon P, Roudot-Thoraval F. Hepatitis D Virus Infection Markedly Increases the Risk of Hepatocellular Carcinoma in Patients with Viral B Cirrhosis. Clin Gastroenterol Hepatol 2024:S1542-3565(24)00947-9. [PMID: 39461464 DOI: 10.1016/j.cgh.2024.08.046] [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: 02/12/2024] [Revised: 08/23/2024] [Accepted: 08/29/2024] [Indexed: 10/29/2024]
Abstract
BACKGROUND & AIMS The specific causative role of hepatitis delta virus (HDV) infection in the development of hepatocellular carcinoma (HCC) remains debated and was not specifically demonstrated in patients with cirrhosis. Here we compared HCC incidence in hepatitis B virus (HBV)-HDV coinfected and HBV monoinfected patients with cirrhosis. METHODS A total of 142 HBV-HDV and 271 HBV-infected patients with cirrhosis from the French ANRSCO12 CirVir and DeltaVir cohorts, with histologically proven cirrhosis and no history of decompensation, were included in the study. RESULTS HBV-HDV patients were younger than HBV patients (37.2 vs 53.8 years), they were more often immigrants from sub-Saharan Africa, and displayed less comorbidities and more altered liver tests. After adjustment for age, cumulative incidences of HCC in coinfected and monoinfected patients at 1, 3, and 5 years were 5.2%, 11.8%, and 20.2% versus 1.1%, 2.5%, and 4.4%, respectively (P < .001). In multivariate analysis, HDV infection was an independent factor associated with the development of HCC (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.19-7.25; P = .019). Other independent factors were age (HR, 1.08; 95% CI, 1.05-1.11; P < .001), overweight (HR, 0.45; 95% CI, 0.22-0.93; P = .031), smoking (HR, 2.26; 95% CI, 1.23-4.16; P = .009), increased γ-glutamyltransferase (HR, 2.73; 95% CI, 1.24-6.00; P = .013), total bilirubin >17 μmol/L (HR, 2.68; 95% CI, 1.33-5.42; P = .006), and platelet count <150.000/mm3 (HR, 3.11; 95% CI, 1.51-6.41; P = .002). HDV coinfection was not an independent factor of liver decompensation, transplantation, or death. CONCLUSIONS The incidence of HCC seems significantly higher in HBV-HDV than in HBV-infected patients with cirrhosis. HDV infection emerges as an independent risk factor for HCC, indicating that in patients with cirrhosis, HDV plays a causative role for HCC independently of HBV.
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Affiliation(s)
- Dominique Roulot
- AP-HP, Hôpital Avicenne, Unité d'Hépatologie, Bobigny; Université Sorbonne Paris Nord, F-93000 Bobigny; Inserm U955, équipe 18, Université Paris-Est, Créteil, France.
| | - Richard Layese
- Université Paris-Est Créteil, INSERM, IMRB, CEpiA (Clinical Epidemiology and Ageing Unit) Team, Créteil; AP-HP, Hôpital Henri-Mondor, Unité de Recherche Clinique (URC Mondor), F-94010 Créteil, France
| | - Ségolène Brichler
- AP-HP, Hôpital Avicenne, Laboratoire de Microbiologie Clinique; Université Sorbonne Paris Nord, Centre National de Référence des Hépatites B, C et Delta, Bobigny, Inserm U955, équipe 18, Université Paris-Est, Créteil, France
| | - Nathalie Ganne
- AP-HP, Liver Unit, Bobigny; Université Sorbonne Paris Nord, F-93000 Bobigny; Inserm, UMR-1138 "Functional Genomics of Solid Tumors," Centre de Recherche des Cordeliers, Université de Paris, Paris, France
| | - Tarik Asselah
- AP-HP, Hôpital Beaujon, Service d'hépatologie, Clichy, France
| | - Fabien Zoulim
- Hospices Civils de Lyon, Hôpital Croix Rousse, Service d'hépatologie; Inserm U1052; Université de Lyon, France
| | - Emmanuel Gordien
- AP-HP, Hôpital Avicenne, Laboratoire de Microbiologie Clinique; Université Sorbonne Paris Nord, Centre National de Référence des Hépatites B, C et Delta, Bobigny, Inserm U955, équipe 18, Université Paris-Est, Créteil, France
| | - Pierre Nahon
- AP-HP, Liver Unit, Bobigny; Université Sorbonne Paris Nord, F-93000 Bobigny; Inserm, UMR-1138 "Functional Genomics of Solid Tumors," Centre de Recherche des Cordeliers, Université de Paris, Paris, France
| | - Françoise Roudot-Thoraval
- Université Paris-Est Créteil, INSERM, IMRB, CEpiA (Clinical Epidemiology and Ageing Unit) Team, Créteil; AP-HP, Hôpital Henri-Mondor, Unité de Recherche Clinique (URC Mondor), F-94010 Créteil, France; AP-HP, Hôpital Henri-Mondor, Service d'hépatologie, Créteil, France
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Galasso L, Cerrito L, Maccauro V, Termite F, Mignini I, Esposto G, Borriello R, Ainora ME, Gasbarrini A, Zocco MA. Inflammatory Response in the Pathogenesis and Treatment of Hepatocellular Carcinoma: A Double-Edged Weapon. Int J Mol Sci 2024; 25:7191. [PMID: 39000296 PMCID: PMC11241080 DOI: 10.3390/ijms25137191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent among primary liver tumors (90%) and one of the main causes of cancer-related death. It develops usually in a chronically inflamed environment, ranging from compensatory parenchymal regeneration to fibrosis and cirrhosis: carcinogenesis can potentially happen in each of these stages. Inflammation determined by chronic viral infection (hepatitis B, hepatitis C, and hepatitis delta viruses) represents an important risk factor for HCC etiology through both viral direct damage and immune-related mechanisms. The deregulation of the physiological liver immunological network determined by viral infection can lead to carcinogenesis. The recent introduction of immunotherapy as the gold-standard first-line treatment for HCC highlights the role of the immune system and inflammation as a double-edged weapon in both HCC carcinogenesis and treatment. In this review we highlight how the inflammation is the key for the hepatocarcinogenesis in viral, alcohol and metabolic liver diseases.
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Affiliation(s)
- Linda Galasso
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Lucia Cerrito
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Valeria Maccauro
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Fabrizio Termite
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Irene Mignini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Giorgio Esposto
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Raffaele Borriello
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Elena Ainora
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Antonio Gasbarrini
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
| | - Maria Assunta Zocco
- Department of Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario Agostino, Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Rome, 00168 Rome, Italy
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5
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Juang HH, Hsu CW, Chang KS, Iang SB, Lin YH, Chao M. Investigating the Genetic Diversity of Hepatitis Delta Virus in Hepatocellular Carcinoma (HCC): Impact on Viral Evolution and Oncogenesis in HCC. Viruses 2024; 16:817. [PMID: 38932110 PMCID: PMC11209585 DOI: 10.3390/v16060817] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 06/28/2024] Open
Abstract
Hepatitis delta virus (HDV), an RNA virus with two forms of the delta antigen (HDAg), relies on hepatitis B virus (HBV) for envelope proteins essential for hepatocyte entry. Hepatocellular carcinoma (HCC) ranks third in global cancer deaths, yet HDV's involvement remains uncertain. Among 300 HBV-associated HCC serum samples from Taiwan's National Health Research Institutes, 2.7% (8/300) tested anti-HDV positive, with 62.7% (5/8) of these also HDV RNA positive. Genotyping revealed HDV-2 in one sample, HDV-4 in two, and two samples showed mixed HDV-2/HDV-4 infection with RNA recombination. A mixed-genotype infection revealed novel mutations at the polyadenylation signal, coinciding with the ochre termination codon for the L-HDAg. To delve deeper into the possible oncogenic properties of HDV-2, the predominant genotype in Taiwan, which was previously thought to be less associated with severe disease outcomes, an HDV-2 cDNA clone was isolated from HCC for study. It demonstrated a replication level reaching up to 74% of that observed for a widely used HDV-1 strain in transfected cultured cells. Surprisingly, both forms of HDV-2 HDAg promoted cell migration and invasion, affecting the rearrangement of actin cytoskeleton and the expression of epithelial-mesenchymal transition markers. In summary, this study underscores the prevalence of HDV-2, HDV-4, and their mixed infections in HCC, highlighting the genetic diversity in HCC as well as the potential role of both forms of the HDAg in HCC oncogenesis.
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Affiliation(s)
- Horng-Heng Juang
- Department of Anatomy, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan 333, Taiwan; (H.-H.J.); (K.-S.C.)
- Department of Urology, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan
| | - Chao-Wei Hsu
- Liver Research Center, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; (C.-W.H.); (Y.-H.L.)
- School of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Kang-Shuo Chang
- Department of Anatomy, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan 333, Taiwan; (H.-H.J.); (K.-S.C.)
| | - Shan-Bei Iang
- Department of Microbiology and Immunology and Division of Microbiology, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
| | - Yang-Hsiang Lin
- Liver Research Center, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; (C.-W.H.); (Y.-H.L.)
| | - Mei Chao
- Liver Research Center, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital at Linkou, Taoyuan 333, Taiwan; (C.-W.H.); (Y.-H.L.)
- Department of Microbiology and Immunology and Division of Microbiology, Graduate Institute of Biomedical Sciences, School of Medicine, Chang Gung University, Taoyuan 333, Taiwan;
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6
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Lombardo D, Franzè MS, Caminiti G, Pollicino T. Hepatitis Delta Virus and Hepatocellular Carcinoma. Pathogens 2024; 13:362. [PMID: 38787214 PMCID: PMC11124437 DOI: 10.3390/pathogens13050362] [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: 03/22/2024] [Revised: 04/14/2024] [Accepted: 04/20/2024] [Indexed: 05/25/2024] Open
Abstract
The hepatitis D virus (HDV) is a compact, enveloped, circular RNA virus that relies on hepatitis B virus (HBV) envelope proteins to initiate a primary infection in hepatocytes, assemble, and secrete new virions. Globally, HDV infection affects an estimated 12 million to 72 million people, carrying a significantly elevated risk of developing cirrhosis, liver failure, and hepatocellular carcinoma (HCC) compared to an HBV mono-infection. Furthermore, HDV-associated HCC often manifests at a younger age and exhibits more aggressive characteristics. The intricate mechanisms driving the synergistic carcinogenicity of the HDV and HBV are not fully elucidated but are believed to involve chronic inflammation, immune dysregulation, and the direct oncogenic effects of the HDV. Indeed, recent data highlight that the molecular profile of HCC associated with HDV is unique and distinct from that of HBV-induced HCC. However, the question of whether the HDV is an oncogenic virus remains unanswered. In this review, we comprehensively examined several crucial aspects of the HDV, encompassing its epidemiology, molecular biology, immunology, and the associated risks of liver disease progression and HCC development.
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Affiliation(s)
| | | | | | - Teresa Pollicino
- Department of Clinical and Experimental Medicine, University Hospital of Messina, 98124 Messina, Italy; (D.L.); (M.S.F.); (G.C.)
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7
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Capasso M, Cossiga V, Guarino M, Ranieri L, Morisco F. The Role of Hepatitis Viruses as Drivers of Hepatocancerogenesis. Cancers (Basel) 2024; 16:1505. [PMID: 38672587 PMCID: PMC11048534 DOI: 10.3390/cancers16081505] [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: 03/11/2024] [Revised: 04/08/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Recently, metabolic associated steatotic liver disease (MASLD) became the leading cause of chronic liver disease worldwide and one of the most frequent causes of hepatocellular carcinoma (HCC). Nonetheless, in this epidemiological trend, viral hepatitis remains the major driver in hepatic carcinogenesis. Globally, hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma, with an overall attributable risk of approximately 40%, followed by hepatitis C virus (HCV), which accounts for 28-30% of cases, with significant geographic variations between the Eastern and Western world. Considering all the etiologies, HCC risk increases proportionally with the progression of liver disease, but the risk is consistently higher in patients with viral triggers. This evidence indicates that both direct (due to the oncogenic properties of the viruses) and indirect (through the mechanisms of chronic inflammation that lead to cirrhosis) mechanisms are involved, alongside the presence of co-factors contributing to liver damage (smoking, alcohol, and metabolic factors) that synergistically enhance the oncogenic process. The aim of this review is to analyze the oncogenic role of hepatitis viruses in the liver, evaluating epidemiological changes and direct and indirect viral mechanisms that lead to liver cancer.
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Affiliation(s)
| | - Valentina Cossiga
- Diseases of the Liver and Biliary System Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy; (M.C.); (M.G.); (L.R.); (F.M.)
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8
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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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9
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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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10
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Smirnova OA, Ivanova ON, Mukhtarov F, Valuev-Elliston VT, Fedulov AP, Rubtsov PM, Zakirova NF, Kochetkov SN, Bartosch B, Ivanov AV. Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2/ARE Pathway, and Induce Unfolded Protein Response. Antioxidants (Basel) 2023; 12:antiox12040974. [PMID: 37107349 PMCID: PMC10136299 DOI: 10.3390/antiox12040974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 04/20/2023] [Accepted: 04/20/2023] [Indexed: 04/29/2023] Open
Abstract
Hepatitis delta virus (HDV) is a viroid-like satellite that may co-infect individuals together with hepatitis B virus (HBV), as well as cause superinfection by infecting patients with chronic hepatitis B (CHB). Being a defective virus, HDV requires HBV structural proteins for virion production. Although the virus encodes just two forms of its single antigen, it enhances the progression of liver disease to cirrhosis in CHB patients and increases the incidence of hepatocellular carcinoma. HDV pathogenesis so far has been attributed to virus-induced humoral and cellular immune responses, while other factors have been neglected. Here, we evaluated the impact of the virus on the redox status of hepatocytes, as oxidative stress is believed to contribute to the pathogenesis of various viruses, including HBV and hepatitis C virus (HCV). We show that the overexpression of large HDV antigen (L-HDAg) or autonomous replication of the viral genome in cells leads to increased production of reactive oxygen species (ROS). It also leads to the upregulated expression of NADPH oxidases 1 and 4, cytochrome P450 2E1, and ER oxidoreductin 1α, which have previously been shown to mediate oxidative stress induced by HCV. Both HDV antigens also activated the Nrf2/ARE pathway, which controls the expression of a spectrum of antioxidant enzymes. Finally, HDV and its large antigen also induced endoplasmic reticulum (ER) stress and the concomitant unfolded protein response (UPR). In conclusion, HDV may enhance oxidative and ER stress induced by HBV, thus aggravating HBV-associated pathologies, including inflammation, liver fibrosis, and the development of cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Olga A Smirnova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Olga N Ivanova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Furkat Mukhtarov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | | | - Artemy P Fedulov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Petr M Rubtsov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Natalia F Zakirova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Sergey N Kochetkov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Birke Bartosch
- Centre de Recherche en Cancérologie de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, 69434 Lyon, France
| | - Alexander V Ivanov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
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12
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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: 8] [Impact Index Per Article: 4.0] [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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Wu S, Yi W, Gao Y, Deng W, Bi X, Lin Y, Yang L, Lu Y, Liu R, Chang M, Shen G, Hu L, Zhang L, Li M, Xie Y. Immune Mechanisms Underlying Hepatitis B Surface Antigen Seroclearance in Chronic Hepatitis B Patients With Viral Coinfection. Front Immunol 2022; 13:893512. [PMID: 35634301 PMCID: PMC9130599 DOI: 10.3389/fimmu.2022.893512] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 04/11/2022] [Indexed: 12/28/2022] Open
Abstract
It is considered that chronic hepatitis B patients have obtained functional cure if they get hepatitis B surface antigen (HBsAg) seroclearance after treatment. Serum HBsAg is produced by cccDNA that is extremely difficult to clear and dslDNA that is integrated with host chromosome. High HBsAg serum level leads to failure of host immune system, which makes it unable to produce effective antiviral response required for HBsAg seroclerance. Therefore, it is very difficult to achieve functional cure, and fewer than 1% of chronic hepatitis B patients are cured with antiviral treatment annually. Some chronic hepatitis B patients are coinfected with other chronic viral infections, such as HIV, HCV and HDV, which makes more difficult to cure. However, it is found that the probability of obtaining HBsAg seroclearance in patients with coinfection is higher than that in patients with HBV monoinfection, especially in patients with HBV/HIV coinfection who have an up to 36% of HBsAg 5-year-seroclerance rate. The mechanism of this interesting phenomenon is related to the functional reconstruction of immune system after antiretroviral therapy (ART). The quantity increase and function recovery of HBV specific T cells and B cells, and the higher level of cytokines and chemokines such as IP-10, GM-CSF, promote HBsAg seroclearance. This review summarizes recent studies on the immune factors that have influence on HBsAg seroconversion in the chronic hepatitis B patients with viral coinfection, which might provide new insights for the development of therapeutic approaches to partially restore the specific immune response to HBV and other viruses.
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Affiliation(s)
- Shuling Wu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wei Yi
- Department of Gynecology and Obstetrics, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yuanjiao Gao
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wen Deng
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Xiaoyue Bi
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yanjie Lin
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Liu Yang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Yao Lu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ruyu Liu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Min Chang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Ge Shen
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Leiping Hu
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Lu Zhang
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Minghui Li
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
| | - Yao Xie
- Department of Hepatology Division 2, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Department of Hepatology Division 2, Peking University Ditan Teaching Hospital, Beijing, China
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14
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Usai C, Gill US, Riddell AC, Asselah T, Kennedy P. Review article: emerging insights into the immunopathology, clinical and therapeutic aspects of hepatitis delta virus. Aliment Pharmacol Ther 2022; 55:978-993. [PMID: 35292991 PMCID: PMC9314912 DOI: 10.1111/apt.16807] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/06/2021] [Accepted: 01/25/2022] [Indexed: 12/16/2022]
Abstract
BACKGROUND Hepatitis delta virus (HDV), which causes the most severe form of viral hepatitis, is an obligated hepatitis B (HBV) satellite virus that can either infect naïve subjects simultaneously with HBV (co-infection), or chronically infect HBV carriers (super-infection). An estimated 12 million people are infected by HDV worldwide. AIMS To summarise the most relevant aspects of the molecular biology of HDV, and to discuss the latest understanding of the induced pathology, interactions with the immune system, as well as both approved and investigational treatment options. METHODS References for this review were identified through searches of PubMed with the terms "HDV" "viral hepatitis" "co-infection" and "super-infection," published between 1980 and October 2021 RESULTS: The limited access to the HDV-infected liver has hampered the investigation of the intrahepatic compartment and our understanding of the mechanisms of HDV pathogenesis. In the absence of standardised and sensitive diagnostic tools, HDV is often underdiagnosed and owing to its strong dependence on host cellular factors, the development of direct antiviral agents has been challenging. New therapeutic agents targeting different steps of the viral cycle have recently been investigated, among which bulevirtide (which was conditionally approved by EMA in July 2020) and lonafarnib; both drugs having received orphan drug designation from both the EMA and FDA. CONCLUSIONS The HBV cure programme potentially offers a unique opportunity to enhance HDV treatment strategies. In addition, a more comprehensive analysis of the intrahepatic compartment is mandated to better understand any liver-confined interaction of HDV with the host immune system.
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Affiliation(s)
- Carla Usai
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK,Present address:
Unitat mixta d’Investigació IRTA‐UAB en Sanitat AnimalCentre de Recerca en Sanitat Animal (CReSA)Campus de la Universitat Autònoma de Barcelona (UAB)Bellaterra08193Spain
| | - Upkar S. Gill
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK,The Royal London HospitalBarts Health NHS TrustLondonUK
| | - Anna C. Riddell
- Division of Infection, Virology DepartmentBarts Health NHS TrustLondonUK
| | - Tarik Asselah
- Centre de recherche sur l'inflammation, Inserm U1149Université́ de ParisParisFrance,Department of Hepatology, AP‐HPHôpital BeaujonClichyFrance
| | - Patrick T. Kennedy
- Centre for Immunobiology, Blizard Institute, Barts and The London School of Medicine and DentistryQueen Mary University of LondonLondonUK,The Royal London HospitalBarts Health NHS TrustLondonUK
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15
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Boulahtouf Z, Virzì A, Baumert TF, Verrier ER, Lupberger J. Signaling Induced by Chronic Viral Hepatitis: Dependence and Consequences. Int J Mol Sci 2022; 23:ijms23052787. [PMID: 35269929 PMCID: PMC8911453 DOI: 10.3390/ijms23052787] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 02/27/2022] [Accepted: 03/01/2022] [Indexed: 12/12/2022] Open
Abstract
Chronic viral hepatitis is a main cause of liver disease and hepatocellular carcinoma. There are striking similarities in the pathological impact of hepatitis B, C, and D, although these diseases are caused by very different viruses. Paired with the conventional study of protein-host interactions, the rapid technological development of -omics and bioinformatics has allowed highlighting the important role of signaling networks in viral pathogenesis. In this review, we provide an integrated look on the three major viruses associated with chronic viral hepatitis in patients, summarizing similarities and differences in virus-induced cellular signaling relevant to the viral life cycles and liver disease progression.
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Affiliation(s)
- Zakaria Boulahtouf
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
| | - Alessia Virzì
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
| | - Thomas F. Baumert
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
- Service d’Hépato-Gastroentérologie, Hôpitaux Universitaires de Strasbourg, F-67000 Strasbourg, France
- Institut Universitaire de France (IUF), F-75005 Paris, France
| | - Eloi R. Verrier
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
| | - Joachim Lupberger
- Institut de Recherche sur les Maladies Virales et Hepatiques UMR_S1110, Université de Strasbourg, Inserm, F-67000 Strasbourg, France; (Z.B.); (A.V.); (T.F.B.); (E.R.V.)
- Correspondence:
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Abstract
Hepatitis D virus (HDV) infection causes the most severe form of viral hepatitis with rapid progression to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. Although discovered > 40 years ago, little attention has been paid to this pathogen from both scientific and public communities. However, effectively combating hepatitis D requires advanced scientific knowledge and joint efforts from multi-stakeholders. In this review, we emphasized the recent advances in HDV virology, epidemiology, clinical feature, treatment, and prevention. We not only highlighted the remaining challenges but also the opportunities that can move the field forward.
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Zaki MYW, Fathi AM, Samir S, Eldafashi N, William KY, Nazmy MH, Fathy M, Gill US, Shetty S. Innate and Adaptive Immunopathogeneses in Viral Hepatitis; Crucial Determinants of Hepatocellular Carcinoma. Cancers (Basel) 2022; 14:1255. [PMID: 35267563 PMCID: PMC8909759 DOI: 10.3390/cancers14051255] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/01/2022] [Accepted: 02/04/2022] [Indexed: 02/08/2023] Open
Abstract
Viral hepatitis B (HBV) and hepatitis C (HCV) infections remain the most common risk factors for the development of hepatocellular carcinoma (HCC), and their heterogeneous distribution influences the global prevalence of this common type of liver cancer. Typical hepatitis infection elicits various immune responses within the liver microenvironment, and viral persistence induces chronic liver inflammation and carcinogenesis. HBV is directly mutagenic but can also cause low-grade liver inflammation characterized by episodes of intermittent high-grade liver inflammation, liver fibrosis, and cirrhosis, which can progress to decompensated liver disease and HCC. Equally, the absence of key innate and adaptive immune responses in chronic HCV infection dampens viral eradication and induces an exhausted and immunosuppressive liver niche that favors HCC development and progression. The objectives of this review are to (i) discuss the epidemiological pattern of HBV and HCV infections, (ii) understand the host immune response to acute and chronic viral hepatitis, and (iii) explore the link between this diseased immune environment and the development and progression of HCC in preclinical models and HCC patients.
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Affiliation(s)
- Marco Y. W. Zaki
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
| | - Ahmed M. Fathi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Samara Samir
- Department of Biochemistry, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt;
| | - Nardeen Eldafashi
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Kerolis Y. William
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo 12613, Egypt;
| | - Maiiada Hassan Nazmy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Moustafa Fathy
- Department of Biochemistry, Faculty of Pharmacy, Minia University, Minia 61732, Egypt; (A.M.F.); (N.E.); (M.H.N.); (M.F.)
| | - Upkar S. Gill
- Barts Liver Centre, Centre for Immunobiology, Barts & The London School of Medicine & Dentistry, QMUL, London E1 2AT, UK;
| | - Shishir Shetty
- National Institute for Health Research Birmingham Liver Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
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18
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Adaptive Immune Responses, Immune Escape and Immune-Mediated Pathogenesis during HDV Infection. Viruses 2022; 14:v14020198. [PMID: 35215790 PMCID: PMC8880046 DOI: 10.3390/v14020198] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/14/2022] [Accepted: 01/16/2022] [Indexed: 12/13/2022] Open
Abstract
The hepatitis delta virus (HDV) is the smallest known human virus, yet it causes great harm to patients co-infected with hepatitis B virus (HBV). As a satellite virus of HBV, HDV requires the surface antigen of HBV (HBsAg) for sufficient viral packaging and spread. The special circumstance of co-infection, albeit only one partner depends on the other, raises many virological, immunological, and pathophysiological questions. In the last years, breakthroughs were made in understanding the adaptive immune response, in particular, virus-specific CD4+ and CD8+ T cells, in self-limited versus persistent HBV/HDV co-infection. Indeed, the mechanisms of CD8+ T cell failure in persistent HBV/HDV co-infection include viral escape and T cell exhaustion, and mimic those in other persistent human viral infections, such as hepatitis C virus (HCV), human immunodeficiency virus (HIV), and HBV mono-infection. However, compared to these larger viruses, the small HDV has perfectly adapted to evade recognition by CD8+ T cells restricted by common human leukocyte antigen (HLA) class I alleles. Furthermore, accelerated progression towards liver cirrhosis in persistent HBV/HDV co-infection was attributed to an increased immune-mediated pathology, either caused by innate pathways initiated by the interferon (IFN) system or triggered by misguided and dysfunctional T cells. These new insights into HDV-specific adaptive immunity will be discussed in this review and put into context with known well-described aspects in HBV, HCV, and HIV infections.
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Datfar T, Doulberis M, Papaefthymiou A, Hines IN, Manzini G. Viral Hepatitis and Hepatocellular Carcinoma: State of the Art. Pathogens 2021; 10:pathogens10111366. [PMID: 34832522 PMCID: PMC8619105 DOI: 10.3390/pathogens10111366] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 09/26/2021] [Accepted: 10/18/2021] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis is one of the main causes leading to hepatocellular carcinoma (HCC). The continued rise in incidence of HCC suggests additional factors following infection may be involved. This review examines recent studies investigating the molecular mechanisms of chronic hepatitis and its association with hepatocarcinogenesis. Hepatitis B virus patients with genotype C display an aggressive disease course leading to HCC more than other genotypes. Furthermore, hepatitis B excretory antigen (HBeAg) seems to be a more sensitive predictive tumor marker exhibiting a six-fold higher relative risk in patients with positive HBsAg and HBeAg than those with HBsAg only. Single or combined mutations of viral genome can predict HCC development in up to 80% of patients. Several mutations in HBx-gene are related with higher HCC incidence. Overexpression of the core protein in HCV leads to hepatocellular lipid accumulation associated with oncogenesis. Reduced number and decreased functionality of natural killer cells in chronic HCV individuals dysregulate their surveillance function in tumor and viral cells resulting in HCC. Furthermore, high T-cell immunoglobulin and mucin 3 levels supress CD8+ T-cells, which lead to immunological dysregulation. Hepatitis D promotes HCC development indirectly via modifications to innate immunity, epigenetic alterations and production of reactive oxygen species with the LHDAg being the most highly associated with HCC development. Summarizing the results, HBV and HCV infection represent the most associated forms of viral hepatitis causing HCC. Further studies are warranted to further improve the prediction of high-risk patients and development of targeted therapeutics preventing the transition from hepatic inflammation–fibrosis to cancer.
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Affiliation(s)
- Toofan Datfar
- Department of General and Visceral Surgery, Hospital of Aarau, 5001 Aarau, Switzerland;
- Correspondence: ; Tel.: +41-76-4930834
| | - Michael Doulberis
- Department of Gastroenterology and Hepatology, Hospital of Aarau, 5001 Aarau, Switzerland;
| | | | - Ian N. Hines
- Department of Nutrition Science, East Carolina University, Greenville, NC 27858, USA;
| | - Giulia Manzini
- Department of General and Visceral Surgery, Hospital of Aarau, 5001 Aarau, Switzerland;
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20
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Dziri S, Rodriguez C, Gerber A, Brichler S, Alloui C, Roulot D, Dény P, Pawlotsky JM, Gordien E, Le Gal F. Variable In Vivo Hepatitis D Virus (HDV) RNA Editing Rates According to the HDV Genotype. Viruses 2021; 13:v13081572. [PMID: 34452437 PMCID: PMC8402866 DOI: 10.3390/v13081572] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/26/2021] [Accepted: 08/04/2021] [Indexed: 12/21/2022] Open
Abstract
Human hepatitis delta virus (HDV) is a small defective RNA satellite virus that requires hepatitis B virus (HBV) envelope proteins to form its own virions. The HDV genome possesses a single coding open reading frame (ORF), located on a replicative intermediate, the antigenome, encoding the small (s) and the large (L) isoforms of the delta antigen (s-HDAg and L-HDAg). The latter is produced following an editing process, changing the amber/stop codon on the s-HDAg-ORF into a tryptophan codon, allowing L-HDAg synthesis by the addition of 19 (or 20) C-terminal amino acids. The two delta proteins play different roles in the viral cell cycle: s-HDAg activates genome replication, while L-HDAg blocks replication and favors virion morphogenesis and propagation. L-HDAg has also been involved in HDV pathogenicity. Understanding the kinetics of viral editing rates in vivo is key to unravel the biology of the virus and understand its spread and natural history. We developed and validated a new assay based on next-generation sequencing and aimed at quantifying HDV RNA editing in plasma. We analyzed plasma samples from 219 patients infected with different HDV genotypes and showed that HDV editing capacity strongly depends on the genotype of the strain.
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Affiliation(s)
- Samira Dziri
- Centre National de Référence des Hépatites Virales B, C et Delta, Laboratoire de Microbiologie Clinique, Hôpital-Avicenne, Assistance Publique Hôpitaux de Paris, Université Sorbonne Paris Cité, 93000 Bobigny, France; (S.D.); (A.G.); (S.B.); (C.A.); (P.D.); (E.G.)
| | - Christophe Rodriguez
- Centre National de référence des Hépatites Virales B, C et Delta, Département de Virologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris-Est, 94000 Créteil, France; (C.R.); (J.M.P.)
- Unité INSERM U955, équipe 18, 94000 Créteil, France;
| | - Athenaïs Gerber
- Centre National de Référence des Hépatites Virales B, C et Delta, Laboratoire de Microbiologie Clinique, Hôpital-Avicenne, Assistance Publique Hôpitaux de Paris, Université Sorbonne Paris Cité, 93000 Bobigny, France; (S.D.); (A.G.); (S.B.); (C.A.); (P.D.); (E.G.)
| | - Ségolène Brichler
- Centre National de Référence des Hépatites Virales B, C et Delta, Laboratoire de Microbiologie Clinique, Hôpital-Avicenne, Assistance Publique Hôpitaux de Paris, Université Sorbonne Paris Cité, 93000 Bobigny, France; (S.D.); (A.G.); (S.B.); (C.A.); (P.D.); (E.G.)
- Unité INSERM U955, équipe 18, 94000 Créteil, France;
| | - Chakib Alloui
- Centre National de Référence des Hépatites Virales B, C et Delta, Laboratoire de Microbiologie Clinique, Hôpital-Avicenne, Assistance Publique Hôpitaux de Paris, Université Sorbonne Paris Cité, 93000 Bobigny, France; (S.D.); (A.G.); (S.B.); (C.A.); (P.D.); (E.G.)
- Unité INSERM U955, équipe 18, 94000 Créteil, France;
| | - Dominique Roulot
- Unité INSERM U955, équipe 18, 94000 Créteil, France;
- Unité d’hépatologie, Hôpital Avicenne, Assistance Publique-Hôpitaux de Paris, Université Sorbonne-Paris-Cité, 93000 Bobigny, France
| | - Paul Dény
- Centre National de Référence des Hépatites Virales B, C et Delta, Laboratoire de Microbiologie Clinique, Hôpital-Avicenne, Assistance Publique Hôpitaux de Paris, Université Sorbonne Paris Cité, 93000 Bobigny, France; (S.D.); (A.G.); (S.B.); (C.A.); (P.D.); (E.G.)
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052-UMR CNRS 5286, 69001 Lyon, France
| | - Jean Michel Pawlotsky
- Centre National de référence des Hépatites Virales B, C et Delta, Département de Virologie, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris-Est, 94000 Créteil, France; (C.R.); (J.M.P.)
- Unité INSERM U955, équipe 18, 94000 Créteil, France;
| | - Emmanuel Gordien
- Centre National de Référence des Hépatites Virales B, C et Delta, Laboratoire de Microbiologie Clinique, Hôpital-Avicenne, Assistance Publique Hôpitaux de Paris, Université Sorbonne Paris Cité, 93000 Bobigny, France; (S.D.); (A.G.); (S.B.); (C.A.); (P.D.); (E.G.)
- Unité INSERM U955, équipe 18, 94000 Créteil, France;
| | - Frédéric Le Gal
- Centre National de Référence des Hépatites Virales B, C et Delta, Laboratoire de Microbiologie Clinique, Hôpital-Avicenne, Assistance Publique Hôpitaux de Paris, Université Sorbonne Paris Cité, 93000 Bobigny, France; (S.D.); (A.G.); (S.B.); (C.A.); (P.D.); (E.G.)
- Unité INSERM U955, équipe 18, 94000 Créteil, France;
- Correspondence:
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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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22
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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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D'souza S, Lau KCK, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol 2020; 26:5759-5783. [PMID: 33132633 PMCID: PMC7579760 DOI: 10.3748/wjg.v26.i38.5759] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/03/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV), hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins. DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.
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Affiliation(s)
- Simmone D'souza
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Keith CK Lau
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Carla S Coffin
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Trushar R Patel
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge T1K3M4, AB, Canada
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Baskiran A, Akbulut S, Sahin TT, Koc C, Karakas S, Ince V, Yurdaydin C, Yilmaz S. Effect of HBV-HDV co-infection on HBV-HCC co-recurrence in patients undergoing living donor liver transplantation. Hepatol Int 2020; 14:869-880. [PMID: 32895876 DOI: 10.1007/s12072-020-10085-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/20/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE To evaluate the effect of hepatitis D virus (HDV) on hepatitis B virus-hepatocellular carcinoma (HBV-HCC) co-recurrence in patients undergoing living donor liver transplantation (LDLT) for HBV alone or HBV-HDV coinfection. METHODS Between 2002 and 2019, 254 HBV-HCC patients underwent LDLT. The patients were divided into two groups after the application of the exclusion criteria: HBV-HCC (Group B; n = 163) and HBV-HDV-HCC (Group D; n = 31). First, the B and D groups were compared in terms of demographic and clinical parameters. Second, patients with (n = 16) and without (n = 178) post-transplant HBV-HCC co-recurrences were grouped and compared in terms of the same parameters. RESULTS Although the risk of HBV-HCC co-recurrence in group D was 4.99-fold higher than in group B, the risk of HBV recurrence alone in group D was 12.5-fold lower than in group B. The AFP (OR = 4.4), Milan criteria (beyond; OR = 18.8), and HDV (OR = 8.1) were identified as the independent risk factors affecting post-transplant HBV-HCC co-recurrence. The Milan criteria (OR = 2.1) and HBV-HCC co-recurrence (OR = 10.9) were identified as the risk factors affecting post-transplant mortality. HBV-HCC co-recurrence developed in 26.5% of patients in Group B and 100% in Group D (OR = 40; p = 0.001). HCC recurrence alone developed in 10% of patients without HBV recurrence in group B and 0% of patients without HBV recurrence in group D (OR = 5.7). CONCLUSION This study showed that the risk of HBV recurrence alone was reduced by 12.5-fold in the presence of HDV; however, the HCC recurrence occurred in all patients with HDV when HBV recurrence developed.
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Affiliation(s)
- Adil Baskiran
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey
| | - Sami Akbulut
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey.
| | - Tevfik Tolga Sahin
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey
| | - Cemalettin Koc
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey
| | - Serdar Karakas
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey
| | - Volkan Ince
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey
| | - Cihan Yurdaydin
- Department of Gastroenterology, Faculty of Medicine, Koc University, 34450, Istanbul, Turkey
| | - Sezai Yilmaz
- Department of Surgery, Faculty of Medicine, Liver Transplant Institute, Inonu University, Elazig Yolu 10. Km, 44280, Malatya, Turkey
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25
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Jung S, Altstetter SM, Protzer U. Innate immune recognition and modulation in hepatitis D virus infection. World J Gastroenterol 2020; 26:2781-2791. [PMID: 32550754 PMCID: PMC7284172 DOI: 10.3748/wjg.v26.i21.2781] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 03/30/2020] [Accepted: 05/23/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis D virus (HDV) is a global health threat with more than 15 million humans affected. Current treatment options are largely unsatisfactory leaving chronically infected humans at high risk to develop liver cirrhosis and hepatocellular carcinoma. HDV is the only human satellite virus known. It encodes only two proteins, and requires Hepatitis B virus (HBV) envelope protein expression for productive virion release and spread of the infection. How HDV could evolve and why HBV was selected as a helper virus remains unknown. Since the discovery of Na+-taurocholate co-transporting polypeptide as the essential uptake receptor for HBV and HDV, we are beginning to understand the interactions of HDV and the immune system. While HBV is mostly regarded a stealth virus, that escapes innate immune recognition, HBV-HDV coinfection is characterized by a strong innate immune response. Cytoplasmic RNA sensor melanoma differentiation antigen 5 has been reported to recognize HDV RNA replication and activate innate immunity. Innate immunity, however, seems not to impair HDV replication while it inhibits HBV. In this review, we describe what is known up-to-date about the interplay between HBV as a helper and HDV’s immune evasion strategy and identify where additional research is required.
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MESH Headings
- Carcinoma, Hepatocellular/immunology
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Coinfection/complications
- Coinfection/immunology
- Coinfection/pathology
- Coinfection/virology
- Hepatitis B virus/genetics
- Hepatitis B virus/immunology
- Hepatitis B virus/metabolism
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/immunology
- Hepatitis B, Chronic/pathology
- Hepatitis B, Chronic/virology
- Hepatitis D, Chronic/complications
- Hepatitis D, Chronic/immunology
- Hepatitis D, Chronic/pathology
- Hepatitis D, Chronic/virology
- Hepatitis Delta Virus/genetics
- Hepatitis Delta Virus/immunology
- Hepatitis Delta Virus/metabolism
- Hepatitis delta Antigens/immunology
- Hepatitis delta Antigens/metabolism
- Humans
- Immune Evasion
- Immunity, Innate
- Interferon-Induced Helicase, IFIH1/metabolism
- Liver/immunology
- Liver/pathology
- Liver/virology
- Liver Cirrhosis/immunology
- Liver Cirrhosis/pathology
- Liver Cirrhosis/virology
- Liver Neoplasms/immunology
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Organic Anion Transporters, Sodium-Dependent/metabolism
- RNA, Viral/immunology
- RNA, Viral/metabolism
- Receptors, Pattern Recognition/immunology
- Receptors, Pattern Recognition/metabolism
- Satellite Viruses/genetics
- Satellite Viruses/immunology
- Satellite Viruses/metabolism
- Symporters/metabolism
- Virus Replication/immunology
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Affiliation(s)
- Stephanie Jung
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich D-81675, Germany
| | | | - Ulrike Protzer
- Institute of Virology, Technical University of Munich/Helmholtz Zentrum München, Munich D-81675, Germany
- German Center for Infection Research (DZIF), Munich Partner Site, Munich D-81675, Germany
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26
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Statin inhibits large hepatitis delta antigen-Smad3 -twist-mediated epithelial-to-mesenchymal transition and hepatitis D virus secretion. J Biomed Sci 2020; 27:65. [PMID: 32434501 PMCID: PMC7240974 DOI: 10.1186/s12929-020-00659-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2020] [Accepted: 05/14/2020] [Indexed: 01/01/2023] Open
Abstract
Background Hepatitis D virus (HDV) infection may induce fulminant hepatitis in chronic hepatitis B patients (CHB) or rapid progression of CHB to cirrhosis or hepatocellular carcinoma. There is no effective treatment for HDV infection. HDV encodes small delta antigens (S-HDAg) and large delta antigens (L-HDAg). S-HDAg is essential for HDV replication. Prenylated L-HDAg plays a key role in HDV assembly. Previous studies indicate that L-HDAg transactivates transforming growth factor beta (TGF-β) and induces epithelial-mesenchymal transition (EMT), possibly leading to liver fibrosis. However, the mechanism is unclear. Methods The mechanisms of the activation of Twist promoter by L-HDAg were investigated by luciferase reporter assay, chromatin immunoprecipitation, and co-immunoprecipitation analysis. ELISA and Western blotting were used to analyze L-HDAg prenylation, TGF-β secretion, expression of EMT markers, and to evaluate efficacy of statins for HDV treatment. Results We found that L-HDAg activated Twist expression, TGF-β expression and consequently induced EMT, based on its interaction with Smad3 on Twist promoter. The treatment of statin, a prenylation inhibitor, resulted in reduction of Twist promoter activity, TGF-β expression, and EMT, and reduces the release of HDV virions into the culture medium. Conclusions We demonstrate that L-HDAg activates EMT via Twist and TGF-β activation. Treatment with statins suppressed Twist expression, and TGF-β secretion, leading to downregulation of EMT. Our findings clarify the mechanism of HDV-induced EMT, and provide a basis for possible novel therapeutic strategies against HDV infection.
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27
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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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28
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Miao Z, Zhang S, Ou X, Li S, Ma Z, Wang W, Peppelenbosch MP, Liu J, Pan Q. Estimating the Global Prevalence, Disease Progression, and Clinical Outcome of Hepatitis Delta Virus Infection. J Infect Dis 2020; 221:1677-1687. [PMID: 31778167 PMCID: PMC7184909 DOI: 10.1093/infdis/jiz633] [Citation(s) in RCA: 215] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 11/27/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatitis delta virus (HDV) coinfects with hepatitis B virus (HBV) causing the most severe form of viral hepatitis. However, its exact global disease burden remains largely obscure. We aim to establish the global epidemiology, infection mode-stratified disease progression, and clinical outcome of HDV infection. METHODS We conducted a meta-analysis with a random-effects model and performed data synthesis. RESULTS The pooled prevalence of HDV is 0.80% (95% confidence interval [CI], 0.63-1.00) among the general population and 13.02% (95% CI, 11.96-14.11) among HBV carriers, corresponding to 48-60 million infections globally. Among HBV patients with fulminant hepatitis, cirrhosis, or hepatocellular carcinoma, HDV prevalence is 26.75% (95% CI, 19.84-34.29), 25.77% (95% CI, 20.62-31.27), and 19.80% (95% CI, 10.97-30.45), respectively. The odds ratio (OR) of HDV infection among HBV patients with chronic liver disease compared with asymptomatic controls is 4.55 (95% CI, 3.65-5.67). Hepatitis delta virus-coinfected patients are more likely to develop cirrhosis than HBV-monoinfected patients with OR of 3.84 (95% CI, 1.79-8.24). Overall, HDV infection progresses to cirrhosis within 5 years and to hepatocellular carcinoma within 10 years, on average. CONCLUSIONS Findings suggest that HDV poses a heavy global burden with rapid progression to severe liver diseases, urging effective strategies for screening, prevention, and treatment.
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Affiliation(s)
- Zhijiang Miao
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Shaoshi Zhang
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Xumin Ou
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Shan Li
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
- Department of Hepatobiliary Surgery, Daping Hospital (Army Medical Center), Third Military Medical University (Army Medical University), Chongqing, China
| | - Zhongren Ma
- Biomedical Research Center, Northwest Minzu University, Lanzhou, People’s Republic of China
| | - Wenshi Wang
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
- Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Jiaye Liu
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, The Netherlands
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29
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Puigvehí M, Moctezuma-Velázquez C, Villanueva A, Llovet JM. The oncogenic role of hepatitis delta virus in hepatocellular carcinoma. JHEP Rep 2019; 1:120-130. [PMID: 32039360 PMCID: PMC7001537 DOI: 10.1016/j.jhepr.2019.05.001] [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: 02/17/2019] [Revised: 04/18/2019] [Accepted: 05/05/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis delta virus (HDV) is a small defective virus that needs hepatitis B virus (HBV) to replicate and propagate. HDV infection affects 20-40 million people worldwide and pegylated interferon (PegIFN) is the only recommended therapy. There is limited data on the contribution of HDV infection to HBV-related liver disease or liver cancer. Evidence from retrospective and cohort studies suggests that HBV/HDV coinfection accelerates progression to cirrhosis and is associated with an increased risk of hepatocellular carcinoma (HCC) development compared to HBV monoinfection. Although the life cycle of HDV is relatively well known, there is only ancillary information on the molecular mechanisms that can drive specific HDV-related oncogenesis. No thorough reports on the specific landscape of mutations or molecular classes of HDV-related HCC have been published. This information could be critical to better understand the uniqueness, if any, of HDV-related HCC and help identify novel targetable mutations. Herein, we review the evidence supporting an oncogenic role of HDV, the main reported mechanisms of HDV involvement and their impact on HCC development.
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Affiliation(s)
- Marc Puigvehí
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Hepatology Section, Gastroenterology Department, Hospital del Mar, IMIM, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
| | - Carlos Moctezuma-Velázquez
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Augusto Villanueva
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA.,Denotes co-senior authorship
| | - Josep M Llovet
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.,Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain.,Institució Catalana de Recerca i Estudis Avançats, Barcelona, Catalonia, Spain.,Denotes co-senior authorship
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30
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Goodrum G, Pelchat M. Insight into the Contribution and Disruption of Host Processes during HDV Replication. Viruses 2018; 11:v11010021. [PMID: 30602655 PMCID: PMC6356607 DOI: 10.3390/v11010021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2018] [Revised: 12/18/2018] [Accepted: 12/30/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatitis delta virus (HDV) is unique among animal viruses. HDV is a satellite virus of the hepatitis B virus (HBV), however it shares no sequence similarity with its helper virus and replicates independently in infected cells. HDV is the smallest human pathogenic RNA virus and shares numerous characteristics with viroids. Like viroids, HDV has a circular RNA genome which adopts a rod-like secondary structure, possesses ribozyme domains, replicates in the nucleus of infected cells by redirecting host DNA-dependent RNA polymerases (RNAP), and relies heavily on host proteins for its replication due to its small size and limited protein coding capacity. These similarities suggest an evolutionary relationship between HDV and viroids, and information on HDV could allow a better understanding of viroids and might globally help understanding the pathogenesis and molecular biology of these subviral RNAs. In this review, we discuss the host involvement in HDV replication and its implication for HDV pathogenesis.
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Affiliation(s)
- Gabrielle Goodrum
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
| | - Martin Pelchat
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada.
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31
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Golemis EA, Scheet P, Beck TN, Scolnick EM, Hunter DJ, Hawk E, Hopkins N. Molecular mechanisms of the preventable causes of cancer in the United States. Genes Dev 2018; 32:868-902. [PMID: 29945886 PMCID: PMC6075032 DOI: 10.1101/gad.314849.118] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Annually, there are 1.6 million new cases of cancer and nearly 600,000 cancer deaths in the United States alone. The public health burden associated with these numbers has motivated enormous research efforts into understanding the root causes of cancer. These efforts have led to the recognition that between 40% and 45% of cancers are associated with preventable risk factors and, importantly, have identified specific molecular mechanisms by which these exposures modify human physiology to induce or promote cancer. The increasingly refined knowledge of these mechanisms, which we summarize here, emphasizes the need for greater efforts toward primary cancer prevention through mitigation of modifiable risk factors. It also suggests exploitable avenues for improved secondary prevention (which includes the development of therapeutics designed for cancer interception and enhanced techniques for noninvasive screening and early detection) based on detailed knowledge of early neoplastic pathobiology. Such efforts would complement the current emphasis on the development of therapeutic approaches to treat established cancers and are likely to result in far greater gains in reducing morbidity and mortality.
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Affiliation(s)
- Erica A Golemis
- Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
| | - Paul Scheet
- Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA
| | - Tim N Beck
- Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Molecular and Cell Biology and Genetics Program, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA
| | - Eward M Scolnick
- Eli and Edythe L. Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA
| | - David J Hunter
- Nuffield Department of Population Health, University of Oxford, Medical Sciences Division, Oxford OX3 7LF, United Kingdom
| | - Ernest Hawk
- Division of Cancer Prevention and Population Sciences, University of Texas M.D. Anderson Cancer Center, Houston Texas 77030, USA
| | - Nancy Hopkins
- Koch Institute for Integrative Cancer Research, Biology Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
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32
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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: 186] [Impact Index Per Article: 20.7] [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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33
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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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34
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Abbas Z, Abbas M. Management of hepatitis delta: Need for novel therapeutic options. World J Gastroenterol 2015; 21:9461-9465. [PMID: 26327754 PMCID: PMC4548107 DOI: 10.3748/wjg.v21.i32.9461] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2014] [Accepted: 06/10/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis D virus (HDV) is the smallest single stranded RNA virus infecting humans. The hepatitis B surface antigen envelope protein protects the HDV nucleocapsid antigen and provides a means for the virus to enter and exit the hepatocyte. Hepatitis B and D viruses exploit the human sodium taurocholate co-transporting polypeptide (NTCP), a receptor, for their entry into hepatocytes. Prenylation of the large delta antigen is a critical determinant of HDV particle assembly. Treatment with pegylated interferon results in sustained virological response six months post-treatment in one fourth of the patients. Nucleos(t)ide analogs (NAs) have been widely tested in hepatitis delta, but they appear to be ineffective. Combination treatment of NAs with interferon also proved to be disappointing so there is a need for novel therapeutic options. The receptor function of NTCP is blocked by Myrcludex B, a synthetic N-acylated preS1 lipopeptide that competes with infectious virions for receptor binding. There are already some approved drugs available, including irbesartan, ezetimibe, and ritonavir and cyclosporin A, with documented inhibitory effects on NTCP’s metabolic function. These drugs may have a role in HDV treatment. Interference with host-mediated post-translational changes of proteins that are crucial to the HDV life cycle, such as prenylation may become an important tool to control HDV infection and prevent replication. Lonafarnib, a prenylation inhibitor significantly reduces virus levels in hepatitis delta patients. Antisense oligodeoxynucleotides which are complementary to genomic HDV ribozyme self-cleavage site and stem I regions can inhibit genomic HDV ribozyme activity.
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Abbas Z, Abbas M, Abbas S, Shazi L. Hepatitis D and hepatocellular carcinoma. World J Hepatol 2015; 7:777-786. [PMID: 25914778 PMCID: PMC4404383 DOI: 10.4254/wjh.v7.i5.777] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Revised: 10/05/2014] [Accepted: 01/19/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis D virus (HDV) is a defective circular shape single stranded HDV RNA virus with two types of viral proteins, small and large hepatitis D antigens, surrounded by hepatitis B surface antigen. Superinfection with HDV in chronic hepatitis B is associated with a more threatening form of liver disease leading to rapid progression to cirrhosis. In spite of some controversy in the epidemiological studies, HDV infection does increase the risk of hepatocellular carcinoma (HCC) compared to hepatitis B virus (HBV) monoinfection. Hepatic decompensation, rather than development of HCC, is the first usual clinical endpoint during the course of HDV infection. Oxidative stress as a result of severe necroinflammation may progress to HCC. The large hepatitis D antigen is a regulator of various cellular functions and an activator of signal transducer and activator of transcription (STAT)3 and the nuclear factor kappa B pathway. Another proposed epigenetic mechanism by which HCC may form is the aberrant silencing of tumor suppressor genes by DNA Methyltransferases. HDV antigens have also been associated with increased histone H3 acetylation of the clusterin promoter. This enhances the expression of clusterin in infected cells, increasing cell survival potential. Any contribution of HBV DNA integration with chromosomes of infected hepatocytes is not clear at this stage. The targeted inhibition of STAT3 and cyclophilin, and augmentation of peroxisome proliferator-activated receptor γ have a potential therapeutic role in HCC.
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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: 11] [Impact Index Per Article: 1.1] [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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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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Abstract
BACKGROUND There are limited data on hepatitis D in children. The aim of this study was to assess the clinical presentation of hepatitis D virus (HDV) infection in Pakistani children. MATERIALS AND METHODS All pediatric patients (age≤18 years) seen in the clinic with chronic HDV infection and detectable HDV RNA (n=48) were compared with consecutive hepatitis B virus (HBV) monoinfection patients (n=48). A total of 50 patients underwent liver biopsy: 28 in the HDV group and 22 in the HBV group. RESULTS There was a male preponderance (85.4%). Significant differences were noted in age (P=0.012), presence of cirrhosis (P=0.004), splenomegaly (P<0.001), esophageal varices (P=0.006), splenic varices (P=0.022), alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transferase levels (P<0.001 each), platelet count (P=0.015), international normalized ratio (P<0.001), severity of inflammation on liver biopsy (P=0.007), and advanced fibrosis (P=0.016) in the two groups, indicating more severe disease in the HDV group. In the HDV group, six patients had normal ALT, of whom three were positive for hepatitis B e antigen (HBeAg) and HBV DNA. HBV DNA was detectable in 50% and HBeAg in 52% of the HDV patients. There were no differences in the severity of liver disease in HBeAg-reactive and HBeAg-nonreactive patients. Six patients with hepatitis D had decompensation at the time of presentation; five were HBV DNA positive and three had reactive HBeAg. Only one patient with HBV monoinfection had decompensation. CONCLUSION Children with HDV infection have more aggressive liver disease than HBV monoinfection irrespective of HBeAg status.
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Elpek G&O. Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: An update. World J Gastroenterol 2014; 20:7260-7276. [PMID: 24966597 PMCID: PMC4064072 DOI: 10.3748/wjg.v20.i23.7260] [Citation(s) in RCA: 264] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 02/08/2014] [Accepted: 05/26/2014] [Indexed: 02/06/2023] Open
Abstract
There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis. Recent data indicate that the termination of fibrogenic processes and the restoration of deficient fibrolytic pathways may allow the reversal of advanced fibrosis and even cirrhosis. Therefore, efforts have been made to better clarify the cellular and molecular mechanisms that are involved in liver fibrosis. Activation of hepatic stellate cells (HSCs) remains a central event in fibrosis, complemented by other sources of matrix-producing cells, including portal fibroblasts, fibrocytes and bone marrow-derived myofibroblasts. These cells converge in a complex interaction with neighboring cells to provoke scarring in response to persistent injury. Defining the interaction of different cell types, revealing the effects of cytokines on these cells and characterizing the regulatory mechanisms that control gene expression in activated HSCs will enable the discovery of new therapeutic targets. Moreover, the characterization of different pathways associated with different etiologies aid in the development of disease-specific therapies. This article outlines recent advances regarding the cellular and molecular mechanisms involved in liver fibrosis that may be translated into future therapies. The pathogenesis of liver fibrosis associated with alcoholic liver disease, non-alcoholic fatty liver disease and viral hepatitis are also discussed to emphasize the various mechanisms involved in liver fibrosis.
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Panebianco C, Saracino C, Pazienza V. Epithelial-mesenchymal transition: molecular pathways of hepatitis viruses-induced hepatocellular carcinoma progression. Tumour Biol 2014; 35:7307-15. [PMID: 24833096 DOI: 10.1007/s13277-014-2075-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 05/07/2014] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma is the fifth most common tumor and the third cause of death for cancer in the world. Among the main causative agents of this tumor is the chronic infection by hepatitis viruses B and C, which establish a context of chronic inflammation degenerating in fibrosis, cirrhosis, and, finally, cancer. Recent findings, however, indicate that hepatitis viruses are not only responsible for cancer onset but also for its progression towards metastasis. Indeed, they are able to promote epithelial-mesenchymal transition, a process of cellular reprogramming underlying tumor spread. In this manuscript, we review the currently known molecular mechanisms by which hepatitis viruses induce epithelial-mesenchymal transition and, thus, hepatocellular carcinoma progression.
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Affiliation(s)
- Concetta Panebianco
- Gastroenterology Unit, Fondazione "Casa Sollievo della Sofferenza" IRCCS Hospital, San Giovanni Rotondo, FG, Italy
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Kim MS, Kim S, Myung H. Degradation of AIMP1/p43 induced by hepatitis C virus E2 leads to upregulation of TGF-β signaling and increase in surface expression of gp96. PLoS One 2014; 9:e96302. [PMID: 24816397 PMCID: PMC4015952 DOI: 10.1371/journal.pone.0096302] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Accepted: 04/05/2014] [Indexed: 12/25/2022] Open
Abstract
Hepatitis C virus (HCV) causes chronic hepatitis leading to liver fibrosis and autoimmune diseases. AIMP1/p43 is a multifunctional protein initially known as a cofactor of aminoacyl tRNA synthetase complex. Its function includes negative regulation of TGF-β signaling and suppression of Lupus-like autoimmune disease by inhibition of surface expression of gp96. HCV E2 was shown to directly interact with AIMP1/p43 by GST pulldown assay and coimmunoprecipitation. Their subcellular colocalization was observed in an immunofluorescence confocal microscopy. We showed that HCV E2 led to degradation of AIMP1/p43 in two ways. First, in the presence of HCV E2, endogenous AIMP1/p43 was shown to be degraded in an ubiquitin-dependent proteasome pathway. Second, grp78, an ER chaperone, was shown to interact with and stabilize AIMP1/p43. And HCV E2 inhibited this interaction leading to reduction of cellular AIMP1/p43. The degradation of AIMP1/p43 by HCV E2 resulted in increase of TGF-β signaling and cell surface expression of gp96. Thus we suggest that these are novel mechanisms responsible for liver fibrosis and autoimmune diseases caused by HCV.
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Affiliation(s)
- Min Soo Kim
- Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Yong-In, Gyung-Gi Do, Korea
| | - Sunghoon Kim
- Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Heejoon Myung
- Department of Bioscience and Biotechnology, Hankuk University of Foreign Studies, Yong-In, Gyung-Gi Do, Korea
- * E-mail:
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Abbas Z, Afzal R. Life cycle and pathogenesis of hepatitis D virus: A review. World J Hepatol 2013; 5:666-675. [PMID: 24409335 PMCID: PMC3879688 DOI: 10.4254/wjh.v5.i12.666] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2013] [Revised: 11/06/2013] [Accepted: 11/16/2013] [Indexed: 02/06/2023] Open
Abstract
Hepatitis D virus (HDV) is a defective RNA virus which requires the help of hepatitis B virus (HBV) virus for its replication and assembly of new virions. HDV genome contains only one actively transcribed open reading frame which encodes for two isoforms of hepatitis delta antigen. Post-translational modifications of small and large delta antigens (S-HDAg and L-HDAg) involving phosphorylation and isoprenylation respectively confer these antigens their specific properties. S-HDAg is required for the initiation of the viral genome replication, whereas L-HDAg serves as a principal inhibitor of replication and is essential for the assembly of new virion particles. Immune mediation has usually been implicated in HDV-associated liver damage. The pathogenesis of HDV mainly involves interferon-α signaling inhibition, HDV-specific T-lymphocyte activation and cytokine responses, and tumor necrosis factor-alpha and nuclear factor kappa B signaling. Due to limited protein coding capacity, HDV makes use of host cellular proteins to accomplish their life cycle processes, including transcription, replication, post-transcriptional and translational modifications. This intimate host-pathogen interaction significantly alters cell proteome and is associated with an augmented expression of pro-inflammatory, growth and anti-apoptotic factors which explains severe necroinflammation and increased cell survival and an early progression to hepatocellular carcinoma in HDV patients. The understanding of the process of viral replication, HBV-HDV interactions, and etio-pathogenesis of the severe course of HDV infection is helpful in identifying the potential therapeutic targets in the virus life cycle for the prophylaxis and treatment of HDV infection and complications.
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Impact of hepatitis B and delta virus co-infection on liver disease in Mauritania: a cross sectional study. J Infect 2013; 67:448-57. [PMID: 23796871 DOI: 10.1016/j.jinf.2013.06.008] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Revised: 05/22/2013] [Accepted: 06/05/2013] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Mauritania is a highly endemic region for hepatitis B (HBV) and delta (HDV) viruses. No data are available on HDV's impact on the severity of liver disease in consecutive HBV-infected patients in Africa. This study evaluated the degree of liver fibrosis in a cohort of chronic HBV carriers. METHODS Three-hundred consecutive HBV-infected Mauritanian patients were checked for HDV infection via the detection of anti-HDV antibodies (Ab) and viral RNA. HBV- vs. HBV/HDV-infected patients were compared by physical examination, biological analyses, and the APRI (aspartate aminotransferase to platelet ratio index) and FibroMeter tests for determination of liver fibrosis. RESULTS More than 30% of the patients had anti-HDVAb. Among these, 62.2% were HDV-RNA positive. Co-infected patients were older (>8-years) than HBV-mono-infected patients. They had more liver tests abnormalities and clinical or ultrasound signs of liver fibrosis. APRI and FibroMeter scores were also significantly increased in these patients. In multivariate analysis, beyond HDVAb, male gender and HBV-VL >3.7 log IU/mL were the only markers linked to significant liver fibrosis. CONCLUSIONS In Mauritania, HDV co-infection worsens liver disease, both clinically and biologically, as confirmed by the APRI and FibroMeter tests. These tests may be useful for the management of delta hepatitis, which is a major health problem in Mauritania.
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Williams V, Brichler S, Khan E, Chami M, Dény P, Kremsdorf D, Gordien E. Large hepatitis delta antigen activates STAT-3 and NF-κB via oxidative stress. J Viral Hepat 2012; 19:744-53. [PMID: 22967106 DOI: 10.1111/j.1365-2893.2012.01597.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis delta virus (HDV) coinfection or superinfection in hepatitis B virus (HBV)-infected patients results in a more aggressive liver disease, with more often fulminant forms and more rapid progression to cirrhosis and hepatocellular carcinoma. The mechanism(s) for this pejorative evolution remains unclear. To explore a specific HDV pathogenesis, we used a model of transient transfection of plasmids expressing the small (sHDAg or p24) or the large (LHDAg or p27) delta antigen in hepatocyte cell lines. We found that the production of reactive oxygen species was significantly higher in cells expressing p27. Consequently, p27 activated the signal transducer and activator of transcription-3 (STAT-3) and the nuclear factor kappa B (NF-κB) via the oxidative stress pathway. Moreover in the presence of antioxidants (PDTC, NAC) or calcium inhibitors (TMB-8, BAPTA-AM, Ruthenium Red), p27-induced activation of STAT-3 and NF-κB was dramatically reduced. Similarly, using a mutated form of p27, where the cysteine 211-isoprenylation residue was replaced by a serine, a significant reduction of STAT-3 and NF-κB activation was seen, suggesting the involvement of isoprenylation in this process. Additionally, we show that p27 is able to induce oxidative stress through activation of NADPH oxidase-4. These results provide insight into the mechanisms by which p27 can alter intracellular events relevant to HDV-related liver pathogenesis.
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Affiliation(s)
- V Williams
- Service de bactériologie, virologie - hygiène, hôpital Avicenne, Assistance Publique des Hôpitaux de Paris, Laboratoire associé au Centre National de Référence des Hépatites B, C et Delta, Université Paris Nord, Paris
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45
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Hepatitis D virus isolates with low replication and epithelial-mesenchymal transition-inducing activity are associated with disease remission. J Virol 2012; 86:9044-54. [PMID: 22674995 DOI: 10.1128/jvi.00130-12] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Clearance of hepatitis D virus (HDV) viremia leads to disease remission. Large hepatitis delta antigen (L-HDAg) has been reported to activate transforming growth factor β, which may induce epithelial-mesenchymal transition (EMT) and fibrogenesis. This study analyzed serum HDV RNA "quasispecies" in HDV-infected patients at two stages of infection: before and after alanine aminotransferase (ALT) elevations. Included in the study were four patients who went into remission after ALT elevation and three patients who did not go into remission and progressed to cirrhosis or hepatocellular carcinoma. Full-length HDV cDNA clones were obtained from the most abundant HDV RNA species at the pre- and post-ALT elevation stages. Using an in vitro model consisting of Huh-7 cells transfected with cloned HDV cDNAs, the pre- or post-ALT elevation dominant HDV RNA species were characterized for (i) their replication capacity by measuring HDV RNA and HDAg levels in transfected cells and (ii) their capacity to induce EMT by measuring the levels of the mesenchymal-cell-specific protein vimentin, the EMT regulators twist and snail, and the epithelial-cell-specific protein E-cadherin. Results show that in patients in remission, the post-ALT elevation dominant HDV RNA species had a lower replication capacity in vitro and lower EMT activity than their pre-ALT elevation counterparts. This was not true of patients who did not go into remission. The expression of L-HDAg, but not small HDAg, increased the expression of the EMT-related proteins. It is concluded that in chronically infected patients, HDV quasispecies with a low replication capacity and low EMT activity are associated with disease remission.
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Lim YS, Tran HTL, Park SJ, Yim SA, Hwang SB. Peptidyl-prolyl isomerase Pin1 is a cellular factor required for hepatitis C virus propagation. J Virol 2011; 85:8777-88. [PMID: 21680504 PMCID: PMC3165832 DOI: 10.1128/jvi.02533-10] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2010] [Accepted: 05/27/2011] [Indexed: 12/17/2022] Open
Abstract
The life cycle of hepatitis C virus (HCV) is highly dependent on cellular factors. Using small interfering RNA (siRNA) library screening, we identified peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) as a host factor involved in HCV propagation. Here we demonstrated that silencing of Pin1 expression resulted in decreases in HCV replication in both HCV replicon cells and cell culture-grown HCV (HCVcc)-infected cells, whereas overexpression of Pin1 increased HCV replication. Pin1 interacted with both the NS5A and NS5B proteins. However, Pin1 expression was increased only by the NS5B protein. Both the protein binding and isomerase activities of Pin1 were required for HCV replication. Juglone, a natural inhibitor of Pin1, inhibited HCV propagation by inhibiting the interplay between the Pin1 and HCV NS5A/NS5B proteins. These data indicate that Pin1 modulates HCV propagation and may contribute to HCV-induced liver pathogenesis.
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Affiliation(s)
- Yun-Sook Lim
- National Research Laboratory of Hepatitis C Virus, Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-dong, Dongan-gu, Anyang 431-060, South Korea
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Giannelli G, Mazzocca A, Fransvea E, Lahn M, Antonaci S. Inhibiting TGF-β signaling in hepatocellular carcinoma. Biochim Biophys Acta Rev Cancer 2011; 1815:214-23. [PMID: 21129443 DOI: 10.1016/j.bbcan.2010.11.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2010] [Revised: 11/18/2010] [Accepted: 11/20/2010] [Indexed: 12/17/2022]
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McMurray RJ, Gadegaard N, Dalby MJ, Tsimbouri MP, Maclaine S, Meek D, McNamara LE, Child H, Berry C. Research Highlights. Nanomedicine (Lond) 2010. [DOI: 10.2217/nnm.10.119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Rebecca J McMurray
- Centre for Cell Engineering, Institute of Molecular, Cell & Systems Biology, College of Medical, Veterinary & Life Sciences, Joseph Black Building, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Nikolaj Gadegaard
- Centre for Cell Engineering, Institute of Molecular, Cell & Systems Biology, College of Medical, Veterinary & Life Sciences, Joseph Black Building, University of Glasgow, Glasgow, G12 8QQ, UK
| | | | - Monica P Tsimbouri
- Centre for Cell Engineering, Institute of Molecular, Cell & Systems Biology, College of Medical, Veterinary & Life Sciences, Joseph Black Building, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Sarah Maclaine
- Centre for Cell Engineering, Institute of Molecular, Cell & Systems Biology, College of Medical, Veterinary & Life Sciences, Joseph Black Building, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Dominic Meek
- Department of Orthopaedic Surgery, Southern General Hospital, Glasgow, UK
| | - Laura E McNamara
- Centre for Cell Engineering, Institute of Molecular, Cell & Systems Biology, College of Medical, Veterinary & Life Sciences, Joseph Black Building, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Hannah Child
- Centre for Cell Engineering, Institute of Molecular, Cell & Systems Biology, College of Medical, Veterinary & Life Sciences, Joseph Black Building, University of Glasgow, Glasgow, G12 8QQ, UK
| | - Catherine Berry
- Centre for Cell Engineering, Institute of Molecular, Cell & Systems Biology, College of Medical, Veterinary & Life Sciences, Joseph Black Building, University of Glasgow, Glasgow, G12 8QQ, UK
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Thoelking G, Reiss B, Wegener J, Oberleithner H, Pavenstaedt H, Riethmuller C. Nanotopography follows force in TGF-beta1 stimulated epithelium. NANOTECHNOLOGY 2010; 21:265102. [PMID: 20522928 DOI: 10.1088/0957-4484/21/26/265102] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2023]
Abstract
Inflammation and cellular fibrosis often imply an involvement of the cytokine TGF-beta1. TGF-beta1 induces epithelial-to-mesenchymal transdifferentiation (EMT), a term describing the loss of epithelium-specific function. Indicative for this process are an elongated cell shape parallel to stress fibre formation. Many signalling pathways of TGF-beta1 have been discovered, but mechanical aspects have not yet been investigated. In this study, atomic force microscopy (AFM) was used to analyse surface topography and mechanical properties of EMT in proximal kidney tubule epithelium (NRK52E). Elongated cells, an increase of stress fibre formation and a loss of microvillus compatible structures were observed as characteristic signs of EMT. Furthermore, AFM could identify an increase in stiffness by 71% after six days of stimulation with TGF-beta1. As a novel topographical phenomenon, nodular protrusions emerged at the cell-cell junctions. They occurred preferentially at sites where stress fibres cross the border. Since these nodular protrusions were sensitive to inhibitors of force generation, they can indicate intracellular tension. The results demonstrate a manifest impact of elevated tension on the cellular topography.
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