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1
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Gadji M, Ba A, Gueye YB, Senghor AB, Dieye TN, Diop S. Improvement of blood transfusion safety using the chemiluminescence technique for viral marker screening of blood donors in sub Saharan Africa. Hematol Transfus Cell Ther 2024:S2531-1379(24)00292-X. [PMID: 39317575 DOI: 10.1016/j.htct.2024.04.120] [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: 07/19/2023] [Revised: 12/31/2023] [Accepted: 04/20/2024] [Indexed: 09/26/2024] Open
Abstract
INTRODUCTION Sub-Saharan Africa struggles continuously with insufficient resources and inadequate infrastructure that hinder the establishment of a safer blood supply despite improvements in transfusion safety over recent decades. This study aimed to evaluate the impact of the chemiluminescence technique in combination with immunoenzymatic and immunochromatographic tests for viral marker screening of hepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency virus (HIV) in donated blood in a country of sub-Saharan Africa. METHOD This study was conducted in a population of 113,406 blood donors at the National Centre of Blood Transfusion in Senegal. The data were obtained from the 'INLOG' software and donor registers. Statistical analyses used Excel 2010 and Epi Info v6. Screening for HBsAg viral markers, anti-HCV Ab, HIV p24 Ag, anti-HIV1 and anti-HIV2 antibodies were first carried out using the chemiluminescence technique. Blood donations screened positive for HBV or HCV were retested in a second chemiluminescence equipment. HIV-positive donations and their controls were subjected to solid phase immunochromatographic and indirect enzyme immunoassay techniques. RESULTS The prevalence among donors of HBV was 8.39 %, 0.56 % for HCV and 0.18 % for HIV. Of the donors tested positive for HIV in screenings and in doubled-controls, only 61.54 % were confirmed by the alternative tests; 34.02 % were negative and 4.44 % discordant between the three techniques. CONCLUSION This study shows the importance of introducing the chemiluminescence technique in association with serological screening of transfusion-transmitted viruses to improve blood supply safety in low-income countries.
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Affiliation(s)
- Macoura Gadji
- Service of Biological Haematology & Oncology-Haematology (BHOH), Department of Biology and Applied Pharmaceutical Sciences, Faculty of Medicine, Pharmacy and Odonto-Stomatology (FMPOS), University Cheikh Anta Diop of Dakar (UCAD), Dakar, Senegal; National Centre of Blood Transfusion (NCBT/CNTS), Dakar, Senegal.
| | - Aissata Ba
- Service of Biological Haematology & Oncology-Haematology (BHOH), Department of Biology and Applied Pharmaceutical Sciences, Faculty of Medicine, Pharmacy and Odonto-Stomatology (FMPOS), University Cheikh Anta Diop of Dakar (UCAD), Dakar, Senegal; National Centre of Blood Transfusion (NCBT/CNTS), Dakar, Senegal
| | | | | | - Tandakha Ndiaye Dieye
- National Centre of Blood Transfusion (NCBT/CNTS), Dakar, Senegal; Service of Immunology; Department of Biology and Applied Pharmaceutical Sciences; Faculty of Medicine, Pharmacy and Odonto-Stomatology (FMPOS), University Cheikh Anta Diop of Dakar (UCAD), Dakar, Senegal
| | - Saliou Diop
- National Centre of Blood Transfusion (NCBT/CNTS), Dakar, Senegal; Service of Haematology; Department of Medicine; Faculty of Medicine, Pharmacy and Odonto-Stomatology (FMPOS), University Cheikh Anta Diop of Dakar (UCAD), Dakar, Senegal
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2
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Hofmann S, Luther J, Plank V, Oswald A, Mai J, Simons I, Miller J, Falcone V, Hansen-Palmus L, Hengel H, Nassal M, Protzer U, Schreiner S. Arsenic trioxide impacts hepatitis B virus core nuclear localization and efficiently interferes with HBV infection. Microbiol Spectr 2024; 12:e0378823. [PMID: 38567974 PMCID: PMC11064512 DOI: 10.1128/spectrum.03788-23] [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: 10/30/2023] [Accepted: 03/14/2024] [Indexed: 05/03/2024] Open
Abstract
The key to a curative treatment of hepatitis B virus (HBV) infection is the eradication of the intranuclear episomal covalently closed circular DNA (cccDNA), the stable persistence reservoir of HBV. Currently, established therapies can only limit HBV replication but fail to tackle the cccDNA. Thus, novel therapeutic approaches toward curative treatment are urgently needed. Recent publications indicated a strong association between the HBV core protein SUMOylation and the association with promyelocytic leukemia nuclear bodies (PML-NBs) on relaxed circular DNA to cccDNA conversion. We propose that interference with the cellular SUMOylation system and PML-NB integrity using arsenic trioxide provides a useful tool in the treatment of HBV infection. Our study showed a significant reduction in HBV-infected cells, core protein levels, HBV mRNA, and total DNA. Additionally, a reduction, albeit to a limited extent, of HBV cccDNA could be observed. Furthermore, this interference was also applied for the treatment of an established HBV infection, characterized by a stably present nuclear pool of cccDNA. Arsenic trioxide (ATO) treatment not only changed the amount of expressed HBV core protein but also induced a distinct relocalization to an extranuclear phenotype during infection. Moreover, ATO treatment resulted in the redistribution of transfected HBV core protein away from PML-NBs, a phenotype similar to that previously observed with SUMOylation-deficient HBV core. Taken together, these findings revealed the inhibition of HBV replication by ATO treatment during several steps of the viral replication cycle, including viral entry into the nucleus as well as cccDNA formation and maintenance. We propose ATO as a novel prospective treatment option for further pre-clinical and clinical studies against HBV infection. IMPORTANCE The main challenge for the achievement of a functional cure for hepatitis B virus (HBV) is the covalently closed circular DNA (cccDNA), the highly stable persistence reservoir of HBV, which is maintained by further rounds of infection with newly generated progeny viruses or by intracellular recycling of mature nucleocapsids. Eradication of the cccDNA is considered to be the holy grail for HBV curative treatment; however, current therapeutic approaches fail to directly tackle this HBV persistence reservoir. The molecular effect of arsenic trioxide (ATO) on HBV infection, protein expression, and cccDNA formation and maintenance, however, has not been characterized and understood until now. In this study, we reveal ATO treatment as a novel and innovative therapeutic approach against HBV infections, repressing viral gene expression and replication as well as the stable cccDNA pool at low micromolar concentrations by affecting the cellular function of promyelocytic leukemia nuclear bodies.
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Affiliation(s)
- Samuel Hofmann
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (Resolving Infection Susceptibility, EXC 2155), Hannover Medical School, Hannover, Germany
- Division of Pediatric Neurology and Metabolic Medicine, Center for Pediatric and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany
| | - Julius Luther
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (Resolving Infection Susceptibility, EXC 2155), Hannover Medical School, Hannover, Germany
| | - Verena Plank
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Andreas Oswald
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Julia Mai
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (Resolving Infection Susceptibility, EXC 2155), Hannover Medical School, Hannover, Germany
- Department of Internal Medicine II/Molecular Biology, University Hospital Freiburg, Freiburg, Germany
| | - Ilka Simons
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (Resolving Infection Susceptibility, EXC 2155), Hannover Medical School, Hannover, Germany
| | - Julija Miller
- Department of Internal Medicine II/Molecular Biology, University Hospital Freiburg, Freiburg, Germany
| | - Valeria Falcone
- Institute of Virology, Medical Center – University of Freiburg, Freiburg, Germany
| | - Lea Hansen-Palmus
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Hartmut Hengel
- Institute of Virology, Medical Center – University of Freiburg, Freiburg, Germany
| | - Michael Nassal
- Department of Internal Medicine II/Molecular Biology, University Hospital Freiburg, Freiburg, Germany
| | - Ulrike Protzer
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
- Institute of Virology, Helmholtz Zentrum München, Munich, Germany
- German Center for Infection Research (DZIF), Munich, Germany
| | - Sabrina Schreiner
- Institute of Virology, School of Medicine, Technical University of Munich, Munich, Germany
- Institute of Virology, Hannover Medical School, Hannover, Germany
- Cluster of Excellence RESIST (Resolving Infection Susceptibility, EXC 2155), Hannover Medical School, Hannover, Germany
- Institute of Virology, Medical Center – University of Freiburg, Freiburg, Germany
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3
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Lawrence P, Chabane M, Abrouk L, Thiesson A, Berthé D, Diarra AB, Bengaly K, Traoré B, Kassogué D, Durand G, Voegele C, Le Calvez-Kelm F, Steenkeste N, Hainaut P, Kouriba B, Gormally E. First Molecular Characterization of Chronic Hepatitis B Carriers in Timbuktu, Mali. Diagnostics (Basel) 2023; 13:375. [PMID: 36766478 PMCID: PMC9913942 DOI: 10.3390/diagnostics13030375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/13/2023] [Accepted: 01/17/2023] [Indexed: 01/21/2023] Open
Abstract
In Mali, hepatocellular carcinoma (HCC) is the third and sixth most common cancer in men and women, respectively. Mali comprises several distinct climato-ecological zones. Most studies to date have been conducted in the sub-Sahelian zone of southern Mali, including the capital city Bamako. In this part of the country, the main risk factors for HCC are chronic hepatitis B virus (HBV) carriage and dietary exposure to aflatoxins, a well-known hepatocarcinogen. Data are scarce for other ecological zones, but our preliminary data from 721 blood donors in the area of Timbuktu, presented in this study, suggest that chronic HBV carriage is also endemic in the northern Saharan zone of Mali. For further study, 29 healthy HBV chronic carrier volunteers were recruited from the blood transfusion center in Timbuktu. Successful viral genotyping in 20 volunteers revealed HBV genotype E in 13 cases and D in 7 cases, suggesting that this geographical and anthropological transition zone may also represent a transition zone between HBV genotypes that dominate sub-Saharan and northern Africa, respectively. Sequencing of circulating cell-free plasma DNA (cfDNA) from donors did not reveal the presence of the TP53 R249S mutation in these donors, a marker of dietary exposure to aflatoxins in sub-Saharan Africa. These results suggest that the geo-epidemiological distribution of the risk factors for HCC is not uniform across Mali, but is dependent upon climatic, socioeconomic and anthropological factors that might have an impact on patterns of chronic liver disease and cancer.
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Affiliation(s)
- Philip Lawrence
- CONFLUENCE: Sciences et Humanités Confluence (EA 1598), Université Catholique de Lyon (UCLy), 69002 Lyon, France
| | | | - Lucie Abrouk
- CONFLUENCE: Sciences et Humanités Confluence (EA 1598), Université Catholique de Lyon (UCLy), 69002 Lyon, France
| | - Adrien Thiesson
- CONFLUENCE: Sciences et Humanités Confluence (EA 1598), Université Catholique de Lyon (UCLy), 69002 Lyon, France
| | | | - Amadou B. Diarra
- Centre National de Transfusion Sanguine (CNTS, National Blood Bank), Bamako BPE1520, Mali
| | - Karim Bengaly
- Centre d’Infectiologie Charles Mérieux, Bamako BPE2283, Mali
| | - Brehima Traoré
- Centre d’Infectiologie Charles Mérieux, Bamako BPE2283, Mali
| | | | - Geoffroy Durand
- International Agency for Research on Cancer, 69008 Lyon, France
| | | | | | | | - Pierre Hainaut
- Institute of Advanced Biosciences, INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, 38700 La Tronche, France
| | - Bourema Kouriba
- Centre d’Infectiologie Charles Mérieux, Bamako BPE2283, Mali
| | - Emmanuelle Gormally
- CONFLUENCE: Sciences et Humanités Confluence (EA 1598), Université Catholique de Lyon (UCLy), 69002 Lyon, France
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Hudu SA, Jimoh AO, Ibrahim KG, Alshrari AS. Hepatitis B Therapeutic Vaccine: A Patent Review. Pharmaceuticals (Basel) 2022; 15:1542. [PMID: 36558991 PMCID: PMC9783911 DOI: 10.3390/ph15121542] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/04/2022] [Accepted: 12/05/2022] [Indexed: 12/15/2022] Open
Abstract
Viral hepatitis has long been underrated as a danger to global health. The UN only recently called for worldwide action to tackle viral hepatitis and lessen the disease burden in its "2030 Agenda for Sustainable Development". Hepatitis B virus (HBV), which causes liver cirrhosis and malignancy, is a main cause of death globally. This review analyses innovative HBV therapeutic vaccine candidates for which a patent was filed between January 2010 and March 2022 and presents future improvement techniques for vaccine efficacy. Although there is a preventative vaccine for HBV infection, over 3% of people worldwide have the disease on a long-term basis and can no longer benefit from it. Most people will have chronic HBV infection for the rest of their lives once it has been diagnosed. Moreover, only a small percentage of treated patients experience a functional cure with persistent hepatitis B surface antigen reduction. A significant proportion of deaths are caused by liver cirrhosis and hepatocellular cancer, which are both caused by chronic hepatitis B infection. Hence, there is an urgent need for novel medications due to the inadequacies of the current therapies.
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Affiliation(s)
- Shuaibu Abdullahi Hudu
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan
| | - Abdulgafar Olayiwola Jimoh
- Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto 840001, Nigeria
| | - Kasimu Ghandi Ibrahim
- Department of Basic Medical and Dental Sciences, Faculty of Dentistry, Zarqa University, Zarqa 13110, Jordan
| | - Ahmed Subeh Alshrari
- Department of Basic Health Sciences, Faculty of Pharmacy, Northern Border University, Rafha 91911, Saudi Arabia
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5
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Hamida ME, Raja SM, Petros Y, Wahab M, Elkhidir IM, Achila OO, Tekle F, Berhane IY. Genotyping and sero-virological characterization of hepatitis B virus-infected blood donors in Central Eritrea. Future Virol 2022. [DOI: 10.2217/fvl-2021-0069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Aim: To determine the serological markers and genotype profiles of hepatitis B virus (HBV) isolates in Central Eritrea. Materials & methods: A total of 191 hepatitis B surface antigen (HBsAg)-positive sera were randomly selected for the study. ELISA was used to perform HBV seromarker screening, genotypes were determined using multiplex-nested PCR. Results: Of 191, 77.5% (148/191) were positive for HBcAb (total), among which 99.3% (147/148) and 0.7% (1/148) were positive for HBsAg and hepatitis B surface antibody, respectively. Of the 147 positive HBcAb/HBsAg, 16 (10.9%) and 131 (77.9%) were positive for HBeAg and HBeAb, respectively. A total of 73 HBV isolates were successfully genotyped: 39 (53.4%) D; 10 (13.7%) E; 6 (8.2%) A; 6 (8.2%) C/D; 4 (5.5%) C; 3 (4.1%) C/D/E; 2 (2.7%) A/D; 2 (2.7%) D/E; and 1 (1.4%) B/D. Conclusion: HBV genotype D is the predominant genotype among blood donors in Eritrea.
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Affiliation(s)
| | - Saud Mohammed Raja
- Department of Internal Medicine, Orotta College of Medicine & Health Sciences, Asmara, Eritrea
| | - Yodahi Petros
- National Animal & Plant Health Laboratory, Unit of Molecular Biology, Asmara, Eritrea
| | - Munir Wahab
- National Animal & Plant Health Laboratory, Unit of Molecular Biology, Asmara, Eritrea
| | - Isam Mohammed Elkhidir
- Department of Microbiology, University of Khartoum, Faculty of Medicine, Khartoum, Sudan
| | - Oliver Okoth Achila
- Department of Clinical Laboratory Sciences, Asmara College of Health Science (ACHS), Asmara, Eritrea
| | - Freweini Tekle
- Ministry of Health, National Health Laboratory, Asmara, Eritrea
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6
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Gehring AJ, Mendez P, Richter K, Ertl H, Donaldson EF, Mishra P, Maini M, Boonstra A, Lauer G, de Creus A, Whitaker K, Martinez SF, Weber J, Gainor E, Miller V. Immunological biomarker discovery in cure regimens for chronic hepatitis B virus infection. J Hepatol 2022; 77:525-538. [PMID: 35259469 DOI: 10.1016/j.jhep.2022.02.020] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 01/26/2022] [Accepted: 02/16/2022] [Indexed: 12/16/2022]
Abstract
There have been unprecedented advances in the identification of new treatment targets for chronic hepatitis B that are being developed with the goal of achieving functional cure in patients who would otherwise require lifelong nucleoside analogue treatment. Many of the new investigational therapies either directly target the immune system or are anticipated to impact immunity indirectly through modulation of the viral lifecycle and antigen production. While new viral biomarkers (HBV RNA, HBcAg, small, middle, large HBs isoforms) are proceeding through validation steps in clinical studies, immunological biomarkers are non-existent outside of clinical assays for antibodies to HBs, HBc and HBe. To develop clinically applicable immunological biomarkers to measure mechanisms of action, inform logical combination strategies, and guide clinical management for use and discontinuation of immune-targeting drugs, immune assays must be incorporated into phase I/II clinical trials. This paper will discuss the importance of sample collection, the assays available for immunological analyses, their advantages/disadvantages and suggestions for their implementation in clinical trials. Careful consideration must be given to ensure appropriate immunological studies are included as a primary component of the trial with deeper immunological analysis provided by ancillary studies. Standardising immunological assays and data obtained from clinical trials will identify biomarkers that can be deployed in the clinic, independently of specialised immunology laboratories.
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Affiliation(s)
- Adam J Gehring
- Toronto Centre for Liver Disease, Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada; Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
| | - Patricia Mendez
- Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA
| | - Kirsten Richter
- F. Hoffmann-La Roche, Roche Innovation Center Basel, Grenzacher Strasse 124, CH-4070 Basel, Switzerland
| | | | - Eric F Donaldson
- Division of Antivirals, Center for Drug Evaluation and Research, US Food and Drug Administration, USA
| | - Poonam Mishra
- Division of Antivirals, Center for Drug Evaluation and Research, US Food and Drug Administration, USA
| | - Mala Maini
- Division of Infection and Immunity, University College London, London, UK
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, The Netherlands
| | - Georg Lauer
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | | | - Kathleen Whitaker
- Division of Microbiology Devices Office of In Vitro Diagnostics and Radiological Health Center for Devices and Radiological Health, US Food and Drug Administration, USA
| | - Sara Ferrando Martinez
- Microbial Sciences, Biopharmaceuticals R&D, AstraZeneca, Gaithersburg, US; NeoImmuneTech, LLC 2400 Research Blvd, Suite 250 Rockville, MD 20850, USA
| | - Jessica Weber
- Forum for Collaborative Research, University of California, Berkeley, USA
| | - Emily Gainor
- Forum for Collaborative Research, University of California, Berkeley, USA
| | - Veronica Miller
- Forum for Collaborative Research, University of California, Berkeley, USA
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7
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Biswas S, Rust LN, Wettengel JM, Yusova S, Fischer M, Carson JN, Johnson J, Wei L, Thode T, Kaadige MR, Sharma S, Agbaria M, Bimber BN, Tu T, Protzer U, Ploss A, Smedley JV, Golomb G, Sacha JB, Burwitz BJ. Long-term hepatitis B virus infection of rhesus macaques requires suppression of host immunity. Nat Commun 2022; 13:2995. [PMID: 35637225 PMCID: PMC9151762 DOI: 10.1038/s41467-022-30593-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 05/05/2022] [Indexed: 01/16/2023] Open
Abstract
Hepatitis B virus has infected a third of the world's population, and 296 million people are living with chronic infection. Chronic infection leads to progressive liver disease, including hepatocellular carcinoma and liver failure, and there remains no reliable curative therapy. These gaps in our understanding are due, in large part, to a paucity of animal models of HBV infection. Here, we show that rhesus macaques regularly clear acute HBV infection, similar to adult humans, but can develop long-term infection if immunosuppressed. Similar to patients, we longitudinally detected HBV DNA, HBV surface antigen, and HBV e antigen in the serum of experimentally infected animals. In addition, we discovered hallmarks of HBV infection in the liver, including RNA transcription, HBV core and HBV surface antigen translation, and covalently closed circular DNA biogenesis. This pre-clinical animal model will serve to accelerate emerging HBV curative therapies into the clinic.
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Affiliation(s)
- Sreya Biswas
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, 97006, USA
| | - Lauren N Rust
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, 97006, USA
| | - Jochen M Wettengel
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, 97006, USA
- Institute of Virology, Technical University of Munich / Helmholtz Zentrum München, München, 81675, Germany
| | - Sofiya Yusova
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, 97006, USA
| | - Miranda Fischer
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA
| | - Julien N Carson
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, 97006, USA
| | - Josie Johnson
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA
| | - Lei Wei
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
| | - Trason Thode
- Translational Genomics Research Institute, Phoenix, AZ, 85004, USA
| | - Mohan R Kaadige
- Translational Genomics Research Institute, Phoenix, AZ, 85004, USA
| | - Sunil Sharma
- Translational Genomics Research Institute, Phoenix, AZ, 85004, USA
| | - Majd Agbaria
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 12272, Israel
| | - Benjamin N Bimber
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA
| | - Thomas Tu
- Storr Liver Centre, Westmead Clinical School and Westmead Institute for Medical Research, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, 2145, Australia
- Centre for Infectious Diseases and Microbiology, Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney at Westmead Hospital, Westmead, NSW, 2145, Australia
| | - Ulrike Protzer
- Institute of Virology, Technical University of Munich / Helmholtz Zentrum München, München, 81675, Germany
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, Princeton, NJ, 08544, USA
| | - Jeremy V Smedley
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA
| | - Gershon Golomb
- Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, 12272, Israel
| | - Jonah B Sacha
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, 97006, USA
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA
| | - Benjamin J Burwitz
- Vaccine & Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, 97006, USA.
- Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, 97006, USA.
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8
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Athamneh RY, Arıkan A, Sayan M, Mahafzah A, Sallam M. Variable Proportions of Phylogenetic Clustering and Low Levels of Antiviral Drug Resistance among the Major HBV Sub-Genotypes in the Middle East and North Africa. Pathogens 2021; 10:1333. [PMID: 34684283 PMCID: PMC8540944 DOI: 10.3390/pathogens10101333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/12/2021] [Accepted: 10/14/2021] [Indexed: 11/21/2022] Open
Abstract
Hepatitis B virus (HBV) infection remains a major public health threat in the Middle East and North Africa (MENA). Phylogenetic analysis of HBV can be helpful to study the putative transmission links and patterns of inter-country spread of the virus. The objectives of the current study were to analyze the HBV genotype/sub-genotype (SGT) distribution, reverse transcriptase (RT), and surface (S) gene mutations and to investigate the domestic transmission of HBV in the MENA. All HBV molecular sequences collected in the MENA were retrieved from GenBank as of 30 April 2021. Determination of genotypes/SGT, RT, and S mutations were based on the Geno2pheno (hbv) 2.0 online tool. For the most prevalent HBV SGTs, maximum likelihood phylogenetic analysis was conducted to identify the putative phylogenetic clusters, with approximate Shimodaira-Hasegawa-like likelihood ratio test values ≥ 0.90, and genetic distance cut-off values ≤ 0.025 substitutions/site as implemented in Cluster Picker. The total number of HBV sequences used for genotype/SGT determination was 4352 that represented a total of 20 MENA countries, with a majority from Iran (n = 2103, 48.3%), Saudi Arabia (n = 503, 11.6%), Tunisia (n = 395, 9.1%), and Turkey (n = 267, 6.1%). Genotype D dominated infections in the MENA (86.6%), followed by genotype A (4.1%), with SGT D1 as the most common in 14 MENA countries and SGT D7 dominance in the Maghreb. The highest prevalence of antiviral drug resistance was observed against lamivudine (4.5%) and telbivudine (4.3%). The proportion of domestic phylogenetic clustering was the highest for SGT D7 (61.9%), followed by SGT D2 (28.2%) and genotype E (25.7%). The largest fraction of domestic clusters with evidence of inter-country spread within the MENA was seen in SGT D7 (81.3%). Small networks (containing 3-14 sequences) dominated among domestic phylogenetic clusters. Specific patterns of HBV genetic diversity were seen in the MENA with SGT D1 dominance in the Levant, Iran, and Turkey; SGT D7 dominance in the Maghreb; and extensive diversity in Saudi Arabia and Egypt. A low prevalence of lamivudine, telbivudine, and entecavir drug resistance was observed in the region, with almost an absence of resistance to tenofovir and adefovir. Variable proportions of phylogenetic clustering indicated prominent domestic transmission of SGT D7 (particularly in the Maghreb) and relatively high levels of virus mobility in SGT D1.
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Affiliation(s)
- Rabaa Y. Athamneh
- Department of Medical Microbiology and Clinical Microbiology, Faculty of Medicine, Near East University, Nicosia 99138, Cyprus; (R.Y.A.); (A.A.)
| | - Ayşe Arıkan
- Department of Medical Microbiology and Clinical Microbiology, Faculty of Medicine, Near East University, Nicosia 99138, Cyprus; (R.Y.A.); (A.A.)
- DESAM, Near East University, Nicosia 99138, Cyprus;
| | - Murat Sayan
- DESAM, Near East University, Nicosia 99138, Cyprus;
- Clinical Laboratory, PCR Unit, Faculty of Medicine, Kocaeli University, İzmit 41380, Turkey
| | - Azmi Mahafzah
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, the University of Jordan, Amman 11942, Jordan;
- Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman 11942, Jordan
| | - Malik Sallam
- Department of Pathology, Microbiology and Forensic Medicine, School of Medicine, the University of Jordan, Amman 11942, Jordan;
- Department of Clinical Laboratories and Forensic Medicine, Jordan University Hospital, Amman 11942, Jordan
- Department of Translational Medicine, Faculty of Medicine, Lund University, 22184 Malmö, Sweden
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Watanabe T, Inoue T, Tanaka Y. Hepatitis B Core-Related Antigen and New Therapies for Hepatitis B. Microorganisms 2021; 9:microorganisms9102083. [PMID: 34683404 PMCID: PMC8537336 DOI: 10.3390/microorganisms9102083] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/29/2021] [Accepted: 09/30/2021] [Indexed: 02/06/2023] Open
Abstract
The hepatitis B core-related antigen (HBcrAg) is an unprecedented novel HBV biomarker that plays an essential role in reflecting covalently closed circular DNA (cccDNA) in chronic hepatitis B (CHB) because its levels correlate with intrahepatic cccDNA and serum HBV DNA. In this review, we describe the clinical application of serum HBcrAg in CHB patients, with a particular focus on new therapies targeting intrahepatic HBV replication. (1) HBcrAg can be detected in clinical cases where serum HBV DNA is undetectable during anti-HBV therapy. (2) A highly sensitive HBcrAg assay (iTACT-HBcrAg) may be useful for monitoring HBV reactivation, as an alternative to HBV DNA. (3) Decreased HBcrAg levels have been significantly associated with promising outcomes in CHB patients, reducing the risk of progression or recurrence of hepatocellular carcinoma. Additionally, we focus on and discuss several drugs in development that target HBV replication, and monitoring HBcrAg may be useful for determining the therapeutic efficacies of such novel drugs. In conclusion, HBcrAg, especially when measured by the recently developed iTACT-HBcrAg assay, may be the most appropriate surrogate marker, over other HBV biomarkers, to predict disease progression and treatment response in CHB patients.
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Affiliation(s)
- Takehisa Watanabe
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
| | - Takako Inoue
- Department of Clinical Laboratory Medicine, Nagoya City University Hospital, Nagoya 467-8602, Japan;
| | - Yasuhito Tanaka
- Department of Gastroenterology and Hepatology, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan;
- Correspondence:
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10
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Co-circulation of different genotype, sub-genotype and serotypes of hepatitis B virus (HBV) and its epidemiology in Assam: A north-eastern state of India. Indian J Med Microbiol 2021; 39:352-357. [PMID: 34045082 DOI: 10.1016/j.ijmmb.2021.04.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2020] [Revised: 03/16/2021] [Accepted: 04/30/2021] [Indexed: 11/23/2022]
Abstract
PURPOSE Hepatitis B virus (HBV) infection is a global health problem. HBV has different genotypes and subgenotypes with geographical distinctiveness. AIMS To study the molecular epidemiology and distribution pattern of HBV in Assam; a distinct state of India that may have different genotypic divergence. SETTINGS AND DESIGN Patients attending a tertiary care hospital susceptive of Hepatitis B were included, irrespective of age and sex in different agro-climatic zones of Assam. METHODS Samples positive for Hepatitis B surface antigen test and COBAS®TaqMan® HBV tests were further confirmed by PCR and sequencing followed by phylogenetic analysis. STATISTICAL ANALYSIS USED Chi-square test was used to determine whether there was a significant difference among the results in this study. RESULTS An increase trend of HBV positive cases has been observed in the state. The incidence in female was lower than that of male and age group 26-35 years was most vulnerable. Genotype D, subgenotype D2 and serotype ayw3 were predominant genotype, subgenotype and serotype. The prevalence of subgenotype C3 was a new finding. Phylogenetic analysis showed that the genotypes of HBV prevailing in the state have close relationship with neighboring countries of India which may be due to increased cross border migration of population CONCLUSIONS: This comprehensive study of HBV in Assam described the distribution of HBV genotypes and subgenotypes and serotypes in different agro-climatic zones of Assam. These findings will help to formulate the roadmap for prevention and control of the disease as well as targeted therapy of HBV in this State.
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Genome Sequences of 26 White Sucker Hepatitis B Virus Isolates from White Sucker, Catostomus commersonii, Inhabiting Transboundary Waters from Alberta, Canada, to the Great Lakes, USA. Microbiol Resour Announc 2021; 10:10/11/e01425-20. [PMID: 33737368 PMCID: PMC7975886 DOI: 10.1128/mra.01425-20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
We report 26 genome sequences of the white sucker hepatitis B virus (WSHBV) from the white sucker, Catostomus commersonii The genome length ranged from 3,541 to 3,543 bp, and nucleotide identity was 96.7% or greater across genomes. This work suggests a geographical range of this virus that minimally extends from the Athabasca River, Alberta, Canada, to the Great Lakes, USA.
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12
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Phylogeographic Genetic Diversity in the White Sucker Hepatitis B Virus across the Great Lakes Region and Alberta, Canada. Viruses 2021; 13:v13020285. [PMID: 33673082 PMCID: PMC7918172 DOI: 10.3390/v13020285] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/05/2021] [Accepted: 02/08/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B viruses belong to a family of circular, double-stranded DNA viruses that infect a range of organisms, with host responses that vary from mild infection to chronic infection and cancer. The white sucker hepatitis B virus (WSHBV) was first described in the white sucker (Catostomus commersonii), a freshwater teleost, and belongs to the genus Parahepadnavirus. At present, the host range of WSHBV and its impact on fish health are unknown, and neither genetic diversity nor association with fish health have been studied in any parahepadnavirus. Given the relevance of genomic diversity to disease outcome for the orthohepadnaviruses, we sought to characterize genomic variation in WSHBV and determine how it is structured among watersheds. We identified WSHBV-positive white sucker inhabiting tributaries of Lake Michigan, Lake Superior, Lake Erie (USA), and Lake Athabasca (Canada). Copy number in plasma and in liver tissue was estimated via qPCR. Templates from 27 virus-positive fish were amplified and sequenced using a primer-specific, circular long-range amplification method coupled with amplicon sequencing on the Illumina MiSeq. Phylogenetic analysis of the WSHBV genome identified phylogeographical clustering reminiscent of that observed with human hepatitis B virus genotypes. Notably, most non-synonymous substitutions were found to cluster in the pre-S/spacer overlap region, which is relevant for both viral entry and replication. The observed predominance of p1/s3 mutations in this region is indicative of adaptive change in the polymerase open reading frame (ORF), while, at the same time, the surface ORF is under purifying selection. Although the levels of variation we observed do not meet the criteria used to define sub/genotypes of human and avian hepadnaviruses, we identified geographically associated genome variation in the pre-S and spacer domain sufficient to define five WSHBV haplotypes. This study of WSHBV genetic diversity should facilitate the development of molecular markers for future identification of genotypes and provide evidence in future investigations of possible differential disease outcomes.
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13
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Complex genetic encoding of the hepatitis B virus on-drug persistence. Sci Rep 2020; 10:15574. [PMID: 32968103 PMCID: PMC7511938 DOI: 10.1038/s41598-020-72467-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 09/02/2020] [Indexed: 12/12/2022] Open
Abstract
Tenofovir disoproxil fumarate (TDF) is one of the nucleotide analogs capable of inhibiting the reverse transcriptase (RT) activity of HIV and hepatitis B virus (HBV). There is no known HBV resistance to TDF. However, detectable variation in duration of HBV persistence in patients on TDF therapy suggests the existence of genetic mechanisms of on-drug persistence that reduce TDF efficacy for some HBV strains without affording actual resistance. Here, the whole genome of intra-host HBV variants (N = 1,288) was sequenced from patients with rapid (RR, N = 5) and slow response (SR, N = 5) to TDF. Association of HBV genomic and protein polymorphic sites to RR and SR was assessed using phylogenetic analysis and Bayesian network methods. We show that, in difference to resistance to nucleotide analogs, which is mainly associated with few specific mutations in RT, the HBV on-TDF persistence is defined by genetic variations across the entire HBV genome. Analysis of the inferred 3D-structures indicates no difference in affinity of TDF binding by RT encoded by intra-host HBV variants that rapidly decline or persist in presence of TDF. This finding suggests that effectiveness of TDF recognition and binding does not contribute significantly to on-drug persistence. Differences in patterns of genetic associations to TDF response between HBV genotypes B and C and lack of a single pattern of mutations among intra-host variants sensitive to TDF indicate a complex genetic encoding of the trait. We hypothesize that there are many genetic mechanisms of on-drug persistence, which are differentially available to HBV strains. These pervasive mechanisms are insufficient to prevent viral inhibition completely but may contribute significantly to robustness of actual resistance. On-drug persistence may reduce the overall effectiveness of therapy and should be considered for development of more potent drugs.
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14
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Bahar M, Pervez MT, Ali A, Babar ME. In Silico Analysis of Hepatitis B Virus Genotype D Subgenotype D1 Circulating in Pakistan, China, and India. Evol Bioinform Online 2019; 15:1176934319861337. [PMID: 31320794 PMCID: PMC6610437 DOI: 10.1177/1176934319861337] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 06/05/2019] [Indexed: 12/15/2022] Open
Abstract
The focus of this study was the computational analysis of hepatitis B virus (HBV)
genotype D subgenotype D1 in Pakistan, China, and India. In total, 54 complete
genome sequences of HBV genotype D subgenotype D1 were downloaded from National
Center for Biotechnology Information (NCBI). Of these, 6 complete genome
sequences were from Pakistan, 14 were from China, and 34 were from India.
Sequence alignment showed less than 4% divergence in these sequences. C and X
genes showed divergence of less than 3%. Comparison over the S gene showed more
than 97% similarity among the nucleotide sequences of genotype D subgenotype D1.
The identity and similarity matrix of 54 nucleotide sequences of HBV genotype D
subgenotype D1 from Pakistan, China, and India revealed more than 93% identity
and 93% similarity. Phylogenetic analysis highlighted that complete genome
isolates of HBV circulating in Pakistan had the closest evolutionary
relationship with its neighboring countries China and India. China’s (HQ833466)
and Pakistan’s (AB583680.1) isolates shared the same ancestor. Gene structure
analysis showed that “P” gene exons were the longest, about three-fourth of the
genome size, whereas gene “S” had the second longest coding regions with 2 exons
and 1 intron. However, “C” and “X” genes had 1 smallest exon. X proteins had
proven role in spreading of the HBV infection diseases. For HBx analysis, 1 X
protein sequence of HBV genotype D subgenotype D1 belonging to each country was
obtained. Homology models of the 3 X proteins generated using SWISS-MODEL
revealed GMQE (Global Model Quality Estimation) = 0.1. Global and local quality
estimate scores including Z-scores for Qualitative Model Energy
Analysis (QMEAN) C-beta, all-atom, solvation, and torsion energy scores were
similar indicating good quality, accuracy, and reliability of the predicted
models. Three-dimensional (3D) visualization showed similar structures and
Ramachandran plots showed a high percentage of protein residues into the
favorable region for X protein models.
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Affiliation(s)
- Muneeb Bahar
- Department of Computer Science, Virtual University of Pakistan, Lahore, Pakistan
| | - Muhammad Tariq Pervez
- Department of Bioinformatics and Computational Biology, Virtual University of Pakistan, Lahore, Pakistan
| | - Akhtar Ali
- Department of Biotechnology, Virtual University of Pakistan, Lahore, Pakistan
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15
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Association of Interleukin 13/+110 Gene Polymorphism with Hepatitis B Virus Infection in Golestan Province, Northern Iran. Jundishapur J Microbiol 2019. [DOI: 10.5812/jjm.68270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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16
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Mozhgani SH, Malekpour SA, Norouzi M, Ramezani F, Rezaee SA, Poortahmasebi V, Sadeghi M, Alavian SM, Zarei-Ghobadi M, Ghaziasadi A, Karimzadeh H, Malekzadeh R, Ziaee M, Abedi F, Ataei B, Yaran M, Sayad B, Jahantigh HR, Somi MH, Sarizadeh G, Sanei-Moghaddam I, Mansour-Ghanaei F, Keyvani H, Kalantari E, Fakhari Z, Geravand B, Jazayeri SM. Molecular evolution and phylodynamics of hepatitis B virus infection circulating in Iran. Arch Virol 2018; 163:1479-1488. [PMID: 29442226 DOI: 10.1007/s00705-018-3764-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Accepted: 01/13/2018] [Indexed: 01/16/2023]
Abstract
Previous local and national Iranian publications indicate that all Iranian hepatitis B virus (HBV) strains belong to HBV genotype D. The aim of this study was to analyze the evolutionary history of HBV infection in Iran for the first time, based on an intensive phylodynamic study. The evolutionary parameters, time to most recent common ancestor (tMRCA), and the population dynamics of infections were investigated using the Bayesian Monte Carlo Markov chain (BMCMC). The effective sample size (ESS) and sampling convergence were then monitored. After sampling from the posterior distribution of the nucleotide substitution rate and other evolutionary parameters, the point estimations (median) of these parameters were obtained. All Iranian HBV isolates were of genotype D, sub-type ayw2. The origin of HBV is regarded as having evolved first on the eastern border, before moving westward, where Isfahan province then hosted the virus. Afterwards, the virus moved to the south and west of the country. The tMRCA of HBV in Iran was estimated to be around 1894, with a 95% credible interval between the years 1701 and 1957. The effective number of infections increased exponentially from around 1925 to 1960. Conversely, from around 1992 onwards, the effective number of HBV infections has decreased at a very high rate. Phylodynamic inference clearly demonstrates a unique homogenous pattern of HBV genotype D compatible with a steady configuration of the decreased effective number of infections in the population in recent years, possibly due to the implementation of blood donation screening and vaccination programs. Adequate molecular epidemiology databases for HBV are crucial for infection prevention and treatment programs.
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Affiliation(s)
- Sayed-Hamidreza Mozhgani
- Hepatitis B Lab, Department of Virology, School of Public Health, Tehran University of Medical Sciences, P. O. Box: 15155-6446, Tehran, 14155-6446, Iran
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Amir Malekpour
- School of Mathematics, Statistics and Computer Science, College of Science, University of Tehran, Tehran, Iran
- School of Biological Sciences, Institute for Research in Fundamental Sciences, Tehran, Iran
| | - Mehdi Norouzi
- Hepatitis B Lab, Department of Virology, School of Public Health, Tehran University of Medical Sciences, P. O. Box: 15155-6446, Tehran, 14155-6446, Iran
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ramezani
- Hepatitis B Lab, Department of Virology, School of Public Health, Tehran University of Medical Sciences, P. O. Box: 15155-6446, Tehran, 14155-6446, Iran
| | - Seyed Abdolrahim Rezaee
- Inflammation and Inflammatory Diseases Division, Faculty of Medicine, Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahdat Poortahmasebi
- Hepatitis B Lab, Department of Virology, School of Public Health, Tehran University of Medical Sciences, P. O. Box: 15155-6446, Tehran, 14155-6446, Iran
| | - Mehdi Sadeghi
- National Institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Seyed Moayed Alavian
- Middle East Liver Diseases Center (MELD Centers), Tehran University of Medical Sciences, Tehran, Iran
| | - Mohadeseh Zarei-Ghobadi
- Hepatitis B Lab, Department of Virology, School of Public Health, Tehran University of Medical Sciences, P. O. Box: 15155-6446, Tehran, 14155-6446, Iran
| | - Azam Ghaziasadi
- Hepatitis B Lab, Department of Virology, School of Public Health, Tehran University of Medical Sciences, P. O. Box: 15155-6446, Tehran, 14155-6446, Iran
| | | | - Reza Malekzadeh
- Digestive Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Masood Ziaee
- Department of Internal Medicine, Vali-e-Asr Hospital, Birjand University of Medical Sciences, Birjand, Iran
| | - Farshid Abedi
- Department of Infectious Disease, Birjand University of Medical Sciences, Birjand, Iran
| | - Behrooz Ataei
- Infectious Diseases and Tropical Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Majid Yaran
- Infectious Diseases and Tropical Medicine Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Babak Sayad
- Kermanshah Liver Diseases and Hepatitis Research Center, Kermanshah, Iran
| | - Hamid Reza Jahantigh
- Inflammation and Inflammatory Diseases Division, Faculty of Medicine, Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Hossein Somi
- Liver and Gastrointestinal Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Fariborz Mansour-Ghanaei
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Hossein Keyvani
- Department of Virology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Zahra Fakhari
- Hepatitis B Lab, Department of Virology, School of Public Health, Tehran University of Medical Sciences, P. O. Box: 15155-6446, Tehran, 14155-6446, Iran
| | - Babak Geravand
- Islamic Azad University, South Tehran Branch, Tehran, Iran
| | - Seyed Mohammad Jazayeri
- Hepatitis B Lab, Department of Virology, School of Public Health, Tehran University of Medical Sciences, P. O. Box: 15155-6446, Tehran, 14155-6446, Iran.
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran.
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Ansari MHK, Rasmi Y, Abbasi L. Hepatitis B virus Genotypes in West Azarbayjan Province, Northwest Iran. Open Access Maced J Med Sci 2017; 5:875-879. [PMID: 29362612 PMCID: PMC5771288 DOI: 10.3889/oamjms.2017.206] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 10/02/2017] [Accepted: 10/03/2017] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND: Infections caused by Hepatitis B are one of the world health’s most serious problems. According to assessments, nearly 500,000 to 1.2 million people die each year due to chronic hepatitis, cirrhosis of the liver and hepatocellular carcinoma. Hepatitis B is one of the diseases which can be transferred through blood and its products. Clinical importance of genotypes of hepatitis B virus and their relations with mutations are well known. AIM: Since epidemiological data resulting from determining genotypes and sub-genotypes of hepatitis B can help a lot in defining a vaccination plan, antiretroviral therapy, detection and prevention of diseases, genotypes of this virus in hepatitis B patients were evaluated in West Azarbaijan province. MATERIALS AND METHODS: In this cross-sectional study, serum samples of 100 hepatitis B patients (70 male/30 female) were taken randomly from Urmia University of Medical Sciences (UMSU) referrals, Urmia, Iran; and were tested positive for the presence of surface antigens of hepatitis B virus (HBsAg) using ELISA method. In the first method, after extracting the DNA of the virus, sequencing of S genes was carried out using Sanger method, and the sequences were aligned and edited using Bioedit software. In the next step, phylogenic analysis of the sequences was done in comparison with the reference sequences which were extracted from a gene bank, utilising Neighbour-joining assay method with CLUSTRAL W software. To ensure genotyping accuracy, the samples were tested once more, using Nested PCR method. RESULTS: The results were consistent with the sequence method and the dominant genotype in patients suffering hepatitis was type D. In other words, Iranian’s HBV genotypic types are homogeneous and in close coordination with each other. CONCLUSIONS: The results reveal that D genotype is the main genotype of HBV in West Azarbayjan province, northwest Iran. Presence of this genotype was in conformity conformed withto the low rate of acute liver diseases caused by hepatitis B chronic infection, cirrhosis of the liver and hepatocellular carcinoma.
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Affiliation(s)
| | - Yousef Rasmi
- Department of Biochemistry, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Laya Abbasi
- Department of Microbiology, Azad Islamic University-Urmia Branch, Urmia, Iran
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18
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King B, Tarr AW. How have retrovirus pseudotypes contributed to our understanding of viral entry? Future Virol 2017. [DOI: 10.2217/fvl-2017-0062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Study of virus entry into host cells is important for understanding viral tropism and pathogenesis. Studying the entry of in vitro cultured viruses is not always practicable. Study of highly pathogenic viruses, viruses that do not grow in culture, and viruses that rapidly change phenotype in vitro can all benefit from alternative models of entry. Retrovirus particles can be engineered to display the envelope proteins of heterologous enveloped viruses. This approach, broadly termed ‘pseudotyping’, is an important technique for interrogating virus entry. In this perspective we consider how retrovirus pseudotypes have addressed these challenges and improved our understanding of the entry pathways of diverse virus species, including Ebolavirus, human immunodeficiency virus and hepatitis C virus.
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Affiliation(s)
- Barnabas King
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & the University of Nottingham, Nottingham, UK
- School of Life Sciences, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, UK
| | - Alexander W Tarr
- National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust & the University of Nottingham, Nottingham, UK
- School of Life Sciences, Faculty of Medicine & Health Sciences, University of Nottingham, Nottingham, UK
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19
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Lampe E, Mello FCA, do Espírito-Santo MP, Oliveira CMC, Bertolini DA, Gonçales NSL, Moreira RC, Fernandes CAS, Nascimento HCL, Grotto RMT, Pardini MIMC, On Behalf Of The Brazilian Hepatitis B Research Group. Nationwide overview of the distribution of hepatitis B virus genotypes in Brazil: a 1000-sample multicentre study. J Gen Virol 2017. [PMID: 28631602 DOI: 10.1099/jgv.0.000789] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The influence of hepatitis B virus (HBV) genotypes in the natural history of the disease and its response to antiviral treatment have been addressed in many studies. In Brazil, studies on HBV genotype circulation have been restricted to specific population groups and states. Here, we have conducted a nationwide multicentre study with an unprecedented sample size representing all Brazilian regions in an effort to better understand the viral variants of HBV circulating among chronic carriers. Seven HBV genotypes were found circulating in Brazil. Overall, HBV/A was the most prevalent, identified in 589 (58.7 %) samples, followed by HBV/D (23.4 %) and HBV/F (11.3 %). Genotypes E, G, C and B were found in a minor proportion. The distribution of the genotypes differed markedly from the north to the south of the country. While HBV/A was the most prevalent in the North (71.6 %) and Northeast (65.0 %) regions, HBV/D was found in 78.9 % of the specimens analysed in the South region. HBV/F was the second most prevalent genotype in the Northeast region (23.5 %). It was detected in low proportions (7 to 10 %) in the North, Central-West and Southeast regions, and in only one sample in the South region. HBV/E was detected in all regions except in the South, while monoinfection with HBV/G was found countrywide, with the exception of Central-West states. Our sampling covered 24 of the 26 Brazilian states and the Federal District and is the first report of genotype distribution in seven states. This nationwide study provides the most complete overview of HBV genotype distribution in Brazil to date and reflects the origin and plurality of the Brazilian population.
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Affiliation(s)
- Elisabeth Lampe
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ, Brazil
| | - Francisco C A Mello
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ, Brazil
| | | | - Cintia M C Oliveira
- Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, AM, Brazil
| | - Dennis A Bertolini
- Laboratório de Imunologia Clínica, Departamento de Análise Clínicas e Biomedicina, Universidade Estadual de Maringá, Maringá, PR, Brazil
| | - Neiva S L Gonçales
- Laboratório do Grupo de Estudo das Hepatites, UNICAMP, Campinas, SP, Brazil
| | - Regina C Moreira
- Laboratório de Hepatites, Instituto Adolfo Lutz, São Paulo, SP, Brazil
| | | | | | - Rejane M T Grotto
- Universidade Estadual Paulista (Unesp), Faculdade de Ciências Agronômicas (FCA), Campus de Botucatu, Botucatu, SP, Brazil.,Universidade Estadual Paulista (Unesp), Faculdade de Medicina (FMB), Divisão Hemocentro, Laboratório de Biologia Molecular, Campus de Botucatu, Botucatu, SP, Brazil
| | - Maria Inês M C Pardini
- Universidade Estadual Paulista (Unesp), Faculdade de Medicina (FMB), Divisão Hemocentro, Laboratório de Biologia Molecular, Campus de Botucatu, Botucatu, SP, Brazil
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20
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Kheirabad AK, Farshidfar G, Nasrollaheian S, Gouklani H. Prevalence and Characteristics of Precore Mutation in Iran and Its Correlation with Genotypes of Hepatitis B. Electron Physician 2017; 9:4114-4123. [PMID: 28607644 PMCID: PMC5459281 DOI: 10.19082/4114] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Accepted: 11/03/2016] [Indexed: 01/05/2023] Open
Abstract
Introduction Mutation of the HBV precore gene prevents the production of HBeAg, which is an important target for immune responses. Distribution of this mutation varies along with frequency of HBV genotypes in accordance with geographic and ethnic variations. The general objective of this study was to evaluate the prevalence and characteristics of precore mutation in Iran and its correlation with genotypes of hepatitis B. Methods In this cross-sectional study, viral DNA of 182 Iranian hepatitis B surface antigen positive patients who were admitted to Bandar Abbas Blood Transfusion Organization in 2012 and 2013 was retrieved from their serum samples. HBeAg, anti-HBe, and anti-HBc IgM diagnostic tests were performed using ELISA kits. Precore and Pre-S regions were amplified using specific primers and PCR thereafter to determine the genotypes; precore mutation, PCR, and restriction fragment length polymorphism (RFLP) methods also were applied. SPSS version 12 was used for data analysis by Mann–Whitney U test, Fisher’s exact probability test, and t-test. Results A total of 62 patients (34.1%) had precore mutation (A1896G), and genotype D was the predominant genotype in these patients, which was followed by an unknown genotype that was suspected for genotype B. Interestingly, the relationships between precore mutation and HBeAg (p=0.037) and genotype D (p=0.005) were significant; however, no correlation was observed between this mutation and acute or chronic hepatitis and sex of patients. Conclusion This study found high prevalence of precore mutations in southern Iran, which was significantly associated with HBeAg and genotype D.
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Affiliation(s)
- Ali Kargar Kheirabad
- Ph.D., Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Gholamreza Farshidfar
- Ph.D., Department of Biochemistry, School of Medicine, Hormozgan University of Medical Sciences, Iran
| | | | - Hamed Gouklani
- Ph.D., Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
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Silva Souza ACD, Souza Marasca GD, Kretzmann-Filho NA, Dall-Bello A, Alexandre Kliemann D, Valle Tovo C, Gorini da Veiga AB. Identification of hepatitis B virus A1762T/G1764A double mutant strain in patients in Southern Brazil. Braz J Infect Dis 2017; 21:525-529. [PMID: 28606415 PMCID: PMC9425463 DOI: 10.1016/j.bjid.2017.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 04/12/2017] [Accepted: 05/11/2017] [Indexed: 01/09/2023] Open
Abstract
Infection by hepatitis B virus (HBV) is a worldwide public health problem. Chronic HBV infection with high viral replication may lead to cirrhosis and/or hepatocellular carcinoma. Mutant HBV strains, such as the HBV A1762T/G1764A double mutant, have been associated with poor prognosis and higher risk of the patient for developing cirrhosis and/or hepatocellular carcinoma. This study analyzed the presence of the HBV A1762T/G1764A double mutant in patients with chronic HBV and its association with clinical parameters such as viral load, aminotransferases, and HBV antigens. A total of 49 patients with chronic hepatitis B were included in the study, and the HBV A1762T/G1764A double mutant strain was detected in four samples (8.16%) by polymerase chain reaction followed by restriction fragment length analysis (PCR-RFLP). The viral load was not significantly different between patients with or without the double mutant strain (p=0.43). On the other hand, carriers of the HBV A1762T/G1764A double mutant had higher levels of ALT (p=0.0028), while AST levels did not differ between groups (p=0.051). In this study, 75% of the samples with the HBV A1762T/G1764A double mutation were HBeAg negative and anti-HBe positive, reflecting seroconversion even though they still displayed high viral loads. Our study has shown that the HBV A1762T/G1764A double mutant strain circulates in Brazilian patients, and is associated with elevated levels of ALT and HBeAg seroconversion.
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Affiliation(s)
- Adaliany Cecília da Silva Souza
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil
| | - Giórgia de Souza Marasca
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil
| | - Nélson Alexandre Kretzmann-Filho
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil
| | - Aline Dall-Bello
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil
| | - Dimas Alexandre Kliemann
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil; Hospital Nossa Senhora da Conceição (HNSC), Porto Alegre, RS, Brazil
| | - Cristiane Valle Tovo
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil; Hospital Nossa Senhora da Conceição (HNSC), Porto Alegre, RS, Brazil
| | - Ana Beatriz Gorini da Veiga
- Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Programa de Pos-Graduação em Medicina: Hepatologia, Porto Alegre, RS, Brazil.
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22
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Lawson-Ananissoh LM, Attia KA, Diallo D, Doffou S, Kissi YH, Bangoura D, Kouamé D, Mahassadi KA, Yao-Bathaix F, Yoman TN. Distribution et implications cliniques des génotypes du virus de l’hépatite B chez 33 porteurs chroniques du virus de l’hépatite B en Côte-d’Ivoire. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/s12157-017-0726-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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23
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Riveiro-Barciela M, Bes M, Rodríguez-Frías F, Tabernero D, Ruiz A, Casillas R, Vidal-González J, Homs M, Nieto L, Sauleda S, Esteban R, Buti M. Serum hepatitis B core-related antigen is more accurate than hepatitis B surface antigen to identify inactive carriers, regardless of hepatitis B virus genotype. Clin Microbiol Infect 2017; 23:860-867. [PMID: 28288829 DOI: 10.1016/j.cmi.2017.03.003] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Revised: 02/24/2017] [Accepted: 03/05/2017] [Indexed: 12/14/2022]
Abstract
OBJECTIVES To investigate whether hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HBcrAg) levels are useful to identify inactive carriers among HBeAg-negative patients infected by different hepatitis B virus (HBV) genotypes. METHODS In all, 202 consecutive HBeAg-negative patients with chronic hepatitis B, 135 inactive carriers and 67 with HBV activity, were prospectively followed for 1 year. RESULTS In HBeAg-negative patients, HBsAg levels differed across the different genotypes (p <0.001). The highest levels were observed in genotypes F or H (4.2 ± 0.6 logIU/mL), followed by genotype E (3.4 ± 1.1 logIU/mL), genotype A (3.4 ± 0.8 logIU/mL), and the lowest in genotype D (2.7 ± 1.1 logIU/mL). Variations in HBsAg levels were similar in inactive carriers and patients with HBV activity. HBsAg <3 logIU/mL showed good performance for identifying genotype D inactive carriers: 76% of genotype D inactive carriers met this cut-off versus ≤31% for genotypes A, E, F or H. However, in patients with genotype A, HBsAg levels ≤3.7 logIU/mL better classified inactive carriers. The combination of a single measurement of HBcrAg ≤3 logU/mL plus HBV DNA ≤2000 IU/mL yielded a positive predictive value and diagnostic accuracy >85% in all HBV genotypes, except genotype H or F, with values of 62.5% and 72.7%, respectively, for the two parameters. CONCLUSIONS HBsAg levels varied across genotypes in HBeAg-negative patients. HBsAg levels <3 logIU/mL were only useful for identifying genotype D inactive carriers. A single HBcrAg measurement ≤3 logU/mL plus HBV DNA ≤2000 IU/mL was highly accurate for identifying inactive carriers, regardless of their HBV genotype.
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Affiliation(s)
- M Riveiro-Barciela
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain.
| | - M Bes
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Transfusion Safety Laboratory, Banc de Sang i Teixits, Servei Català de la Salut, Barcelona, Spain
| | - F Rodríguez-Frías
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Pathology Unit, Departments of Biochemistry and Microbiology (Virology Unit) Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain
| | - D Tabernero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Pathology Unit, Departments of Biochemistry and Microbiology (Virology Unit) Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain
| | - A Ruiz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Pathology Unit, Departments of Biochemistry and Microbiology (Virology Unit) Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain
| | - R Casillas
- Vall d'Hebron Institut de Recerca, Barcelona, Spain
| | - J Vidal-González
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M Homs
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Pathology Unit, Departments of Biochemistry and Microbiology (Virology Unit) Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain
| | - L Nieto
- Liver Pathology Unit, Departments of Biochemistry and Microbiology (Virology Unit) Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain
| | - S Sauleda
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Transfusion Safety Laboratory, Banc de Sang i Teixits, Servei Català de la Salut, Barcelona, Spain
| | - R Esteban
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - M Buti
- Liver Unit, Department of Internal Medicine, Hospital Universitari Vall d'Hebron and Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
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Inoue T, Tanaka Y. Hepatitis B virus and its sexually transmitted infection - an update. MICROBIAL CELL 2016; 3:420-437. [PMID: 28357379 PMCID: PMC5354569 DOI: 10.15698/mic2016.09.527] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Epidemiology: incidence and prevalence:
About 5% of the world’s population has chronic hepatitis B virus (HBV)
infection, and nearly 25% of carriers develop chronic hepatitis, cirrhosis, and
hepatocellular carcinoma (HCC). The prevalence of chronic HBV infection in human
immunodeficiency virus (HIV)-infected individuals is 5%-15%; HIV/HBV coinfected
individuals have a higher level of HBV replication, with higher rates of
chronicity, reactivation, occult infection, and HCC than individuals with HBV
only. The prevalence of HBV genotype A is significantly higher among men who
have sex with men (MSM), compared with the rest of the population.
Molecular mechanisms of infection, pathology, and
symptomatology: HBV replication begins with entry into the
hepatocyte. Sodium taurocholate cotransporting polypeptide was identified in
2012 as the entry receptor of HBV. Although chronic hepatitis B develops slowly,
HIV/HBV coinfected individuals show more rapid progression to cirrhosis and HCC.
Transmission and protection: The most common sources
of HBV infection are body fluids. Hepatitis B (HB) vaccination is recommended
for all children and adolescents, and all unvaccinated adults at risk for HBV
infection (sexually active individuals such as MSM, individuals with
occupational risk, and immunosuppressed individuals). Although HB vaccination
can prevent clinical infections (hepatitis), it cannot prevent 100% of
subclinical infections. Treatment and curability:
The goal of treatment is reducing the risk of complications
(cirrhosis and HCC). Pegylated interferon alfa and nucleos(t)ide analogues (NAs)
are the current treatments for chronic HBV infection. NAs have improved the
outcomes of patients with cirrhosis and HCC, and decreased the incidence of
acute liver failure.
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Affiliation(s)
- Takako Inoue
- Clinical Laboratory, Nagoya City University Hospital, Nagoya, Japan
| | - Yasuhito Tanaka
- Clinical Laboratory, Nagoya City University Hospital, Nagoya, Japan. ; Department of Virology & Liver unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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25
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Kim H, Lee SA, Kim BJ. X region mutations of hepatitis B virus related to clinical severity. World J Gastroenterol 2016; 22:5467-5478. [PMID: 27350725 PMCID: PMC4917607 DOI: 10.3748/wjg.v22.i24.5467] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/17/2016] [Accepted: 06/02/2016] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major health problem, with more than 240 million people chronically infected worldwide and potentially 650000 deaths per year due to advanced liver diseases including liver cirrhosis and hepatocellular carcinoma (HCC). HBV-X protein (HBx) contributes to the biology and pathogenesis of HBV via stimulating virus replication or altering host gene expression related to HCC. The HBV X region contains only 465 bp encoding the 16.5 kDa HBx protein, which also contains several critical cis-elements such as enhancer II, the core promoter and the microRNA-binding region. Thus, mutations in this region may affect not only the HBx open reading frame but also the overlapped cis-elements. Recently, several types of HBx mutations significantly associated with clinical severity have been described, although the functional mechanism in most of these cases remains unsolved. This review article will mainly focus on the HBx mutations proven to be significantly related to clinical severity via epidemiological studies.
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26
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Kim H, Lee SA, Do SY, Kim BJ. Precore/core region mutations of hepatitis B virus related to clinical severity. World J Gastroenterol 2016; 22:4287-4296. [PMID: 27158197 PMCID: PMC4853686 DOI: 10.3748/wjg.v22.i17.4287] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 03/10/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
Despite the availability of an effective vaccine, hepatitis B virus (HBV) infection remains a major health problem, with more than 350 million chronically infected people worldwide and over 1 million annual deaths due to cirrhosis and liver cancer. HBV mutations are primarily generated due both to a lack of proofreading capacity by HBV polymerase and to host immune pressure, which is a very important factor for predicting disease progression and therapeutic outcomes. Several types of HBV precore/core (preC/C) mutations have been described to date. The host immune response against T cells drives mutation in the preC/C region. Specifically, preC/C mutations in the MHC class II restricted region are more common than in other regions and are significantly related to hepatocellular carcinoma. Certain mutations, including preC G1896A, are also significantly related to HBeAg-negative chronic infection. This review article mainly focuses on the HBV preC/C mutations that are related to disease severity and on the HBeAg serostatus of chronically infected patients.
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27
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Winer BY, Ding Q, Gaska JM, Ploss A. In vivo models of hepatitis B and C virus infection. FEBS Lett 2016; 590:1987-99. [PMID: 27009462 DOI: 10.1002/1873-3468.12157] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Revised: 03/16/2016] [Accepted: 03/22/2016] [Indexed: 12/17/2022]
Abstract
Globally, more than 500 million individuals are chronically infected with hepatitis B (HBV), delta (HDV), and/or C (HCV) viruses, which can result in severe liver disease. Mechanistic studies of viral persistence and pathogenesis have been hampered by the scarcity of animal models. The limited species and cellular host range of HBV, HDV, and HCV, which robustly infect only humans and chimpanzees, have posed challenges for creating such animal models. In this review, we will discuss the barriers to interspecies transmission and the progress that has been made in our understanding of the HBV, HDV, and HCV life cycles. Additionally, we will highlight a variety of approaches that overcome these barriers and thus facilitate in vivo studies of these hepatotropic viruses.
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Affiliation(s)
| | - Qiang Ding
- Department of Molecular Biology, Princeton University, NJ, USA
| | - Jenna M Gaska
- Department of Molecular Biology, Princeton University, NJ, USA
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, NJ, USA
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28
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Bahri F, Kargar Kheirabad A, Ghasemzadeh I, Shoja S, Gouklani H. Hepatitis Viruses B and D and Human Immunodeficiency Virus Infections in Hemodialysis Patients in the South of Iran: Prevalence and Genotypes. HEPATITIS MONTHLY 2016; 16:e32971. [PMID: 27110260 PMCID: PMC4834196 DOI: 10.5812/hepatmon.32971] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Revised: 11/06/2015] [Accepted: 12/19/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV), hepatitis D virus (HDV), and human immunodeficiency virus (HIV) are transmitted by blood transfusion. Thus, hemodialysis (HD) patients are more prone to become the carriers of these infections due to their treatment demands. OBJECTIVES The aim of this study was to assess the prevalence of HBV and HIV infections among HD patients in Bandar Abbas, Iran, 2015. PATIENTS AND METHODS A total of 153 patients with chronic renal failure undergoing HD at Shahid Mohammadi hospital in Bandar Abbas were examined for hepatitis B surface antigen (HBsAg), anti- hepatitis C virus, and anti-HIV over a period of 2 months. Thereafter, all of the specimens were evaluated for HBV-DNA, HDV-RNA and HIV-RNA using polymerase chain reaction (PCR) and further techniques. All statistical analyses were carried out using SPSS version 12 for Windows with the t-test and chi-square (χ(2)) test. RESULTS Both kinds of assay determined that nine (5.88%) patients were HBV positive (HBsAg-positive), whereas no HIV- and HDV-positive patients were diagnosed. All of the diagnosed HBV samples belonged to genotype D; the prevalence of HBV is associated with age, duration of HD, history of blood transfusion, and using shared HD devices. CONCLUSIONS In conclusion, the prevalence of HBV infection was low in the south of Iran, but genotype D represented the major HBV genotype in this population. Among the variables, age, duration of HD, history of blood transfusion, and using shared HD devices influenced the prevalence of HBV among HD patients.
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Affiliation(s)
- Fahime Bahri
- Department of Microbiology, Jahrom Branch, Islamic Azad University, Jahrom, IR Iran
| | - Ali Kargar Kheirabad
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
| | - Iman Ghasemzadeh
- Infectious and Tropical Disease Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, IR Iran
| | - Saeed Shoja
- Infectious and Tropical Disease Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, IR Iran
| | - Hamed Gouklani
- Molecular Medicine Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, IR Iran
- Corresponding Author: Hamed Gouklani, Molecular Medicine Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, IR Iran. Tel: +98-9365966501, Fax: +98-7633668478, E-mail:
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Esmail MA, Mahdi WKM, Khairy RM, Abdalla NH. Genotyping of occult hepatitis B virus infection in Egyptian hemodialysis patients without hepatitis C virus infection. J Infect Public Health 2016; 9:452-7. [PMID: 26778093 DOI: 10.1016/j.jiph.2015.11.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 10/21/2015] [Accepted: 11/10/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Occult hepatitis B viral infection is the presence of hepatitis B viral nucleic acids in the serum and/or liver in the absence of hepatitis B surface antigen. AIM The study aimed to determine the prevalence of occult hepatitis B virus infection among hepatitis C virus-negative hemodialysis patients and to identify their genotypes. METHODS of 144 patients on maintenance hemodialysis, 50 hepatitis B surface antigen and hepatitis C virus nucleic acid-negative patients were selected according to strict inclusion criteria to avoid the effect of confounding variables. The following investigations were done: serum AST and ALT; HBsAg; HBcAb; HCV-Ab; HCV-RNA; and HBV-DNA. RESULTS Positive hepatitis B viral nucleic acid was confirmed in 12/144 (8.3%) hemodialysis patients and 12/50 (24%) in our study group (occult infection). Mean hemodialysis periods for negative patients and occult hepatitis B virus patients were 27.3±18.8 and 38.4±8.14 months, respectively, and this difference was significant (p-value=0.02). Mean alanine transaminase levels were 20.27±5.5IU/L and 25.3±9.6 in negative patients and occult infection patients, respectively. This difference was non-significant. Aspartate transaminase levels were 21.4±10.2IU/L and 27.3±4.6IU/L, respectively, in negative patients and infected patients; this difference was significant (p-value=0.03). Half (6/12) of the positive samples belonged to genotype 'B', 33.3% (4/12) to 'C', and 16.6% (2/12) to genotype 'D'. CONCLUSION OBI is likely among hemodialysis patients even without HCV coinfection (24%). Genotype D cannot be the only genotype distributed in Upper Egypt, as the current study reported relatively new results that 50% of the patients with occult B carry genotype B, 33.3% carry genotype C and only 16.6% carry genotype D.
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Affiliation(s)
- Mona A Esmail
- Microbiology and Immunology Department, Faculty of Medicine, Minia University, El Minia 61519, Egypt.
| | - Wafaa K M Mahdi
- Microbiology and Immunology Department, Faculty of Medicine, Minia University, El Minia 61519, Egypt
| | - Rasha M Khairy
- Microbiology and Immunology Department, Faculty of Medicine, Minia University, El Minia 61519, Egypt.
| | - Nilly H Abdalla
- Internal Medicine Department, Faculty of Medicine, Beni Suif University, Egypt.
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Higher numbers of memory B-cells and Th2-cytokine skewing in high responders to hepatitis B vaccination. Vaccine 2015; 34:2281-9. [PMID: 26721327 DOI: 10.1016/j.vaccine.2015.12.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2015] [Revised: 11/22/2015] [Accepted: 12/09/2015] [Indexed: 12/23/2022]
Abstract
In the present study, differences in hepatitis B surface antigen (HBsAg)-specific memory B-cell responses between low and high responders to hepatitis B vaccine (HepB), based on levels of antibodies against HBsAg (anti-HBs), were determined. In addition, HBsAg specific T-cell responses between high (anti-HBs level >20,000 IU/L) and low (anti-HBs level <1500 IU/L) responders were compared. Numbers of HBsAg-specific B-cells, plasma immunoglobulin G (Ig) levels, and T-cell cytokine concentrations were measured in low and high responders directly before and one month after the second booster vaccination. In advance, an Enzyme-linked Immunosorbent Spot (ELISpot) Assay was optimized for the determination of HBsAg-specific B-cell responses. The number of HBsAg-specific B-cells was significantly higher (p<0.01) in the high responder group compared to the low responder group after a booster vaccination with HepB. In addition, the plasma IgG levels and numbers of HBsAg-specific B-cells were significantly correlated (RS=0.66, p<0.01). The HBsAg-specific Th1 cell response showed the same values in the low and high responder group and did not change by the booster vaccination with HepB. However, a significant correlation (RS=0.6975, p=0.007) between the IL-13 levels and the plasma IgG levels post-booster was found. Subsequently, the IL-13 level in the high-responder group post-booster was significantly higher compared to the low-responder group. Since activation of the B-cell response after vaccination is induced by Th2 cells and IL-13 is produced by these cells, we conclude that the difference in HBsAg-specific Th2 cells is involved in determining the differences in anti-HBs level and memory B-cell numbers between low and high responders.
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31
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Manzoor S, Saalim M, Imran M, Resham S, Ashraf J. Hepatitis B virus therapy: What’s the future holding for us? World J Gastroenterol 2015; 21:12558-12575. [PMID: 26640332 PMCID: PMC4658610 DOI: 10.3748/wjg.v21.i44.12558] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 07/24/2015] [Accepted: 10/20/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B is one of the leading causes of liver cancer worldwide and unfortunately the number of people affected with hepatitis B virus (HBV) infection is still on the rise. Although the HBV has been known to cause fatal illness since decades but the population effected by this lethal virus have still only a few options for its management. The major treatment strategies include interferons and nucleos(t)ide analogues. These agents have so far produced unsatisfactory results in terms of complete virus eradication. Interferons cannot be used for long term therapy because of their potential side effects. Prolong treatment with nucleos(t)ide analogues has also been reported to cause serious side effects besides the increasing resistance by the virus. The need for new innovative solutions for treatment of HBV has been realized by global research institutes and pharmaceutical industry. Present review focuses in detail on the new ideas that are being transformed into therapeutic tools for use as future therapies in HBV infection. Modern drug designing and screening methods have made the drug discovery process shorter and more reliable. HBV therapeutics will take a new turn in coming years owing to these intelligent drug designing and screening methods. Future therapy of HBV is aiming to include the use of vaccines (both prophylactic and therapeutic), immunomodulators such as antibodies, non-nucleoside antivirals such as RNAi and inhibitors of viral life cycle.
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Martin P, Lau DTY, Nguyen MH, Janssen HLA, Dieterich DT, Peters MG, Jacobson IM. A Treatment Algorithm for the Management of Chronic Hepatitis B Virus Infection in the United States: 2015 Update. Clin Gastroenterol Hepatol 2015; 13:2071-87.e16. [PMID: 26188135 DOI: 10.1016/j.cgh.2015.07.007] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Revised: 07/01/2015] [Accepted: 07/09/2015] [Indexed: 02/07/2023]
Abstract
Chronic hepatitis B (CHB) continues to be an important public health problem worldwide, including in the United States. An algorithm for managing CHB was developed by a panel of United States hepatologists in 2004 and subsequently updated in 2006 and 2008. Since 2008, additional data on long-term safety and efficacy of licensed therapies have become available and have better defined therapeutic options for CHB. The evidence indicates that potent antiviral therapy can lead to regression of extensive fibrosis or even cirrhosis, thus potentially altering the natural history of CHB. In addition, appropriate choice of antiviral agent can minimize the risk of resistance. This updated algorithm for managing CHB is based primarily on evidence from the scientific literature. Where data were lacking, the panel relied on clinical experience and consensus expert opinion. The primary aim of antiviral therapy for CHB is durable suppression of serum hepatitis B virus (HBV) DNA to low or undetectable levels. CHB patients who have HBV DNA >2000 IU/mL, elevated alanine aminotransferase level, and any degree of fibrosis should receive antiviral therapy regardless of their hepatitis B e antigen status. CHB patients with HBV DNA >2000 IU/mL and elevated alanine aminotransferase level but no evidence of fibrosis may also be considered for antiviral therapy. Approved antiviral therapies for CHB are interferon alfa-2b, peginterferon alfa-2a, lamivudine, adefovir, entecavir, telbivudine, and tenofovir, although the preferred first-line treatment choices are peginterferon alfa-2a, entecavir, and tenofovir. In determining choice of therapy, considerations include efficacy, safety, rate of resistance, method of administration, duration, and cost.
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Affiliation(s)
- Paul Martin
- Division of Hepatology, University of Miami School of Medicine, Miami, Florida.
| | - Daryl T-Y Lau
- Liver Center, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, California
| | - Harry L A Janssen
- Toronto Centre for Liver Diseases, University Health Network, Toronto, Canada
| | | | - Marion G Peters
- Division of Gastroenterology, University of California, San Francisco, San Francisco, California
| | - Ira M Jacobson
- Department of Medicine, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, New York
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Huang SM, Cai WP, Hu FY, Lan Y, Liao BL, Chen YP, Tang XP. Epidemiological and clinical characteristics of hepatitis B virus in HIV-infected patients in Guangdong, China. Int J STD AIDS 2015; 27:890-7. [PMID: 26384940 DOI: 10.1177/0956462415600570] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2015] [Accepted: 07/20/2015] [Indexed: 01/04/2023]
Abstract
This study investigated the epidemiological and clinical characteristics of hepatitis B virus (HBV) in HIV-infected adults at the time of antiretroviral therapy (ART) initiation in Guangdong province, China. A total of 2793 HIV-infected adults were enrolled between January 2004 and September 2011. Demographic data and laboratory parameters were collected, HBV-DNA levels were measured, and HBV genotypes were identified before ART initiation. The prevalence of hepatitis B surface antigen (HBsAg) in HIV-infected patients was 13.2%. A total of 266 HIV/HBV co-infected patients and 1469 HIV mono-infected patients were recruited. The median alanine aminotransferase and aspartate aminotransferase levels of HIV/HBV co-infected patients were higher than HIV mono-infected patients (32 U/L vs. 22 U/L, p < 0.001 and 35 U/L vs. 24 U/L, p < 0.001, respectively), whereas the median CD4 cell count of HIV/HBV co-infected patients was lower than HIV mono-infected patients (59 cells/mm(3) vs. 141 cells/mm(3), p < 0.001). The level of CD4 cell count was lower in hepatitis B e-antigen (HBeAg)-positive co-infected patients than HBeAg-negative patients (36 cells/mm(3) vs. 69 cells/mm(3), p = 0.014). A similar result was found in high level of HBV-DNA and low level of HBV-DNA groups (33 cells/mm(3) vs. 89 cells/mm(3), p < 0.001). HBV genotypes were classified as genotypes B and C. Patients infected with genotypes B and C differed significantly in terms of proportion of those who were HBeAg-positive (40.5% vs. 62.2%, p = 0.014). This study indicates a high prevalence of HBsAg in HIV-infected adults in Guangdong. The level of CD4 cell count in HIV/HBV co-infected patients was much lower than HIV mono-infected patients, especially in patients who were HBeAg-positive and had a high level of HBV-DNA. The predominant HBV genotype in HIV/HBV co-infected patients is genotype B.
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Affiliation(s)
- S M Huang
- Department of Infectious Diseases, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - W P Cai
- Number Eight People's Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, China
| | - F Y Hu
- Number Eight People's Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, China
| | - Y Lan
- Number Eight People's Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, China
| | - B L Liao
- Number Eight People's Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, China
| | - Y P Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Jinan University, Guangzhou, China
| | - X P Tang
- Department of Infectious Diseases, The First Affiliated Hospital of Jinan University, Guangzhou, China Number Eight People's Hospital of Guangzhou, Guangzhou Medical University, Guangzhou, China
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Liu WC, Lin CP, Cheng CP, Ho CH, Lan KL, Cheng JH, Yen CJ, Cheng PN, Wu IC, Li IC, Chang BCH, Tseng VS, Chiu YC, Chang TT. Aligning to the sample-specific reference sequence to optimize the accuracy of next-generation sequencing analysis for hepatitis B virus. Hepatol Int 2015. [PMID: 26208819 PMCID: PMC4722079 DOI: 10.1007/s12072-015-9645-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background Hepatitis B virus (HBV) quasispecies are crucial in the pathogenesis of chronic liver disease. Next-generation sequencing (NGS) is powerful for identifying viral quasispecies. To improve mapping quality and single nucleotide variant (SNV) calling accuracy in the NGS analysis of HBV, we compared different mapping references, including the sample-specific reference sequence, same genotype sequences and different genotype sequences, according to the sample. Methods Real Illumina HBV datasets from 86 patients, and simulated datasets from 158 HBV strains in the GenBank database, were used to assess mapping quality. SNV calling accuracy was evaluated using different mapping references to align Real Illumina datasets from a single HBV clone. Results Using the sample-specific reference sequence as a mapping reference produced the largest number of mappable reads and coverages. With a different genotype mapping reference, the consensus sequence derived from the Real Illumina datasets of the single HBV clone showed 21 false SNV callings in polymerase and surface genes, the regions most divergent between the mapping reference and this HBV clone. A ~6 % coverage of most of these false SNVs was yielded even with a same genotype mapping reference, but none with the sample-specific reference sequence. Conclusions Using sample-specific reference sequences as a mapping reference in NGS analysis optimized mapping quality and the SNV calling accuracy for HBV quasispecies. Electronic supplementary material The online version of this article (doi:10.1007/s12072-015-9645-x) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Wen-Chun Liu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan. .,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan.
| | | | - Chun-Pei Cheng
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan, Taiwan.
| | - Cheng-Hsun Ho
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan. .,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan.
| | - Kuo-Lun Lan
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan, Taiwan.
| | - Ji-Hong Cheng
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan, Taiwan.
| | - Chia-Jui Yen
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan. .,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan.
| | - Pin-Nan Cheng
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan.
| | - I-Chin Wu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan. .,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan.
| | - I-Chen Li
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan.
| | | | - Vincent S Tseng
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan, Taiwan.
| | - Yen-Cheng Chiu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan. .,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan.
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng-Li Road, Tainan, 70403, Taiwan. .,Infectious Disease and Signaling Research Center, National Cheng Kung University, Tainan, Taiwan.
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Godon O, Evlachev A, Bourgine M, Meritet JF, Martin P, Inchauspe G, Michel ML. Recognition of core-derived epitopes from a novel HBV-targeted immunotherapeutic by T-cells from patients infected by different viral genotypes. Vaccine 2015. [PMID: 26209840 DOI: 10.1016/j.vaccine.2015.07.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Hepatitis B virus (HBV) infects millions of people worldwide and is a leading cause of liver cirrhosis and hepatocellular carcinoma. Current therapies based on nucleos(t)ide analogs or pegylated-interferon-α lead to control of viral replication in most patients but rarely achieve cure. A potential strategy to control chronic hepatitis B is to restore or induce functional anti-HBV T-cell immune responses using HBV-specific immunotherapeutics. However, viral diversity is a challenge to the development of this class of products as HBV genotypes display a sequence diversity of up to 8%. We have developed a novel HBV-targeted immunotherapeutic, TG1050, based on a non-replicative Adenovirus vector encoding a unique and large fusion protein composed of multiple antigenic regions derived from a HBV genotype D sequence. Using peripheral blood mononuclear cells from 23 patients chronically infected by five distinct genotypes (gt A, B, C, D and E) and various sets of peptides encompassing conserved versus divergent regions of HBV core we have measured ability of TG1050 genotype D core-derived peptides to be recognized by T-cells from patients infected by various genotypes. Overall, PBMCs from 78% of genotype B or C- and 100% genotype A or E-infected patients lead to detection of HBV core-specific T-cells recognizing genotype D antigenic domains located both in conserved and variable regions. This proof-of-concept study supports the clinical development of TG1050 in large patient populations independently of infecting genotypes.
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Affiliation(s)
- Ophelie Godon
- Laboratoire de Pathogenèse des virus de l'hépatite B, Département de Virologie, Institut Pasteur, 28, rue du Docteur Roux, Paris Cedex 15 75724, France
| | - Alexei Evlachev
- Transgene SA, Department of Infectious Diseases, Lyon, France
| | - Maryline Bourgine
- Laboratoire de Pathogenèse des virus de l'hépatite B, Département de Virologie, Institut Pasteur, 28, rue du Docteur Roux, Paris Cedex 15 75724, France
| | | | - Perrine Martin
- Transgene SA, Department of Infectious Diseases, Lyon, France
| | | | - Marie-Louise Michel
- Laboratoire de Pathogenèse des virus de l'hépatite B, Département de Virologie, Institut Pasteur, 28, rue du Docteur Roux, Paris Cedex 15 75724, France; INSERM U994, Département de Virologie, Institut Pasteur, Paris, France.
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Determinants of hepatitis B and delta virus host tropism. Curr Opin Virol 2015; 13:109-16. [PMID: 26164658 DOI: 10.1016/j.coviro.2015.06.004] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2015] [Accepted: 06/11/2015] [Indexed: 01/03/2023]
Abstract
Hepatitis B virus (HBV) infections are a global health problem afflicting approximately 360 million patients. Of these individuals, 15-20 million are co-infected with hepatitis delta virus (HDV). Progress toward curative therapies has been impeded by the highly restricted host tropism of HBV, which is limited to productive infections in humans and chimpanzees. Here, we will discuss different approaches that have been taken to study HBV and HDV infections in vivo. The development of transgenic and humanized mice has lead to deeper insights into HBV pathogenesis. An improved understanding of the determinants governing HBV and HDV species tropism will aid in the construction of a small animal model with inheritable susceptible to HBV/HDV.
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Amaddeo G, Cao Q, Ladeiro Y, Imbeaud S, Nault JC, Jaoui D, Gaston Mathe Y, Laurent C, Laurent A, Bioulac-Sage P, Calderaro J, Zucman-Rossi J. Integration of tumour and viral genomic characterizations in HBV-related hepatocellular carcinomas. Gut 2015; 64:820-9. [PMID: 25021421 PMCID: PMC4392232 DOI: 10.1136/gutjnl-2013-306228] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 05/14/2014] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Hepatocellular carcinoma (HCC) is the most common liver cancer. We characterised HCC associated with infection compared with non-HBV-related HCC to understand interactions between viral and hepatocyte genomic alterations and their relationships with clinical features. METHODS Frozen HBV (n=86) or non-HBV-related (n=90) HCC were collected in two French surgical departments. Viral characterisation was performed by sequencing HBS and HBX genes and quantifying HBV DNA and cccDNA. Nine genes were screened for somatic mutations and expression profiling of 37 genes involved in hepatocarcinogenesis was studied. RESULTS HBX revealed frequent non-sense, frameshift and deletions in tumours, suggesting an HBX inactivation selected in HCC. The number of viral copies was frequently lower in tumour than in non-tumour tissues (p=0.0005) and patients with low HBV copies in the non-tumour liver tissues presented additional risk factor (HCV, alcohol or non-alcoholic steato-hepatitis, p=0.006). P53 was the most frequently altered pathway in HBV-related HCC (47%, p=0.001). Furthermore, TP53 mutations were associated with shorter survival only in HBV-related HCC (p=0.02) whereas R249S mutations were identified exclusively in migrants. Compared with other aetiologies, HBV-HCC were more frequently classified in tumours subgroups with upregulation of genes involved in cell-cycle regulation and a progenitor phenotype. Finally, in HBV-related HCC, transcriptomic profiles were associated with specific gene mutations (HBX, TP53, IRF2, AXIN1 and CTNNB1). CONCLUSIONS Integrated genomic characterisation of HBV and non-HBV-related HCC emphasised the immense molecular diversity of HCC closely related to aetiologies that could impact clinical care of HCC patients.
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Affiliation(s)
- Giuliana Amaddeo
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Qian Cao
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Yannick Ladeiro
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Sandrine Imbeaud
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | - Jean-Charles Nault
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France
| | | | | | | | - Alexis Laurent
- Assistance Publique-Hôpitaux de Paris, digestive, hepatobiliary and liver transplantation, CHU Henri Mondor, Créteil, France,IMRB—Inserm U955 Equipe n. 18 “Virologie moleculaire et immunologie –Physiopathologie et therapeutique des Hépatites virales chroniques”, Créteil, France
| | - Paulette Bioulac-Sage
- Inserm, UMR-1053; Université Victor Segalen Bordeaux 2, Bordeaux, France,Department of Pathology, CHU de Bordeaux, Pellegrin Hospital, Bordeaux, France
| | - Julien Calderaro
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France,Department of Pathology, CHU Henri Mondor, Créteil, France
| | - Jessica Zucman-Rossi
- Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, Paris, France,Université Paris Descartes, Labex Immuno-oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France,Hopital Europeen Georges Pompidou, Paris, France
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Zhand S, Karami C, Hosseinzadeh Adli A, Tabarraei A, Khodabakhshi B, Moradi A. Correlation Between Hepatitis B G1896A Precore Mutations and HBeAg in Chronic HBV Patients. Jundishapur J Microbiol 2015; 8:e17126. [PMID: 25825644 PMCID: PMC4376977 DOI: 10.5812/jjm.17126] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Revised: 07/14/2014] [Accepted: 09/27/2014] [Indexed: 02/06/2023] Open
Abstract
Background: Hepatitis B virus (HBV) infection is an important health concern worldwide, with critical outcomes. Hepatitis B e antigen (HBeAg) negative chronic hepatitis B is frequently caused by a mutation (G1896A) in the hepatitis B virus (HBV) precore (PC) reading frame, which creates a stop codon, causing premature termination of the HBe protein. Objectives: This study aimed to investigate the G1896A PC mutation and its effect on HBeAg detection in chronic HBV patients. Patients and Methods: In this study, 120 chronic HBV patients neither vaccinated or who had benefited from immunoglobulin therapy, were recruited. The HBV-DNA was extracted from plasma and polymerase chain reaction (PCR) was performed. Positive PCR products were subjected to automated sequencing. The HBV serological markers [hepatitis B s antigen (HBsAg), HBeAg] were tested. Results: One hundred out of 120 (83.3%) patients were HBeAg negative and 100% were HBsAg positive. The comparison of nucleotide sequences with the reference sequence (Accession number: AB033559) in HBeAg negative patients showed that there was a high rate of mutations in G1896A (93.18%). Conclusions: This study indicates that the rate of G1896A mutation at the PC region among HBeAg negative patients, in the Golestan province of Iran, was similar to the average rate encountered in other parts of Iran. The PC stop codon mutation was detected in 93.18% of HBeAg negative patients. Further studies with larger sample sizes are required to elucidate the exact role of these mutations in the clinical course of chronic HBV infection.
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Affiliation(s)
- Sareh Zhand
- Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, IR Iran
| | - Chiman Karami
- Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, IR Iran
| | - Ahmad Hosseinzadeh Adli
- Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, IR Iran
| | - Alijan Tabarraei
- Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, IR Iran
| | - Behnaz Khodabakhshi
- Infectious Diseases Research Centre, Golestan University of Medical Sciences, Gorgan, IR Iran
| | - Abdolvahab Moradi
- Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, IR Iran
- Corresponding author: Abdolvahab Moradi, Department of Microbiology, School of Medicine, Golestan University of Medical Sciences, Gorgan, IR Iran. Tel: +98-9111772107, Fax: + 98-1714440225, E-mail:
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Datta S, Roychoudhury S, Ghosh A, Dasgupta D, Ghosh A, Chakraborty B, Roy S, Gupta S, Santra AK, Datta S, Das K, Dhali GK, Chowdhury A, Banerjee S. Distinct distribution pattern of hepatitis B virus genotype C and D in liver tissue and serum of dual genotype infected liver cirrhosis and hepatocellular carcinoma patients. PLoS One 2014; 9:e102573. [PMID: 25032957 PMCID: PMC4102524 DOI: 10.1371/journal.pone.0102573] [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: 04/24/2014] [Accepted: 06/20/2014] [Indexed: 12/27/2022] Open
Abstract
Aims The impact of co-infection of several hepatitis B virus (HBV) genotypes on the clinical outcome remains controversial. This study has for the first time investigated the distribution of HBV genotypes in the serum and in the intrahepatic tissue of liver cirrhotic (LC) and hepatocellular carcinoma (HCC) patients from India. In addition, the genotype-genotype interplay and plausible mechanism of development of HCC has also been explored. Methods The assessment of HBV genotypes was performed by nested PCR using either surface or HBx specific primers from both the circulating virus in the serum and replicative virus that includes covalently closed circular DNA (cccDNA) and relaxed circular DNA (rcDNA) of HBV from the intrahepatic tissue. The integrated virus within the host chromosome was genotyped by Alu-PCR method. Each PCR products were cloned and sequences of five randomly selected clones were subsequently analysed. Results HBV/genotype D was detected in the serum of all LC and HCC patients whereas the sequences of the replicative HBV DNA (cccDNA and rcDNA) from the intrahepatic tissue of the same patients revealed the presence of both HBV/genotype C and D. The sequences of the integrated viruses exhibited the solo presence of HBV/genotype C in the majority of LC and HCC tissues while both HBV/genotype C and D clones were found in few patients in which HBV/genotype C was predominated. Moreover, compared to HBV/genotype D, genotype C had higher propensity to generate double strand breaks, ER stress and reactive oxygen species and it had also showed higher cellular homologous-recombination efficiency that engendered more chromosomal rearrangements, which ultimately led to development of HCC. Conclusions Our study highlights the necessity of routine analysis of HBV genotype from the liver tissue of each chronic HBV infected patient in clinical practice to understand the disease prognosis and also to select therapeutic strategy.
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MESH Headings
- Adult
- Base Sequence
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/virology
- Cell Line, Tumor
- Coinfection
- DNA Breaks, Double-Stranded
- DNA, Circular/blood
- DNA, Circular/genetics
- DNA, Viral/blood
- DNA, Viral/genetics
- Genotype
- Hep G2 Cells
- Hepatitis B e Antigens/blood
- Hepatitis B e Antigens/immunology
- Hepatitis B virus/classification
- Hepatitis B virus/genetics
- Hepatitis B, Chronic/genetics
- Hepatitis B, Chronic/virology
- Humans
- India
- Liver/pathology
- Liver/virology
- Liver Cirrhosis/mortality
- Liver Cirrhosis/pathology
- Liver Cirrhosis/virology
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- Liver Neoplasms/virology
- Liver Transplantation
- Male
- Middle Aged
- Molecular Sequence Data
- Prognosis
- Reactive Oxygen Species/metabolism
- Sequence Alignment
- Sequence Analysis, DNA
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Affiliation(s)
- Somenath Datta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Shrabasti Roychoudhury
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Alip Ghosh
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Debanjali Dasgupta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Amit Ghosh
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Bidhan Chakraborty
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Sukanta Roy
- Department of Gastro-Intestinal surgery, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Subash Gupta
- Centre for Liver and Biliary Surgery, Indraprastha Apollo Hospital, New Delhi, India
| | - Amal Kumar Santra
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Simanti Datta
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Kausik Das
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Gopal Krishna Dhali
- Department Gastroenterology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Abhijit Chowdhury
- Department of Hepatology, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Soma Banerjee
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
- * E-mail:
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Sagnelli C, Ciccozzi M, Pisaturo M, Zehender G, Lo Presti A, Alessio L, Starace M, Lovero D, Sagnelli E, Coppola N. Molecular epidemiology of hepatitis B virus genotypes circulating in acute hepatitis B patients in the Campania region. J Med Virol 2014; 86:1683-93. [PMID: 24980631 DOI: 10.1002/jmv.24005] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2014] [Indexed: 12/11/2022]
Abstract
Fifty-three HBV-DNA-positive patients with symptomatic acute hepatitis B were enrolled from 1999 to 2010 to evaluate molecular and phylogenetic changes in HBV in southern Italy. HBV polymerase region was evaluated by direct sequencing in plasma samples obtained at first observation. Different data sets were aligned and a phylogenetic tree was inferred using PhyML program. Statistical robustness was confirmed with a bootstrap analysis. A Bayesian Markov chain Monte Carlo method and a Bayesian skyline plot were used to estimate the evolution of our samples. The dN/dS rate (ω) was estimated by the maximum likelihood approach to investigate the presence of codons under positive selection. The MacClade program was used to test viral gene out/in flow only among HBV-D3 subgenotype patients with different risk factors. Of the 53 patients, 83% were born in Italy and 17% were foreigners. HBV genotype D was prevalent (64.1%), followed by genotype A (26.4%), E (3.8%), and F (5.7%). The prevalent subgenotype was D3 (70.6%). The Bayesian tree of the 24 D3 subgenotypes showed two main clades both dated 1994; 40% of viral gene flow observed was from intravenous drugs users and heterosexual patients. Phylogenetic analysis of HBV isolates showed that HBV-D3 remains the prevalent genotype, but also subgenotype A2 has become frequent in southern Italy. This may be of clinical relevance in years to come, since patients with HBV-genotype-A chronic infection less frequently than those with genotype D develop HBeAg-negative chronic hepatitis and respond more frequently to alfa-interferon treatment.
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Affiliation(s)
- Caterina Sagnelli
- Department of Clinical and Experimental Medicine and Surgery "F. Magrassi e A. Lanzara", Second University of Naples, Naples, Italy
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Aljarbou AN. The Emergent Concern of Hepatitis B globally with special attention to Kingdom of Saudi Arabia. Int J Health Sci (Qassim) 2014; 7:333-40. [PMID: 24533027 DOI: 10.12816/0006062] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Chronic viral hepatitis is highly prevalent and creates a substantial burden to healthcare systems globally. The World Health Organization (WHO) estimates that over 350 and 250 million people worldwide are chronic carrier of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection respectively. These two diseases are the cause of significant global mortality and morbidity with approximately 1 million deaths each year attributable to them and their sequelae, liver disease and primary liver cancer. Although the efforts have been met with the long-lasting level of success and holds the promise for large reductions in disease burden in spite of the huge numbers of HBV infected population. The viral hepatitis has also been emerged as a leading public health concern and continues to be major disease burden in the Eastern Mediterranean. The WHO, estimates that approximately 4.3 million persons are infected with HBV in the Region each year. Saudi Arabia has been classified as a country with an intermediate prevalence of HBV showed up to 7% in Saudi children in late 1980s but declined to as low as 0.3% in 1997 since the introduction of universal vaccination of all Saudi children in 1989. In spite of this remarkable decline, the burden of decompensated liver disease secondary to hepatitis B is estimated to increase drastically in the next 40 years as the previously infected children start aging.
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Affiliation(s)
- Ahmad N Aljarbou
- Department of Pharmaceutics, College of Pharmacy, Qassim University, Buraidah, Saudi Arabia
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Wang YZ, Zhu Z, Zhang HY, Zhu MZ, Xu X, Chen CH, Liu LG. Detection of hepatitis B virus A1762T/G1764A mutant by amplification refractory mutation system. Braz J Infect Dis 2014; 18:261-5. [PMID: 24389280 PMCID: PMC9427444 DOI: 10.1016/j.bjid.2013.09.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Revised: 08/03/2013] [Accepted: 09/11/2013] [Indexed: 01/25/2023] Open
Affiliation(s)
- Yong-Zhong Wang
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, China
| | - Zhen Zhu
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, China
| | - Hong-Yu Zhang
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, China
| | - Min-Zhi Zhu
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, China
| | - Xin Xu
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, China
| | - Chun-Hua Chen
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, China
| | - Long-Gen Liu
- Institute for the Study of Liver Diseases, The Third People's Hospital of Changzhou, Changzhou, China.
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Karimi A, Salimzadeh L, Bagheri N. Hepatitis B virus genotyping among chronic hepatitis B individuals with resistance to Lamivudine in shahrekord, iran. Jundishapur J Microbiol 2014; 7:e10196. [PMID: 25147693 PMCID: PMC4138629 DOI: 10.5812/jjm.10196] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 05/05/2013] [Accepted: 05/11/2013] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Hepatitis B infection, caused by hepatitis B Virus (HBV), is one of the major global public health problems. Hepatitis B Virus genotypes appear to show varying geographic distribution with possible pathogenic and therapeutic differences. Knowledge of HBV genotypes is very important for clinical treatment. Lamivudine is a nucleoside analogue that is clinically used to treat chronic hepatitis B infection. However, the main problem with the application of lamivudine is the development of viral resistance to the treatment with this anti viral drug. Besides, it has been suggested that lamivudine -resistant HBV may be genotype dependent. However, HBV genotype distribution and the biological relevance in this region are poorly understood. OBJECTIVES The current study aimed to determine hepatitis B genotypes and their correlation with lamivudine- resistant HBV frequency among patients with chronic hepatitis B from Shahrekord, Iran. METHODS AND MATERIALS Hepatitis B virus DNA was detected by conventional PCR in some of the serum samples obtained from HBsAg-positive Chronic Hepatitis B (CHB) patients who were referred to Health Centers of Shahrekord for routine monitoring of the disease. Subsequently, using real-time PCR, the DNA samples were used for genotyping and analysis of resistance to lamivudine. RESULTS The DNA was detected in 23 out of 116 (19.82%) of the studied samples. Genotypes D and C were found in 17 out of 23 (73.9%), and in 6 out of 23 (26.1%) of the samples, respectively. To the authors' best knowledge, the current study is the first report on isolation of Genotype C from Iran. Two out of 17 (11.76%), and 6 out of 6 (100%) of genotypes D and C were resistant to lamivudine, respectively. Resistance to this drug was significantly different between genotypes C and D (P <0.001). CONCLUSIONS In addition to genotype D, other lamivudine resistant hepatitis B genotypes might be distributed in Iran.
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Affiliation(s)
- Ali Karimi
- Medicinal Plant Research Center, Shahrekord University of Medical Sciences, Shahrekord, IR Iran
| | - Loghman Salimzadeh
- Medicinal Plant Research Center, Shahrekord University of Medical Sciences, Shahrekord, IR Iran
- Corresponding author: Loghman Salimzadeh, Medicinal Plant Research Center, Shahrekord University of Medical Sciences, Shahrekord, IR Iran. Tel:+98-3813334691, Fax:+98-3813334911, E-mail:
| | - Nader Bagheri
- Department of Immunology, School of Public Health, Tehran University of Medical Sciences, Tehran, IR Iran
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Tuteja A, Siddiqui AB, Madan K, Goyal R, Shalimar, Sreenivas V, Kaur N, Panda SK, Narayanasamy K, Subodh S, Acharya SK. Mutation profiling of the hepatitis B virus strains circulating in North Indian population. PLoS One 2014; 9:e91150. [PMID: 24637457 PMCID: PMC3956465 DOI: 10.1371/journal.pone.0091150] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 02/07/2014] [Indexed: 12/11/2022] Open
Abstract
AIMS The aim of this study was to investigate the genomic mutations in the circulating Hepatitis B virus strains causing infection in the Indian population. Further, we wanted to analyze the biological significance of these mutations in HBV mediated disease. METHODS 222 HBsAg positive patients were enrolled in the study. The genotype and mutation profile was determined for the infecting HBV isolate by sequencing overlapping fragments. These sequences were analyzed by using different tools and compared with previously available HBV sequence information. Mutation Frequency Index (MFI) for the Genes and Diagnosis group was also calculated. RESULTS HBV Genotype D was found in 55% (n = 121) of the patient group and genotype A was found in 30% (n = 66) of samples. The majority (52%) of the HBV-infected individuals in the present study were HBeAg-negative in all the age groups studied. Spontaneous drug associated mutations implicated in resistance to antiviral therapy were also identified in about quarter of our patients, which is of therapeutic concern. The MFI approach used in the study indicated that Core peptide was the most conserved region in both genotypes and Surface peptide had highest mutation frequency. Few mutations in X gene (T36A and G50R) showed high frequency of association with HCC. A rare recombinant strain of HBV genotype A and D was also identified in the patient group. CONCLUSIONS HBV genotype D was found out to be most prevalent. More than half of the patients studied had HBeAg negative disease. Core region was found to be most conserved. Drug Associated mutations were detected in 22% of the patient group and T36A and G50R mutations in X gene were found to be associated with HCC.
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Affiliation(s)
- Amit Tuteja
- Institute of Molecular Medicine, New Delhi, India
- Amity Institute of Biotechnology, Amity University, Noida, India
| | | | - Kaushal Madan
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Rohit Goyal
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | - Shalimar
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Navkiran Kaur
- Amity Institute of Biotechnology, Amity University, Noida, India
| | - Subrat K. Panda
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Swati Subodh
- Institute of Molecular Medicine, New Delhi, India
- Open Source Drug Discovery Unit, Council of Scientific & Industrial Research, New Delhi, India
| | - Subrat K. Acharya
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
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Morrison EA, Garner S, Echaubard P, Lesbarrères D, Kyle CJ, Brunetti CR. Complete genome analysis of a frog virus 3 (FV3) isolate and sequence comparison with isolates of differing levels of virulence. Virol J 2014; 11:46. [PMID: 24620832 PMCID: PMC3995667 DOI: 10.1186/1743-422x-11-46] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 03/06/2014] [Indexed: 01/05/2023] Open
Abstract
Background Frog virus 3 (FV3) is the type species of the genus Ranavirus, and in the past few decades, FV3 infections have resulted in considerable morbidity and mortality in a range of wild and cultivated amphibian species in the Americas, Europe, and Asia. The reasons for the pathogenicity of FV3 are not well understood. Findings We investigated three FV3 isolates designated SSME, wt-FV3, and aza-Cr, and reported that our wt-FV3 and aza-Cr strains showed similar levels of virulence, while SSME was the least virulent in an in vivo study with Lithiobates pipiens tadpoles. Using 454 GS-FLX sequencing technology, we sequenced SSME and compared it to the published wt-FV3 genome. SSME had multiple amino acid deletions in ORFs 49/50L, 65L, 66L, and 87L, which may explain its reduced virulence. We also investigated repeat regions and found that repeat copy number differed between isolates, with only one group of 3 isolates and 1 pair of isolates being identical at all 3 locations. Conclusions In this study we have shown that genetic variability is present between closely related FV3 isolates, both in terms of deletions/insertions, and even more so at select repeat locations. These genomic areas with deletions/insertions may represent regions that affect virulence, and therefore require investigation. Furthermore, we have identified repeat regions that may prove useful in future phylogeographical tracking and identification of ranaviral strains across different environmental regions.
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Affiliation(s)
| | | | | | | | | | - Craig R Brunetti
- Department of Biology, Trent University, 1600 East Bank Dr,, Peterborough, Ontario K9J 7B8, Canada.
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Clinical implications of evolutionary patterns of homologous, full-length hepatitis B virus quasispecies in different hosts after perinatal infection. J Clin Microbiol 2014; 52:1556-65. [PMID: 24574300 DOI: 10.1128/jcm.03338-13] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection via perinatal transmission is common in the Asia-Pacific region, but related quasispecies (QS) characteristics are not yet defined. To investigate the homologous, full-length HBV QS after perinatal infection and their clinical implications, five pairs of mother-daughter patients with chronic HBV infection (one patient with liver cirrhosis, one with immune tolerance, and eight with chronic hepatitis) were included. Full-length HBV were amplified by PCR from serum samples before antiviral treatment and cloned; an average of 17 clones per sample were sequenced, and the QS complexities, diversities, and evolution patterns were analyzed. Full-length HBV sequence similarities within mother-daughter pairs were 91.3 to 98.3%. The QS complexities of full-length HBV were similar between mothers and daughters (median of 0.9734 compared to 0.9688, P>0.05), as were the diversities (median of 3.396×10(-3) compared to 4.617×10(-3) substitutions/site, P>0.05). However, the distribution patterns of QS complexities and diversities within specific genes were different, and QS genetic distances of the mothers were higher than those of daughters, both more evident in pairs with different antiviral responses and different immune phases or stages. The nucleotide substitution rate of full-length HBV was 14.388×10(-5) substitutions/site/year, whereas the preC/C gene rate was the highest. Mutations and indels were more common in clones from the mothers, which decreased the affinity of epitopes by 6- to 89-fold. The various genes from homologous HBV genomes evolved in different patterns despite numerically comparable full-length QS complexities and diversities. The different patterns may correlate with the immune stages of chronic HBV infection, which warrants further study.
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Homs M, Caballero A, Gregori J, Tabernero D, Quer J, Nieto L, Esteban R, Buti M, Rodriguez-Frias F. Clinical application of estimating hepatitis B virus quasispecies complexity by massive sequencing: correlation between natural evolution and on-treatment evolution. PLoS One 2014; 9:e112306. [PMID: 25393280 PMCID: PMC4231103 DOI: 10.1371/journal.pone.0112306] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 10/14/2014] [Indexed: 02/07/2023] Open
Abstract
AIM To evaluate HBV quasispecies (QA) complexity in the preCore/Core regions in relation to HBeAg status, and explore QA changes under natural evolution and nucleoside analogue (NUC) treatment. METHODS Ultra-deep pyrosequencing of HBV preCore/Core regions in 30 sequential samples (baseline [diagnosis], treatment-free, and treatment-nonresponse) from 10 retrospectively selected patients grouped according to HBeAg status over time: HBeAg+ (N = 4), HBeAg- (N = 2), and fluctuating HBeAg (transient seroreversion/seroconversion pattern) (N = 4). QA complexity was defined by Shannon entropy, mutation frequency, nucleotide diversity, and mutation frequency of amino acids (MfAA) in preCore and Core. RESULTS The QA was less complex in HBeAg+ than in HBeAg- or fluctuating HBeAg. High complexity in preCore was associated with decreased viral replication (preCore MfAA negatively correlated with HBV-DNA, p = 0.005). QA complexity in the treatment-free period negatively correlated with values seen during treatment. Specific variants were mainly selected in the Core region in HBeAg- and fluctuating HBeAg patients, suggesting higher immune pressure than in HBeAg+. CONCLUSIONS The negative correlation between QA natural evolution and on-treatment evolution indicates the importance of pre-treatment QA study to predict QA changes in NUC nonresponders. Study of QA complexity could be useful for managing HBV infection.
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Affiliation(s)
- Maria Homs
- Centro de investigación biomédica en red: enfermedades hepáticas y digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
- Virology Unit, Department of Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Andrea Caballero
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Josep Gregori
- Centro de investigación biomédica en red: enfermedades hepáticas y digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Diseases, Research Institute Hospital Vall d'Hebron, Barcelona, Spain
| | - David Tabernero
- Centro de investigación biomédica en red: enfermedades hepáticas y digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
- Virology Unit, Department of Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Josep Quer
- Centro de investigación biomédica en red: enfermedades hepáticas y digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Diseases, Research Institute Hospital Vall d'Hebron, Barcelona, Spain
| | - Leonardo Nieto
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
- Virology Unit, Department of Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Rafael Esteban
- Centro de investigación biomédica en red: enfermedades hepáticas y digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Maria Buti
- Centro de investigación biomédica en red: enfermedades hepáticas y digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Unit, Department of Internal Medicine, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Francisco Rodriguez-Frias
- Centro de investigación biomédica en red: enfermedades hepáticas y digestivas (CIBERehd), Instituto de Salud Carlos III, Barcelona, Spain
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
- Virology Unit, Department of Microbiology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
- * E-mail:
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Kim H, Kim BJ. Naturally Occurring Mutations of Hepatitis B virus and Hepatitis C Virus in Korean Chronic Patients by Distinct CD4 T Cell Responses. JOURNAL OF BACTERIOLOGY AND VIROLOGY 2014; 44:37. [DOI: 10.4167/jbv.2014.44.1.37] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Affiliation(s)
- Hong Kim
- Department of Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - Bum-Joon Kim
- Department of Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea
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Zingaretti C, De Francesco R, Abrignani S. Why is it so difficult to develop a hepatitis C virus preventive vaccine? Clin Microbiol Infect 2013; 20 Suppl 5:103-9. [PMID: 24829939 DOI: 10.1111/1469-0691.12493] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
With an estimated 3% of the world's population chronically infected, hepatitis C virus (HCV) represents a major health problem for which an efficient vaccination strategy would be highly desirable. Indeed, chronic hepatitis C is recognized as one of the major causes of cirrhosis, hepatocarcinoma and liver failure worldwide and it is the most common indication for liver transplantation, accounting for 40-50% of liver transplants. Much progress has been made in the prevention of HCV transmission and in therapeutic intervention. However, even if a new wave of directly acting antivirals promise to overcome the problems of low efficacy and adverse effects observed for the current standard of care, which include interferon-α and ribavirin, an effective vaccine would be the only means to definitively eradicate infection and to diminish the burden of HCV-related diseases at affordable costs. Although there is strong evidence that the goal of a prophylactic vaccine could be achieved, there are huge development issues that have impeded reaching this goal and that still have to be addressed. In this article we address the question of whether an HCV vaccine is needed, whether it will eventually be feasible, and why it is so difficult to produce.
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Bertoletti A, Gehring AJ. Immune therapeutic strategies in chronic hepatitis B virus infection: virus or inflammation control? PLoS Pathog 2013; 9:e1003784. [PMID: 24367255 PMCID: PMC3868509 DOI: 10.1371/journal.ppat.1003784] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Antonio Bertoletti
- Program in Emerging Viral Diseases, Duke-NUS Graduate Medical School, Singapore
- Viral Hepatitis Unit, Singapore Institute for Clinical Sciences, Agency for Science, Technology and Research (A*Star), Singapore
- * E-mail:
| | - Adam J. Gehring
- Molecular Microbiology and Immunology Department, Saint Louis University School of Medicine, St. Louis, Missouri, United States of America
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