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Sukowati CHC, Jayanti S, Turyadi T, Muljono DH, Tiribelli C. Hepatitis B virus genotypes in precision medicine of hepatitis B-related hepatocellular carcinoma: Where we are now. World J Gastrointest Oncol 2024; 16:1097-1103. [PMID: 38660644 PMCID: PMC11037070 DOI: 10.4251/wjgo.v16.i4.1097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 01/30/2024] [Accepted: 03/06/2024] [Indexed: 04/10/2024] Open
Abstract
Hepatitis B virus (HBV) infection is a major player in chronic hepatitis B that may lead to the development of hepatocellular carcinoma (HCC). HBV genetics are diverse where it is classified into at least 9 genotypes (A to I) and 1 putative genotype (J), each with specific geographical distribution and possible different clinical outcomes in the patient. This diversity may be associated with the precision medicine for HBV-related HCC and the success of therapeutical approaches against HCC, related to different pathogenicity of the virus and host response. This Editorial discusses recent updates on whether the classification of HBV genetic diversity is still valid in terms of viral oncogenicity to the HCC and its precision medicine, in addition to the recent advances in cellular and molecular biology technologies.
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Affiliation(s)
- Caecilia H C Sukowati
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia, Jakarta 10340, Indonesia
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
| | - Sri Jayanti
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia, Jakarta 10340, Indonesia
| | - Turyadi Turyadi
- Eijkman Research Center for Molecular Biology, Research Organization for Health, National Research and Innovation Agency of Indonesia, Jakarta 10340, Indonesia
| | - David H Muljono
- Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
- Faculty of Medicine and Health, University of Sydney, Sydney 2050, Australia
| | - Claudio Tiribelli
- Liver Cancer Unit, Fondazione Italiana Fegato ONLUS, Trieste 34149, Italy
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Sun B, Andrades Valtueña A, Kocher A, Gao S, Li C, Fu S, Zhang F, Ma P, Yang X, Qiu Y, Zhang Q, Ma J, Chen S, Xiao X, Damchaabadgar S, Li F, Kovalev A, Hu C, Chen X, Wang L, Li W, Zhou Y, Zhu H, Krause J, Herbig A, Cui Y. Origin and dispersal history of Hepatitis B virus in Eastern Eurasia. Nat Commun 2024; 15:2951. [PMID: 38580660 PMCID: PMC10997587 DOI: 10.1038/s41467-024-47358-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 03/28/2024] [Indexed: 04/07/2024] Open
Abstract
Hepatitis B virus is a globally distributed pathogen and the history of HBV infection in humans predates 10000 years. However, long-term evolutionary history of HBV in Eastern Eurasia remains elusive. We present 34 ancient HBV genomes dating between approximately 5000 to 400 years ago sourced from 17 sites across Eastern Eurasia. Ten sequences have full coverage, and only two sequences have less than 50% coverage. Our results suggest a potential origin of genotypes B and D in Eastern Asia. We observed a higher level of HBV diversity within Eastern Eurasia compared to Western Eurasia between 5000 and 3000 years ago, characterized by the presence of five different genotypes (A, B, C, D, WENBA), underscoring the significance of human migrations and interactions in the spread of HBV. Our results suggest the possibility of a transition from non-recombinant subgenotypes (B1, B5) to recombinant subgenotypes (B2 - B4). This suggests a shift in epidemiological dynamics within Eastern Eurasia over time. Here, our study elucidates the regional origins of prevalent genotypes and shifts in viral subgenotypes over centuries.
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Affiliation(s)
- Bing Sun
- School of Life Sciences, Jilin University, Changchun, 130012, China
| | - Aida Andrades Valtueña
- Department of Archaeogenetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, 04103, Germany
| | - Arthur Kocher
- Department of Archaeogenetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, 04103, Germany
- Transmission, Infection, Diversification and Evolution Group, Max Planck Institute for the Science of Human History, Jena, 07745, Germany
| | - Shizhu Gao
- School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, China
| | - Chunxiang Li
- School of Life Sciences, Jilin University, Changchun, 130012, China
| | - Shuang Fu
- School of Life Sciences, Jilin University, Changchun, 130012, China
| | - Fan Zhang
- School of Life Sciences, Jilin University, Changchun, 130012, China
| | - Pengcheng Ma
- School of Life Sciences, Jilin University, Changchun, 130012, China
| | - Xuan Yang
- School of Life Sciences, Jilin University, Changchun, 130012, China
| | - Yulan Qiu
- School of Life Sciences, Jilin University, Changchun, 130012, China
| | - Quanchao Zhang
- School of archaeology, Jilin University, Changchun, 130021, China
| | - Jian Ma
- School of Cultural Heritage, Northwest University, Xi'an, 710069, China
| | - Shan Chen
- School of Archaeology and Museology, Liaoning University, Shenyang, 110136, China
| | - Xiaoming Xiao
- School of Archaeology and Museology, Liaoning University, Shenyang, 110136, China
| | | | - Fajun Li
- School of Sociology and Anthropology, Sun Yat-sen University, Guangzhou, 510275, China
| | - Alexey Kovalev
- Department of archaeological heritage preservation, Institute of Archaeology of Russian Academy of Sciences, Moscow, 117292, Russia
| | - Chunbai Hu
- Institute of Cultural Relics and Archaeology, Inner Mongolia Autonomous Region, Hohhot, 010010, China
| | - Xianglong Chen
- Institute of Archaeology, Chinese Academy of Social Sciences, Beijing, 100101, China
| | - Lixin Wang
- Research Center for Chinese Frontier Archaeology of Jilin University, Jilin University, Changchun, 130012, China
| | - Wenying Li
- Xinjiang Institute of Cultural Relics and Archaeology, Ürümqi, 830011, China
| | - Yawei Zhou
- School of History, Zhengzhou University, Zhengzhou, 450066, China
| | - Hong Zhu
- Research Center for Chinese Frontier Archaeology of Jilin University, Jilin University, Changchun, 130012, China
| | - Johannes Krause
- Department of Archaeogenetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, 04103, Germany.
| | - Alexander Herbig
- Department of Archaeogenetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, 04103, Germany.
| | - Yinqiu Cui
- School of Life Sciences, Jilin University, Changchun, 130012, China.
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Hanson J, Radlof S, Littlejohn M, Hempenstall A, Edwards R, Nakata Y, Gregson S, Hayes R, Smith S, McKinnon M, Binks P, Tong SYC, Davies J, Davis JS. Hepatitis B genotypes in Aboriginal and Torres Strait Islander Australians: correlation with clinical course and implications for management. Intern Med J 2024; 54:647-656. [PMID: 37548345 DOI: 10.1111/imj.16181] [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: 12/15/2022] [Accepted: 07/09/2023] [Indexed: 08/08/2023]
Abstract
BACKGROUND The prevalence of chronic hepatitis B (CHB) in Aboriginal and Torres Strait Islander Australians in Far North Queensland (FNQ) is greater than twice that of the general Australian population. CHB is common in Torres Strait Islanders diagnosed with hepatocellular carcinoma (HCC) - and in Aboriginals with HCC living in the Northern Territory - however, Aboriginals diagnosed with HCC in FNQ very rarely have CHB. The explanation for this apparent disparity is uncertain. AIMS To determine the HBV genotypes in the FNQ Aboriginal and Torres Strait Islander population and their correlation with clinical phenotype. METHODS We determined the HBV genotype of Aboriginal and Torres Strait Islander Australians living with CHB in FNQ and correlated this with demographic and clinical findings. RESULTS 134/197 (68%) enrolled individuals had a sufficient viral load for genotyping. All 40 people with HBV/D genotype had Aboriginal heritage, whereas 85/93 (91%) with HBV/C had Torres Strait Islander heritage (P < 0.0001). Individuals with HBV/D were younger than those with HBV/C (median (interquartile range) age: 43 (39-48) vs 53 (42-66) years, P = 0.0002). However, they were less likely to be HBeAg positive (1/40 (3%) vs 23/93 (25%), P = 0.001). All three HCCs developed in Torres Strait Islanders; two-thirds were infected with HBV/C14; genotyping was not possible in the other individual. All 10 diagnoses of cirrhosis occurred in Torres Strait Islanders, 6/10 were infected with HBV/C14, genotyping was not possible in the other four individuals. CONCLUSIONS HBV genotypes in Aboriginal and Torres Strait Islander Australians in FNQ differ markedly, which could explain the significant differences in the clinical phenotype in the two populations and might be used to inform cost-effective CHB care in the region.
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Affiliation(s)
- Josh Hanson
- Cairns and Hinterland Hospital and Health Service, Cairns, Queensland, Australia
- The Kirby Institute, UNSW, Sydney, New South Wales, Australia
- Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
| | - Sharna Radlof
- Cairns and Hinterland Hospital and Health Service, Cairns, Queensland, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Melbourne, Victoria, Australia
- Department of Infectious Diseases, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | | | - Ros Edwards
- Victorian Infectious Diseases Reference Laboratory, Melbourne, Victoria, Australia
| | - Yoko Nakata
- Torres and Cape Health and Hospital Service, Cairns, Queensland, Australia
| | - Sandra Gregson
- Torres and Cape Health and Hospital Service, Cairns, Queensland, Australia
| | - Richard Hayes
- Torres and Cape Health and Hospital Service, Cairns, Queensland, Australia
| | - Simon Smith
- Cairns and Hinterland Hospital and Health Service, Cairns, Queensland, Australia
| | - Melita McKinnon
- Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
| | - Paula Binks
- Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
| | - Steven Y C Tong
- Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
- Department of Infectious Diseases, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
- Victorian Infectious Diseases Service, The Royal Melbourne Hospital, at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
| | - Jane Davies
- Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
| | - Joshua S Davis
- Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia
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Sirilert S, Khamrin P, Kumthip K, Malasao R, Tongsong T, Maneekarn N. Hepatitis B virus genotypes associated with pregnant women in Northern Thailand. J Infect Public Health 2024; 17:406-411. [PMID: 38262076 DOI: 10.1016/j.jiph.2023.12.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 12/17/2023] [Accepted: 12/26/2023] [Indexed: 01/25/2024] Open
Abstract
BACKGROUND Mother-to-child transmission of hepatitis B virus (HBV) is the major route of transmission causing persistent infection. The prevalence of HBV infection and HBV genotypes found in different geographical areas varies from country to country. Therefore, this study was conducted to identify the HBV genotypes in HBV-infected pregnant women in Northern Thailand. METHODS Stored blood samples that were collected from 145 HBsAg-positive pregnant women who gave birth at Maharaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand from 2017 to 2020 were analyzed. The partial nucleotide sequence of the S gene of HBV was amplified by nested PCR and sequenced. All sequences were analyzed phylogenetically together with the reference strains to define the HBV genotypes. RESULTS A total of 31 blood samples from 145 HBsAg-positive pregnant women were positive for HBV by nested PCR. The detected HBV strains were identified as presumptive subgenotypes C1 (77.4%; 24/31), B9 (9.7%; 3/31), C2 (3.2%; 1/31), B2 (3.2%; 1/31), B4 (3.2%; 1/31), and presumptive B4/C2 recombinant subgenotype (3.2%; 1/31). CONCLUSIONS The findings revealed that presumptive subgenotype C1 was the most common subgenotype circulating in pregnant women in Northern Thailand and accounted for 77.4% of cases, followed by presumptive subgenotypes B9, C2, B2, and B4. Furthermore, this study reported, for the first time in Thailand, the HBV genotypes and presumptive subgenotypes, particularly subgenotype B9 circulating in pregnant women.
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Affiliation(s)
- Sirinart Sirilert
- Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Pattara Khamrin
- Department of Microbiology, Faculty of Medicine, and Emerging and Re-emerging Diarrheal Viruses Cluster, Chiang Mai University, Chiang Mai, Thailand
| | - Kattareeya Kumthip
- Department of Microbiology, Faculty of Medicine, and Emerging and Re-emerging Diarrheal Viruses Cluster, Chiang Mai University, Chiang Mai, Thailand
| | - Rungnapa Malasao
- Department of Community Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Theera Tongsong
- Department of Obstetrics and Gynecology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Niwat Maneekarn
- Department of Microbiology, Faculty of Medicine, and Emerging and Re-emerging Diarrheal Viruses Cluster, Chiang Mai University, Chiang Mai, Thailand.
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Fernandes da Silva C, Keeshan A, Cooper C. Hepatitis B virus genotypes influence clinical outcomes: A review. CANADIAN LIVER JOURNAL 2023; 6:347-352. [PMID: 38020195 PMCID: PMC10652982 DOI: 10.3138/canlivj-2023-0003] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/28/2023] [Indexed: 12/01/2023]
Abstract
Hepatitis B virus (HBV) is a hepatotropic virus that affects approximately 296 million people worldwide. A crucial step to HBV replication is the transcription of its infectious DNA from its viral RNA intermediate. The production of the RNA intermediate hinges on reverse transcription, and therefore the lack of proofreading in that process commonly yields mutants and has led to nine well-described genotypes (A-I) and over 30 known sub-genotypes of the virus. The influence of genotype on HBV infection outcomes, which include fibrosis progression, cirrhosis, and hepatocellular carcinoma (HCC), remain uncertain. This review aims to analyze the influence of HBV genotype on the risk of development of these outcomes. The response to current and future HBV therapies is considered. Further study of larger and more diverse samples will hopefully resolve outstanding uncertainties.
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Affiliation(s)
| | - Alexa Keeshan
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
| | - Curtis Cooper
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, Ontario, Canada
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6
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Ameya G, Birri DJ. The molecular mechanisms of virus-induced human cancers. Microb Pathog 2023; 183:106292. [PMID: 37557930 DOI: 10.1016/j.micpath.2023.106292] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/20/2023] [Accepted: 08/07/2023] [Indexed: 08/11/2023]
Abstract
Cancer is a serious public health problem globally. Many human cancers are induced by viruses. Understanding of the mechanisms by which oncogenic (tumorigenic) viruses induce cancer is essential in the prevention and control of cancer. This review covers comprehensive characteristics and molecular mechanisms of the main virus-attributed cancers caused by human papillomavirus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, human herpesvirus type 8, human T-cell lymphotropic virus, human polyomaviruses, Merkel cell polyomavirus, and HIV. Oncogenic viruses employ biological processes to replicate and avoid detection by host cell immune systems. Tumorigenic infectious agents activate oncogenes in a variety of ways, allowing the pathogen to block host tumour suppressor proteins, inhibit apoptosis, enhance cell proliferation, and promote invasion of host cells. Furthermore, this review assesses many pathways of viruses linked to cancer, including host cellular communication perturbation, DNA damage mechanisms, immunity, and microRNA targets that promote the beginning and progression of cancer. The current cancer prevention is primarily focused on non-communicable diseases, but infection-attributable cancer also needs attention to significantly reduce the rising cancer burden and related deaths.
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Affiliation(s)
- Gemechu Ameya
- Department of Medical Laboratory Sciences, College of Medicine and Health Sciences, Kotebe Metropolitan University, Addis Ababa, Ethiopia; Department of Microbial, Cellular and Molecular Biology, Addis Ababa University, Addis Ababa, Ethiopia
| | - Dagim Jirata Birri
- Department of Microbial, Cellular and Molecular Biology, Addis Ababa University, Addis Ababa, Ethiopia.
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Toyé RM, Loureiro CL, Jaspe RC, Zoulim F, Pujol FH, Chemin I. The Hepatitis B Virus Genotypes E to J: The Overlooked Genotypes. Microorganisms 2023; 11:1908. [PMID: 37630468 PMCID: PMC10459053 DOI: 10.3390/microorganisms11081908] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/17/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
Hepatitis B virus (HBV) genotypes E to J are understudied genotypes. Genotype E is found almost exclusively in West Africa. Genotypes F and H are found in America and are rare in other parts of the world. The distribution of genotype G is not completely known. Genotypes I and J are found in Asia and probably result from recombination events with other genotypes. The number of reported sequences for HBV genotypes E to J is small compared to other genotypes, which could impact phylogenetic and pairwise distance analyses. Genotype F is the most divergent of the HBV genotypes and is subdivided into six subgenotypes F1 to F6. Genotype E may be a recent genotype circulating almost exclusively in sub-Saharan Africa. Genotype J is a putative genotype originating from a single Japanese patient. The paucity of data from sub-Saharan Africa and Latin America is due to the under-representation of these regions in clinical and research cohorts. The purpose of this review is to highlight the need for further research on HBV genotypes E to J, which appear to be overlooked genotypes.
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Affiliation(s)
- Rayana Maryse Toyé
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1052, Centre de Recherche en Cancérologie de Lyon (CRCL), 151 Cours Albert Thomas, 69003 Lyon, France; (R.M.T.); (F.Z.)
| | - Carmen Luisa Loureiro
- Laboratorio de Virología Molecular, Centro de Microbiología y Biología Celular (CMBC), Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas 1020A, Venezuela; (C.L.L.); (R.C.J.)
| | - Rossana Celeste Jaspe
- Laboratorio de Virología Molecular, Centro de Microbiología y Biología Celular (CMBC), Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas 1020A, Venezuela; (C.L.L.); (R.C.J.)
| | - Fabien Zoulim
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1052, Centre de Recherche en Cancérologie de Lyon (CRCL), 151 Cours Albert Thomas, 69003 Lyon, France; (R.M.T.); (F.Z.)
| | - Flor Helene Pujol
- Laboratorio de Virología Molecular, Centro de Microbiología y Biología Celular (CMBC), Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas 1020A, Venezuela; (C.L.L.); (R.C.J.)
- Collégium de Lyon, Institut d’Etudes Avancées, Université Lyon 2, 69007 Lyon, France
| | - Isabelle Chemin
- Institut National de la Santé et de la Recherche Médicale (Inserm) U1052, Centre de Recherche en Cancérologie de Lyon (CRCL), 151 Cours Albert Thomas, 69003 Lyon, France; (R.M.T.); (F.Z.)
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Kim NJ, Cravero A, VoPham T, Vutien P, Carr R, Issaka RB, Johnston J, McMahon B, Mera J, Ioannou GN. Addressing racial and ethnic disparities in US liver cancer care. Hepatol Commun 2023; 7:e00190. [PMID: 37347221 PMCID: PMC10289716 DOI: 10.1097/hc9.0000000000000190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 05/09/2023] [Indexed: 06/23/2023] Open
Abstract
HCC, the most common form of primary liver cancer, is the fastest rising cause of cancer-related death in the United States. HCC disproportionately affects racial and ethnic minorities in the United States. A practical framework is needed to organize the complex patient, provider, health system, and societal factors that drive these racial and ethnic disparities. In this narrative review, we adapted and applied the National Institute on Minority Health and Health Disparities (NIMHD) Research Framework to the HCC care continuum, as a step toward better understanding and addressing existing HCC-related disparities. We first summarize the literature on HCC-related disparities by race and ethnicity organized by the framework's 5 domains (biological, behavioral, physical/built environment, sociocultural environment, and health care system) and 4 levels (individual, interpersonal, community, and societal) of influence. We then offer strategies to guide future research initiatives toward promotion of health equity in HCC care. Clinicians and researchers may help mitigate further inequities and better address racial and ethnic disparities in HCC care by prioritizing the following in HCC research: (1) increasing racial and ethnic minority representation, (2) collecting and reporting HCC-related data by racial and ethnic subgroups, (3) assessing the patient experience of HCC care by race and ethnicity, and (4) evaluating HCC-specific social determinants of health by race and ethnicity. These 4 priorities will help inform the development of future programs and interventions that are tailored to the unique experiences of each racial and ethnic group.
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Affiliation(s)
- Nicole J. Kim
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Anne Cravero
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Trang VoPham
- Epidemiology Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Epidemiology, University of Washington School of Public Health, Seattle, Washington, USA
| | - Philip Vutien
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Rotonya Carr
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA
| | - Rachel B. Issaka
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Janet Johnston
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, Alaska
| | - Brian McMahon
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, Alaska
| | - Jorge Mera
- Cherokee Nation Health Services, Tahlequah, Oklahoma
| | - George N. Ioannou
- Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington, USA
- Division of Gastroenterology, Department of Medicine, Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA
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9
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Villanueva RA, Loyola A. Pre- and Post-Transcriptional Control of HBV Gene Expression: The Road Traveled towards the New Paradigm of HBx, Its Isoforms, and Their Diverse Functions. Biomedicines 2023; 11:1674. [PMID: 37371770 DOI: 10.3390/biomedicines11061674] [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: 05/01/2023] [Revised: 06/04/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
Hepatitis B virus (HBV) is an enveloped DNA human virus belonging to the Hepadnaviridae family. Perhaps its main distinguishable characteristic is the replication of its genome through a reverse transcription process. The HBV circular genome encodes only four overlapping reading frames, encoding for the main canonical proteins named core, P, surface, and X (or HBx protein). However, pre- and post-transcriptional gene regulation diversifies the full HBV proteome into diverse isoform proteins. In line with this, hepatitis B virus X protein (HBx) is a viral multifunctional and regulatory protein of 16.5 kDa, whose canonical reading frame presents two phylogenetically conserved internal in-frame translational initiation codons, and which results as well in the expression of two divergent N-terminal smaller isoforms of 8.6 and 5.8 kDa, during translation. The canonical HBx, as well as the smaller isoform proteins, displays different roles during viral replication and subcellular localizations. In this article, we reviewed the different mechanisms of pre- and post-transcriptional regulation of protein expression that take place during viral replication. We also investigated all the past and recent evidence about HBV HBx gene regulation and its divergent N-terminal isoform proteins. Evidence has been collected for over 30 years. The accumulated evidence simply strengthens the concept of a new paradigm of the canonical HBx, and its smaller divergent N-terminal isoform proteins, not only during viral replication, but also throughout cell pathogenesis.
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Affiliation(s)
| | - Alejandra Loyola
- Centro Ciencia & Vida, Fundación Ciencia & Vida, Santiago 8580702, Chile
- Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago 7510602, Chile
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10
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Jose-Abrego A, Roman S, Laguna-Meraz S, Rebello-Pinho JR, Justo Arevalo S, Panduro A. Tracing the evolutionary history of hepatitis B virus genotype H endemic to Mexico. Front Microbiol 2023; 14:1180931. [PMID: 37293217 PMCID: PMC10244555 DOI: 10.3389/fmicb.2023.1180931] [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: 03/06/2023] [Accepted: 05/02/2023] [Indexed: 06/10/2023] Open
Abstract
Hepatitis B virus (HBV) spreads efficiently among all human populations worldwide. HBV is classified into ten genotypes (A to J) with their geographic distribution and clinical features. In Mexico, HBV genotype H is the leading cause of hepatitis B and has been detected in indigenous populations, suggesting that HBV genotype H may be native to Mexico. However, little is known about the evolutionary history of HBV genotype H. Thus, we aimed to determine the age of HBV genotype H in Mexico using molecular dating techniques. Ninety-two HBV sequences of the reverse transcriptase (RT) domain of the polymerase gene (~1,251 bp) were analyzed; 48 were genotype H, 43 were genotype F, and the oldest HBV sequence from America was included as the root. All sequences were aligned, and the most recent common ancestor (TMRCA) time was calculated using the Bayesian Skyline Evolutionary Analysis. Our results estimate a TMRCA for the genotype H in Mexico of 2070.9 (667.5-4489.2) years before the present (YBP). We identified four major diversification events in genotype H, named H1, H2, H3, and H4. The TMRCA of H1 was 1213.0 (253.3-2638.3) YBP, followed by H2 1175.5 (557.5-2424.2) YBP, H3 949.6 (279.3-2105.0) YBP, and H4 1230.5 (336.3, 2756.7) YBP. We estimated that genotype H diverged from its sister genotype F around 8140.8 (1867.5-18012.8) YBP. In conclusion, this study found that genotype H in Mexico has an estimated age of 2070.9 (667.5-4489.2) YBP and has experienced at least four major diversification events since then.
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Affiliation(s)
- Alexis Jose-Abrego
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, "Fray Antonio Alcalde", Guadalajara, Jalisco, Mexico
- Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Sonia Roman
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, "Fray Antonio Alcalde", Guadalajara, Jalisco, Mexico
- Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Saul Laguna-Meraz
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, "Fray Antonio Alcalde", Guadalajara, Jalisco, Mexico
- Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
- Molecular Biology in Medicine Doctorate Program, Guadalajara, Mexico
| | - João Renato Rebello-Pinho
- Department of Gastroenterology, Institute of Tropical Medicine and School of Medicine, LIM07, University of São Paulo, São Paulo, Brazil
- Hospital Israelita Albert Einstein, São Paulo, Brazil
| | - Santiago Justo Arevalo
- Faculty of Biological Sciences, Ricardo Palma University, Lima, Peru
- Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, Brazil
| | - Arturo Panduro
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, "Fray Antonio Alcalde", Guadalajara, Jalisco, Mexico
- Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
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11
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Xiao Y, Cui Z, Sun L, Zhou X, Li L, Wu L, Quan Y, Cui X. Lack of geographical and ethnic distribution of Hepatitis B virus genotypes in Hainan Island, China. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2023; 107:105401. [PMID: 36586460 DOI: 10.1016/j.meegid.2022.105401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 10/22/2022] [Accepted: 12/27/2022] [Indexed: 12/29/2022]
Abstract
Recent studies showed that the distribution of hepatitis B virus (HBV) genotype exhibited geographical and ethnic characteristics. Haikou city is the largest city on Hainan Island that geographically isolated from mainland of China, and is the home of multiple ethnic groups. The aim of the study was to investigate the characteristics of the HBV genotype/subgenotype distribution in Haikou city. HBV DNA was isolated from180 serum samples derived from the Han and Li groups. The HBV genotype was detected by polymerase chain reaction using genotype-specific primers and was further determined by full-length genome sequences. The results revealed that the genotype B (37.2%) and C (62.8%) were the predominant HBV genotypes in Haikou, regardless of ethnic background., Additionally, the genotype distribution was not significantly different regarding ethnicity, sex or level of serum HBV DNA. Moreover, there were multiple subgenotypes circulating in the region. In conclusion, our study revealed the diverse HBV genotypes/subgenotypes in Haikou. These findings provide a preliminary study of the distribution of HBV genotypes circulating on Hainan Island.
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Affiliation(s)
- Yihan Xiao
- Department of Clinical Laboratory, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 571199, China; School of basic medicine and life science, Hainan Medical University, Haikou, Hainan 571199, China
| | - Zhigang Cui
- School of basic medicine and life science, Hainan Medical University, Haikou, Hainan 571199, China
| | - Long Sun
- Department of Infectious Disease, The first affiliated hospital of Hainan Medical University, Haikou, Hainan 571199, China
| | - Xiaojun Zhou
- Department of Laboratory Medicine, Hainan affiliated hospital of Hainan Medical University, Haikou, Hainan 571199, China
| | - Lihua Li
- School of basic medicine and life science, Hainan Medical University, Haikou, Hainan 571199, China
| | - Lixian Wu
- School of basic medicine and life science, Hainan Medical University, Haikou, Hainan 571199, China
| | - Yunfan Quan
- School of Tropical Medicine, Hainan Medical University, Haikou, Hainan 571199, China.
| | - Xiuji Cui
- School of basic medicine and life science, Hainan Medical University, Haikou, Hainan 571199, China; Key laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Medical University, Haikou, Hainan 571199, China; Hainan Medical University-The University of Hong Kong Joint Laboratory of Tropical Infectious Diseases, Hainan Medical University, Haikou, Hainan 571199, China.
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12
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Roca TP, Villar LM, Nogueira Lima FS, Vasconcelos MPA, Borzacov LMP, Silva EDCE, do Lago BV, da Silva MTL, Botelho Souza LF, Salcedo JMV, dos Santos ADO, Vieira DS. Genomic Variability of Hepatitis B Virus Circulating in Brazilian Western Amazon. Viruses 2022; 14:v14102100. [PMID: 36298655 PMCID: PMC9611064 DOI: 10.3390/v14102100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 12/02/2022] Open
Abstract
The emergence of clinically relevant mutations in the hepatitis B virus (HBV) genome has been a matter of great debate because of the possibility of escape from the host’s immune system, the potential to cause more severe progression of liver diseases and the emergence of treatment-resistant variants. Here we characterized the circulating variants of HBV in Rondônia State, in the north of Brazil. Serum samples of 62 chronic HBV carriers were subjected to PCR assays and clinical data were collected. Mutations and genotypes were characterized through direct sequencing. The findings show the presence of subgenotypes A1 (54.83%, 34/62), D3 (16.13%, 10/62), F2 (16.13%, 10/62), A2 (4.84%, 3/62), D2 (3.23%, 2/62), D1 (1.61%, 1/62), D4 (1.61%, 1/62) and F4 (1.61%, 1/62). Deletions in the pre-S2 region were found in 13.79% (8/58) of the samples, mutations in the S gene in 59.68% (37/62) and RT mutations in 48.39% (30/62). We found a variable genotypic distribution in different locations and important mutations related to immune escape and drug resistance in Western Amazonia, which contributed to genetic surveillance and provided important information to help control the disease.
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Affiliation(s)
- Tárcio Peixoto Roca
- Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-900, Brazil
- Laboratory of Molecular Virology, Oswaldo Cruz Foundation of Rondônia—FIOCRUZ/RO, Porto Velho 76812-245, Brazil
- Correspondence: (T.P.R.); (L.M.V.)
| | - Livia Melo Villar
- Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-900, Brazil
- Correspondence: (T.P.R.); (L.M.V.)
| | - Felipe Souza Nogueira Lima
- Laboratory of Molecular Virology, Oswaldo Cruz Foundation of Rondônia—FIOCRUZ/RO, Porto Velho 76812-245, Brazil
| | | | | | | | - Bárbara Vieira do Lago
- Laboratory of Viral Hepatitis, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro 21040-900, Brazil
| | - Mayara Torquato Lima da Silva
- Laboratory of Biotechnology and Structural Bioengineering, Biophysics Institute Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro 21941-901, Brazil
| | | | - Juan Miguel Villalobos Salcedo
- Laboratory of Molecular Virology, Oswaldo Cruz Foundation of Rondônia—FIOCRUZ/RO, Porto Velho 76812-245, Brazil
- Tropical Medicine Research Center of Rondônia—CEPEM/RO, Porto Velho 76812-329, Brazil
| | | | - Deusilene Souza Vieira
- Laboratory of Molecular Virology, Oswaldo Cruz Foundation of Rondônia—FIOCRUZ/RO, Porto Velho 76812-245, Brazil
- Tropical Medicine Research Center of Rondônia—CEPEM/RO, Porto Velho 76812-329, Brazil
- Postgraduate Program in Experimental Biology, Federal University of Rondônia—PGBIOEXP/UNIR, Porto Velho 76801-059, Brazil
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13
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Gnyawali B, Pusateri A, Nickerson A, Jalil S, Mumtaz K. Epidemiologic and socioeconomic factors impacting hepatitis B virus and related hepatocellular carcinoma. World J Gastroenterol 2022; 28:3793-3802. [PMID: 36157533 PMCID: PMC9367226 DOI: 10.3748/wjg.v28.i29.3793] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 04/10/2022] [Accepted: 07/11/2022] [Indexed: 02/06/2023] Open
Abstract
Chronic Hepatitis B is a highly prevalent disease worldwide and is estimated to cause more than 800000 annual deaths from complications such as cirrhosis and hepatocellular carcinoma (HCC). Although universal hepatitis B vaccination programs may have reduced the incidence and prevalence of chronic hepatitis B and related HCC, the disease still imposes a significant healthcare burden in many endemic regions such as Africa and the Asia-Pacific region. This is especially concerning given the global underdiagnosis of hepatitis B and the limited availability of vaccination, screening, and treatment in low-resource regions. Demographics including male gender, older age, ethnicity, and geographic location as well as low socioeconomic status are more heavily impacted by chronic hepatitis B and related HCC. Methods to mitigate this impact include increasing screening in high-risk groups according to national guidelines, increasing awareness and health literacy in vulnerable populations, and developing more robust vaccination programs in under-served regions.
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Affiliation(s)
- Bipul Gnyawali
- Department of Medicine, Kettering Medical Center, Dayton, OH 45342, United States
| | - Antoinette Pusateri
- Department of Medicine, The Ohio State University, Columbus, OH 43210, United States
| | - Ashley Nickerson
- Department of Medicine, The Ohio State University, Columbus, OH 43210, United States
| | - Sajid Jalil
- Department of Medicine, The Ohio State University, Columbus, OH 43210, United States
| | - Khalid Mumtaz
- Department of Medicine, The Ohio State University, Columbus, OH 43210, United States
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14
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Elizalde MM, Mojsiejczuk L, Speroni M, Bouzas B, Tadey L, Mammana L, Campos RH, Flichman DM. Molecular and biological characterization of hepatitis B virus subgenotype F1b clusters: Unraveling its role in hepatocarcinogenesis. Front Microbiol 2022; 13:946703. [PMID: 35966715 PMCID: PMC9363773 DOI: 10.3389/fmicb.2022.946703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 07/11/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatitis B virus (HBV) subgenotype F1b infection has been associated with the early occurrence of hepatocellular carcinoma in chronically infected patients from Alaska and Peru. In Argentina, however, despite the high prevalence of subgenotype F1b infection, this relationship has not been described. To unravel the observed differences in the progression of the infection, an in-depth molecular and biological characterization of the subgenotype F1b was performed. Phylogenetic analysis of subgenotype F1b full-length genomes revealed the existence of two highly supported clusters. One of the clusters, designated as gtF1b Basal included sequences mostly from Alaska, Peru and Chile, while the other, called gtF1b Cosmopolitan, contained samples mainly from Argentina and Chile. The clusters were characterized by a differential signature pattern of eight nucleotides distributed throughout the genome. In vitro characterization of representative clones from each cluster revealed major differences in viral RNA levels, virion secretion, antigen expression levels, as well as in the localization of the antigens. Interestingly, a differential regulation in the expression of genes associated with tumorigenesis was also identified. In conclusion, this study provides new insights into the molecular and biological characteristics of the subgenotype F1b clusters and contributes to unravel the different clinical outcomes of subgenotype F1b chronic infections.
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Affiliation(s)
- María Mercedes Elizalde
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- *Correspondence: María Mercedes Elizalde,
| | - Laura Mojsiejczuk
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Micaela Speroni
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Belén Bouzas
- Unidad de Virología, Hospital de Infecciosas “Francisco J. Muñiz”, Buenos Aires, Argentina
| | - Luciana Tadey
- Unidad de Virología, Hospital de Infecciosas “Francisco J. Muñiz”, Buenos Aires, Argentina
| | - Lilia Mammana
- Unidad de Virología, Hospital de Infecciosas “Francisco J. Muñiz”, Buenos Aires, Argentina
| | - Rodolfo Héctor Campos
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
- Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Diego Martín Flichman
- Instituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET, Universidad de Buenos Aires, Buenos Aires, Argentina
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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15
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Roberts LR. Untreated Chronic Hepatitis B Is Associated With a Higher Risk of Extrahepatic Malignancies. J Clin Oncol 2022; 40:3357-3360. [DOI: 10.1200/jco.22.01051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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16
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Stella L, Santopaolo F, Gasbarrini A, Pompili M, Ponziani FR. Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment. World J Gastroenterol 2022; 28:2251-2281. [PMID: 35800182 PMCID: PMC9185215 DOI: 10.3748/wjg.v28.i21.2251] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/08/2021] [Accepted: 04/26/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.
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Affiliation(s)
- Leonardo Stella
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesco Santopaolo
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Maurizio Pompili
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
| | - Francesca Romana Ponziani
- Internal Medicine and Gastroenterology, Hepatology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome 00168, Italy
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17
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Araujo NM, Osiowy C. Hepatitis B Virus Genotype G: The Odd Cousin of the Family. Front Microbiol 2022; 13:872766. [PMID: 35432294 PMCID: PMC9009205 DOI: 10.3389/fmicb.2022.872766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 03/18/2022] [Indexed: 11/13/2022] Open
Abstract
With a widespread distribution but low prevalence worldwide, the hepatitis B virus (HBV) genotype G (HBV/G) is a recently described genotype for which the origin and biology are poorly understood. Some unique features make HBV/G the most peculiar of all genotypes. In this review, we reflect on the major milestones in HBV/G research, highlighting the main aspects of its discovery, molecular epidemiology, and virological and clinical characteristics. We also illustrate common pitfalls in the routine detection, which may lead to underestimated rates of HBV/G infection. Large-scale analysis of data from dozens of articles was further performed, with the aim of gaining comprehensive insights into the epidemiological aspects of HBV/G. Finally, we point out recent findings on HBV/G origins and discuss new perspectives regarding the evolutionary history of HBV/G and the plausibility of an African geographic re-emergence of this genotype.
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Affiliation(s)
- Natalia M. Araujo
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil
| | - Carla Osiowy
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada
- *Correspondence: Carla Osiowy,
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18
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Discrepant results of hepatitis B virus genotype determination by PCR and DNA sequencing. J Virol Methods 2022; 303:114503. [DOI: 10.1016/j.jviromet.2022.114503] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 02/22/2022] [Accepted: 02/22/2022] [Indexed: 12/25/2022]
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19
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Wolf JM, Mazeto TK, Pereira VRZB, Simon D, Lunge VR. Recent molecular evolution of hepatitis B virus genotype F in Latin America. Arch Virol 2022; 167:597-602. [DOI: 10.1007/s00705-022-05376-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 12/17/2021] [Indexed: 11/24/2022]
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20
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Mbaga DS, Kenmoe S, Kengne-Ndé C, Ebogo-Belobo JT, Mahamat G, Foe-Essomba JR, Amougou-Atsama M, Tchatchouang S, Nyebe I, Feudjio AF, Kame-Ngasse GI, Magoudjou-Pekam JN, Fokou LKM, Meta-Djomsi D, Maïdadi-Foudi M, Touangnou-Chamda SA, Daha-Tchoffo AG, Selly-Ngaloumo AA, Nayang-Mundo RA, Yéngué JF, Taya-Fokou JB, Kenfack-Momo R, Atembeh Noura E, Demeni Emoh CP, Tazokong HR, Bowo-Ngandji A, Sake CS, Atenguena Okobalemba E, Njiki Bikoi J, Njouom R, Riwom Essama SH. Hepatitis B, C and D virus infections and risk of hepatocellular carcinoma in Africa: A meta-analysis including sensitivity analyses for studies comparable for confounders. PLoS One 2022; 17:e0262903. [PMID: 35061846 PMCID: PMC8782350 DOI: 10.1371/journal.pone.0262903] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 01/09/2022] [Indexed: 01/05/2023] Open
Abstract
INTRODUCTION Africa denotes unique facies for hepatocellular carcinoma (HCC) characterized by a conjunction of low sensitization, restricted access to diagnosis and treatment and associated with the highest incidence and mortality in the world. We investigated whether hepatitis B (HBV), C (HCV) and D (VHD) viruses were etiological agents of HCC in Africa. METHODS Relevant articles were searched in PubMed, Web of Science, African Index Medicus, and African Journal Online databases, as well as manual searches in relevant reviews and included articles. Analytical studies from Africa evaluating the association between HCC development and HBV, HCV, and HDV were included. Relevant studies were selected, data extracted, and the risk of bias assessed independently by at least 2 investigators. The association was estimated using odds ratios (OR) and their 95% confidence interval (95% CI) determined by a random-effects model. Sources of heterogeneity were determined by subgroup analyses. RESULTS A total of 36 case-control studies were included. With controls having non-hepatic disease, the overall results suggested a significantly increased risk of HCC in patients with HBV (HBeAg (OR = 19.9; 95% CI = [3.7-105.2]), HBsAg (OR = 9.9; 95%) CI = [6.2-15.6]) and DNA (OR = 8.9; 95% CI = [5.9-13.4]); HCV (Anti-HCV (OR = 9.4; 95% CI = [6.3-14.0]) and RNA (OR = 16.5; 95% CI = [7.8-34.6]); HDV (Anti-VHD, (OR = 25.8; 95% CI = [5.9-112.2]); and HBV/HCV coinfections (HBV DNA/HCV RNA (OR = 22.5; 95% CI = [1.3-387.8]). With apparently healthy controls, the overall results suggested a significantly increased risk of HCC in patients with HBV (HBsAg, (OR = 8.9; 95% CI = [6.0-13.0]); HCV (Anti-HCV, (OR = 7.7; 95% CI = [5.6-10.6]); and HBV/HCV coinfections (HBsAg/Anti-HCV (OR = 7.8; 95% CI = [4.4-13.6]) Substantial heterogeneity and the absence of publication bias were recorded for these results. CONCLUSIONS In Africa, HBV/HCV coinfections and HBV, HCV, and HDV infections are associated with an increased risk of developing HCC. The implementation of large-scale longitudinal and prospective studies including healthy participants to search for early biomarkers of the risk of progression to HCC is urgently needed.
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Affiliation(s)
| | - Sebastien Kenmoe
- Virology Department, Centre Pasteur of Cameroon, Yaoundé, Cameroon
| | - Cyprien Kengne-Ndé
- Evaluation and Research Unit, National AIDS Control Committee, Yaoundé, Cameroon
| | - Jean Thierry Ebogo-Belobo
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaoundé, Cameroon
| | - Gadji Mahamat
- Department of Microbiology, The University of Yaounde I, Yaoundé, Cameroon
| | | | - Marie Amougou-Atsama
- Centre de Recherche sur les Maladies Émergentes et Re-Emergentes, Institute of Medical Research and Medicinal Plants Studies, Yaoundé, Cameroon
| | | | - Inès Nyebe
- Department of Microbiology, The University of Yaounde I, Yaoundé, Cameroon
| | | | - Ginette Irma Kame-Ngasse
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaoundé, Cameroon
| | | | | | - Dowbiss Meta-Djomsi
- Centre de Recherche sur les Maladies Émergentes et Re-Emergentes, Institute of Medical Research and Medicinal Plants Studies, Yaoundé, Cameroon
| | - Martin Maïdadi-Foudi
- Centre de Recherche sur les Maladies Émergentes et Re-Emergentes, Institute of Medical Research and Medicinal Plants Studies, Yaoundé, Cameroon
| | | | | | | | | | | | | | - Raoul Kenfack-Momo
- Department of Biochemistry, The University of Yaounde I, Yaoundé, Cameroon
| | - Efietngab Atembeh Noura
- Medical Research Centre, Institute of Medical Research and Medicinal Plants Studies, Yaoundé, Cameroon
| | | | | | - Arnol Bowo-Ngandji
- Department of Microbiology, The University of Yaounde I, Yaoundé, Cameroon
| | | | | | - Jacky Njiki Bikoi
- Department of Microbiology, The University of Yaounde I, Yaoundé, Cameroon
| | - Richard Njouom
- Virology Department, Centre Pasteur of Cameroon, Yaoundé, Cameroon
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McMahon BJ, Nolen LD, Snowball M, Homan C, Negus S, Roik E, Spradling PR, Bruden D. HBV Genotype: A Significant Risk Factor in Determining Which Patients With Chronic HBV Infection Should Undergo Surveillance for HCC: The Hepatitis B Alaska Study. Hepatology 2021; 74:2965-2973. [PMID: 34292609 PMCID: PMC10929546 DOI: 10.1002/hep.32065] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 06/03/2021] [Accepted: 06/25/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND AND AIMS Information is limited regarding HBV genotype and the outcome of chronic HBV (CHB) infection. We examined the effect of HBV genotype on HCC occurrence in Alaska Native (AN) persons with CHB, where five HBV genotypes are found: A2, B6, C2, D, and F1. APPROACH AND RESULTS We calculated HCC incidence per 1,000 person-years of follow-up to determine which groups by age, sex, and genotype met current American Association for the Study of Liver Diseases (AASLD) HCC surveillance criteria. We used Poisson regression to compare HCC risk by genotype, age, sex, and Alaska region. Incidence of HCC was calculated using the sex-specific AASLD cutoff recommended for the Asian population of 50 years for women and 40 years for men. HCC screening was conducted semiannually using alpha-fetoprotein levels and abdominal ultrasound. Among 1,185 AN persons, median follow-up was 35.1 years; 667 (63%) were male. The HBV genotype distribution was 49% D, 18% F, 13% A, 6% C, 3% B, 0.1% H, and 12% undetermined. Sixty-three cases of HCC occurred. HCC incidence for genotype F was 5.73 per 1,000 person-years of follow-up, followed by 4.77 for C, 1.28 for A, 0.47 for D, and 0.00 for B. The HCC risk was higher for genotypes F (relative rate [RR], 12.7; 95% CI, 6.1-26.4), C (RR, 10.6; 95% CI, 4.3-26.0), and A (RR, 2.9; 95% CI, 1.0-8.0) compared to genotypes B and D. Among men < 40 years of age and women < 50 years of age, genotype F had the highest incidence (4.79/1,000 person-years). CONCLUSIONS HBV genotype was strongly associated with HCC. HBV genotype should be considered in risk factor stratification.
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Affiliation(s)
- Brian J. McMahon
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA
- Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Arctic Investigations Program, Anchorage, AK, USA
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Leisha D. Nolen
- Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Arctic Investigations Program, Anchorage, AK, USA
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Mary Snowball
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA
- Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Arctic Investigations Program, Anchorage, AK, USA
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Chriss Homan
- Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Arctic Investigations Program, Anchorage, AK, USA
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Susan Negus
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA
- Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Arctic Investigations Program, Anchorage, AK, USA
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Elena Roik
- Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Arctic Investigations Program, Anchorage, AK, USA
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Philip R. Spradling
- Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Arctic Investigations Program, Anchorage, AK, USA
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Dana Bruden
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA
- Division of Preparedness and Emerging Infections, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Arctic Investigations Program, Anchorage, AK, USA
- Division of Viral Hepatitis, National Center for HIV, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention, Atlanta, GA, USA
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22
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Tsuge M. The association between hepatocarcinogenesis and intracellular alterations due to hepatitis B virus infection. Liver Int 2021; 41:2836-2848. [PMID: 34559952 DOI: 10.1111/liv.15065] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/13/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis B virus (HBV) infection is a worldwide health problem leading to severe liver dysfunction, including liver cirrhosis and hepatocellular carcinoma. Although current antiviral therapies for chronic HBV infection have been improved and can lead to a strong suppression of viral replication, it is difficult to completely eliminate the virus with these therapies once chronic HBV infection is established in the host. Furthermore, chronic HBV infection alters intracellular metabolism and signalling pathways, resulting in the activation of carcinogenesis in the liver. HBV produces four viral proteins: hepatitis B surface-, hepatitis B core-, hepatitis B x protein, and polymerase; each plays an important role in HBV replication and the intracellular signalling pathways associated with hepatocarcinogenesis. In vitro and in vivo experimental models for analyzing HBV infection and replication have been established, and gene expression analyses using microarrays or next-generation sequencing have also been developed. Thus, it is possible to clarify the molecular mechanisms for intracellular alterations, such as endoplasmic reticulum stress, oxidative stress, and epigenetic modifications. In this review, the impact of HBV viral proteins and intracellular alterations in HBV-associated hepatocarcinogenesis are discussed.
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Affiliation(s)
- Masataka Tsuge
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.,Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
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23
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Molecular Epidemiology of Hepatitis B Virus Genotypes and Subgenotypes in Ethnic Minority Populations, Yunnan Province, China. Epidemiol Infect 2021; 150:e11. [PMID: 34784995 PMCID: PMC8753486 DOI: 10.1017/s0950268821002326] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The aim of our study was to determine the distribution of hepatitis B virus (HBV) genotypes and subgenotypes in ethnic minorities in Yunnan province to provide evidence supporting the theoretical basis for hepatitis B prevention and control. We obtained serum samples and demographic data from 765 individuals reported by Yunnan province who had either acute or chronic HBV infection and were from one of 20 ethnic minority populations: Achang, Bai, Brown, Tibetan, Dai, Deang, Dulong, Hani, Hui, Jingpo, Lahu, Yi, Lisu Miao, Naxi, Nu, Pumi, Wa, Yao, or Zhuang people. We sequenced the HBV DNA and determined the genotypes and subgenotypes of the isolated HBVs. We mapped the genotype and subgenotype distribution by ethnic minority population and conducted descriptive analyses. There were four genotypes among the 20 ethnic groups: genotype B (21.3% of samples), C (76.6%), D (1.8%) and I (0.3%). The most common subgenotype was C1. There were no genotype differences by gender (P = 0.954) or age (P = 0.274), but there were differences by region (P < 0.001). There were differences in genotype distribution (P < 0.001) and subgenotype distribution (P = 0.011) by ethnic group. Genotype D was most prominent in Tibet and most HBV isolates were C/D recombinant viruses. The only two genotype I virus isolates were in Zhuang people. Susceptibility and geographic patterns may influence HBV prevalence in different ethnic populations, but additional research is needed for such a determination.
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24
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Canonical and Divergent N-Terminal HBx Isoform Proteins Unveiled: Characteristics and Roles during HBV Replication. Biomedicines 2021; 9:biomedicines9111701. [PMID: 34829930 PMCID: PMC8616016 DOI: 10.3390/biomedicines9111701] [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: 10/21/2021] [Revised: 11/11/2021] [Accepted: 11/11/2021] [Indexed: 11/16/2022] Open
Abstract
Hepatitis B virus (HBV) X protein (HBx) is a viral regulatory and multifunctional protein. It is well-known that the canonical HBx reading frame bears two phylogenetically conserved internal in-frame translational initiation codons at Met2 and Met3, thus possibly generating divergent N-terminal smaller isoforms during translation. Here, we demonstrate that the three distinct HBx isoforms are generated from the ectopically expressed HBV HBx gene, named XF (full-length), XM (medium-length), and XS (short-length); they display different subcellular localizations when expressed individually in cultured hepatoma cells. Particularly, the smallest HBx isoform, XS, displayed a predominantly cytoplasmic localization. To study HBx proteins during viral replication, we performed site-directed mutagenesis to target the individual or combinatorial expression of the HBx isoforms within the HBV viral backbone (full viral genome). Our results indicate that of all HBx isoforms, only the smallest HBx isoform, XS, can restore WT levels of HBV replication, and bind to the viral mini chromosome, thereby establishing an active chromatin state, highlighting its crucial activities during HBV replication. Intriguingly, we found that sequences of HBV HBx genotype H are devoid of the conserved Met3 position, and therefore HBV genotype H infection is naturally silent for the expression of the HBx XS isoform. Finally, we found that the HBx XM (medium-length) isoform shares significant sequence similarity with the N-terminus domain of the COMMD8 protein, a member of the copper metabolism MURR1 domain-containing (COMMD) protein family. This novel finding might facilitate studies on the phylogenetic origin of the HBV X protein. The identification and functional characterization of its isoforms will shift the paradigm by changing the concept of HBx from being a unique, canonical, and multifunctional protein toward the occurrence of different HBx isoforms, carrying out different overlapping functions at different subcellular localizations during HBV genome replication. Significantly, our current work unveils new crucial HBV targets to study for potential antiviral research, and human virus pathogenesis.
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25
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Abstract
Hepatitis B was discovered by researchers who were investigating jaundice associated with blood transfusions as well as parenterally administered medications. Through trial and error, the HBV was identified. There are specific tests that detect HBV infection, whether it is a previous exposure or active infection. The various HBV serologies are reviewed in this work as well. Hepatitis B surface antigen has emerged as a tool in defining treatment endpoint and its significance is reviewed. HBV genotypes are distributed uniquely throughout the world, in particular, genotype C is associated with higher rates of hepatocellular carcinoma. Various HBV genotypes and their impact on the clinical course are discussed. The relationship of HBV serologies and HBV DNA to disease progression is outlined. There are specific recommendations on monitoring those infected with HBV and this is reviewed here. HBV mutations have an impact on the disease course and those of significance are also discussed.
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26
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Hayashi S, Nagaoka K, Tanaka Y. Blood-Based Biomarkers in Hepatitis B Virus-Related Hepatocellular Carcinoma, Including the Viral Genome and Glycosylated Proteins. Int J Mol Sci 2021; 22:ijms222011051. [PMID: 34681709 PMCID: PMC8540379 DOI: 10.3390/ijms222011051] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/08/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) development and is a global public health issue. High performance biomarkers can aid the early detection of HCC development in HBV-infected individuals. In addition, advances in the understanding of the pathogenesis of HBV infection and in clinical laboratory techniques have enabled the establishment of disease-specific tests, prediction of the progression of liver diseases, including HCC, and auxiliary diagnosis of HCC, using blood-based methods instead of biopsies of liver or HCC tissues. Viral factors such as the HBV genotype, HBV genetic mutations, HBV DNA, and HBV-related antigens, as well as host factors, such as tumor-associated proteins and post-translational modifications, especially glycosylated proteins, can be blood-based, disease-specific biomarkers for HCC development in HBV-infected patients. In this review, we describe the clinical applications of viral biomarkers, including the HBV genome and glycosylated proteins, for patients at a risk of HBV-related HCC, based on their molecular mechanisms. In addition, we introduce promising biomarker candidates for practical use, including colony stimulating factor 1 receptor (CSF1R), extracellular vesicles, and cell-free, circulating tumor DNA. The clinical use of such surrogate markers may lead to a better understanding of the risk of disease progression and early detection of HCC in HBV-infected patients, thereby improving their prognosis.
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27
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Shah AS, Civelli VF, Bali V, Johnson RH, Heidari A. A Case of S-Variant Hepatitis B Virus: An Immune System Escape Artist. J Investig Med High Impact Case Rep 2021; 9:23247096211045450. [PMID: 34521227 PMCID: PMC8447092 DOI: 10.1177/23247096211045450] [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] [Indexed: 11/29/2022] Open
Abstract
Genomic variants of the hepatitis B virus (HBV) preS/S protein are well-known to
occur. Typically, immunity is gained through recovered HBV infection or by
immunization. Very rarely, there are certain mutations that may enable HBV
escape from the immune detection. PreS/S mutants may present with unpredictable
pathobiologic, clinical, and transmittable implications. Standard laboratory
testing for genomic HBV variants is not routinely performed by reference
guidelines. s-variant HBV management remains challenging. Herein is a case of
s-variant chronic HBV infection in a 55-year-old man. Diagnosis and treatment
are described.
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Affiliation(s)
- Amar S Shah
- UCLA at Kern Medical Center, Bakersfield, CA, USA
| | | | - Varun Bali
- UCLA at Kern Medical Center, Bakersfield, CA, USA
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28
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Elpek GO. Molecular pathways in viral hepatitis-associated liver carcinogenesis: An update. World J Clin Cases 2021; 9:4890-4917. [PMID: 34307543 PMCID: PMC8283590 DOI: 10.12998/wjcc.v9.i19.4890] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 03/14/2021] [Accepted: 05/26/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of cancer among primary malignant tumors of the liver and is a consequential cause of cancer-related deaths worldwide. In recent years, uncovering the molecular mechanisms involved in the development and behavior of this tumor has led to the identification of multiple potential treatment targets. Despite the vast amount of data on this topic, HCC remains a challenging tumor to treat due to its aggressive behavior and complex molecular profile. Therefore, the number of studies aiming to elucidate the mechanisms involved in both carcinogenesis and tumor progression in HCC continues to increase. In this context, the close association of HCC with viral hepatitis has led to numerous studies focusing on the direct or indirect involvement of viruses in the mechanisms contributing to tumor development and behavior. In line with these efforts, this review was undertaken to highlight the current understanding of the molecular mechanisms by which hepatitis B virus (HBV) and hepatitis C virus (HCV) participate in oncogenesis and tumor progression in HCC and summarize new findings. Cumulative evidence indicates that HBV DNA integration promotes genomic instability, resulting in the overexpression of genes related to cancer development, metastasis, and angiogenesis or inactivation of tumor suppressor genes. In addition, genetic variations in HBV itself, especially preS2 deletions, may play a role in malignant transformation. Epigenetic dysregulation caused by both viruses might also contribute to tumor formation and metastasis by modifying the methylation of DNA and histones or altering the expression of microRNAs. Similarly, viral proteins of both HBV and HCV can affect pathways that are important anticancer targets. The effects of these two viruses on the Hippo-Yap-Taz pathway in HCC development and behavior need to be investigated. Additional, comprehensive studies are also needed to determine these viruses' interaction with integrins, farnesoid X, and the apelin system in malignant transformation and tumor progression. Although the relationship of persistent inflammation caused by HBV and HCV hepatitis with carcinogenesis is well defined, further studies are warranted to decipher the relationship among inflammasomes and viruses in carcinogenesis and elucidate the role of virus-microbiota interactions in HCC development and progression.
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Affiliation(s)
- Gulsum Ozlem Elpek
- Department of Pathology, Akdeniz University Medical School, Antalya 07070, Turkey
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29
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Campos-Valdez M, Monroy-Ramírez HC, Armendáriz-Borunda J, Sánchez-Orozco LV. Molecular Mechanisms during Hepatitis B Infection and the Effects of the Virus Variability. Viruses 2021; 13:v13061167. [PMID: 34207116 PMCID: PMC8235420 DOI: 10.3390/v13061167] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/16/2022] Open
Abstract
The immunopathogenesis and molecular mechanisms involved during a hepatitis B virus (HBV) infection have made the approaches for research complex, especially concerning the patients’ responses in the course of the early acute stage. The study of molecular bases involved in the viral clearance or persistence of the infection is complicated due to the difficulty to detect patients at the most adequate points of the disease, especially in the time lapse between the onset of the infection and the viral emergence. Despite this, there is valuable data obtained from animal and in vitro models, which have helped to clarify some aspects of the early immune response against HBV infection. The diversity of the HBV (genotypes and variants) has been proven to be associated not only with the development and outcome of the disease but also with the response to treatments. That is why factors involved in the virus evolution need to be considered while studying hepatitis B infection. This review brings together some of the published data to try to explain the immunological and molecular mechanisms involved in the different stages of the infection, clinical outcomes, viral persistence, and the impact of the variants of HBV in these processes.
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Affiliation(s)
- Marina Campos-Valdez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Hugo C. Monroy-Ramírez
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
| | - Juan Armendáriz-Borunda
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Campus Guadalajara, Zapopan 45201, Jalisco, México
| | - Laura V. Sánchez-Orozco
- Centro Universitario de Ciencias de la Salud, Departamento de Biología Molecular y Genómica, Instituto de Biología Molecular en Medicina, Universidad de Guadalajara, Guadalajara 44340, Jalisco, México; (M.C.-V.); (H.C.M.-R.); (J.A.-B.)
- Correspondence: ; Tel.: +52-33-3954-5677
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30
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Anugwom CM, Allaire M, Akbar SMF, Sultan A, Bollipo S, Mattos AZ, Debes JD. Hepatitis B-related hepatocellular carcinoma: surveillance strategy directed by immune-epidemiology. HEPATOMA RESEARCH 2021; 7. [PMID: 33884303 PMCID: PMC8057710 DOI: 10.20517/2394-5079.2021.06] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hepatitis B infection (HBV) is one of the most common causes of hepatocellular carcinoma (HCC) worldwide. The age of occurrence, prognosis and incidence vary dramatically depending on the region of the world. This geographic variation is largely dependent on the contrasting incidence of HBV, age of transmission of the virus, the timing of integration into the human genome, and different HBV genotypes, as well as environmental factors. It results in a wide difference in viral interaction with the immune system, genomic modulation and the consequent development of HCC in an individual. In this review, we describe many factors implicated in HCC development, provide insight regarding at-risk populations and explain societal recommendations for HCC surveillance in persons living with HBV in different continents of the world.
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Affiliation(s)
- Chimaobi M Anugwom
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis 55455, USA
| | - Manon Allaire
- Sorbonne Université, Service d'Hépatologie, Hôpitaux Universitaires Pitié Salpêtrière - Charles Foix, AP-HP, Paris 75103, France.,Inserm U1149, Centre de Recherche sur l'Inflammation, France Faculté de Médecine, Xavier Bichat, Université Paris Diderot, Paris 75108, France
| | - Sheikh Mohammad Fazle Akbar
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon 791-0295, Japan
| | - Amir Sultan
- College of Health Sciences, Addis Ababa University, Tikur Anbessa Specialized Hospital, Addis Ababa 5657, Ethiopia
| | - Steven Bollipo
- Department of Gastroenterology, John Hunter Hospital, Newcastle, Australia & School of Medicine & Public Health, University of Newcastle, New South Wales 2310, Australia
| | - Angelo Z Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre 90050-170, Brazil.,Gastroenterology and Hepatology Unit, Irmandade Santa Casa de Misericórdia de Porto Alegre 90020-090, Brazil
| | - Jose D Debes
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis 55455, USA.,Department of Medicine, Division of Infectious Diseases, University of Minnesota, Minneapolis, MN 55455, USA.,Department of Gastroenterology & Hepatology, Erasmus MC, Rotterdam 3015-CE, Netherlands
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31
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de Bernardi Schneider A, Osiowy C, Hostager R, Krarup H, Børresen M, Tanaka Y, Morriseau T, Wertheim JO. Analysis of Hepatitis B Virus Genotype D in Greenland Suggests the Presence of a Novel Quasi-Subgenotype. Front Microbiol 2021; 11:602296. [PMID: 33519744 PMCID: PMC7843931 DOI: 10.3389/fmicb.2020.602296] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Accepted: 12/14/2020] [Indexed: 12/12/2022] Open
Abstract
A disproportionate number of Greenland's Inuit population are chronically infected with Hepatitis B virus (HBV; 5-10%). HBV genotypes B and D are most prevalent in the circumpolar Arctic. Here, we report 39 novel HBV/D sequences from individuals residing in southwestern Greenland. We performed phylodynamic analyses with ancient HBV DNA calibrators to investigate the origin and relationship of these taxa to other HBV sequences. We inferred a substitution rate of 1.4 × 10-5 [95% HPD 8.8 × 10-6, 2.0 × 10-5] and a time to the most recent common ancestor of 629 CE [95% HPD 37-1138 CE]. The Greenland taxa form a sister clade to HBV/D2 sequences, specifically New Caledonian and Indigenous Taiwanese sequences. The Greenland sequences share amino acid signatures with subgenotypes D1 and D2 and ~97% sequence identity. Our results suggest the classification of these novel sequences does not fit within the current nomenclature. Thus, we propose these taxa be considered a novel quasi-subgenotype.
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Affiliation(s)
| | - Carla Osiowy
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada
| | - Reilly Hostager
- Department of Medicine, University of California San Diego, San Diego, CA, United States
| | - Henrik Krarup
- Department of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark
- Department of Medical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
- Clinical Institute, Aalborg University, Aalborg, Denmark
| | - Malene Børresen
- Department of Epidemiological Research, Statens Serum Institut, Copenhagen, Denmark
| | - Yasuhito Tanaka
- Department of Virology & Liver, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Taylor Morriseau
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada
| | - Joel O. Wertheim
- Department of Medicine, University of California San Diego, San Diego, CA, United States
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32
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Araujo NM, Teles SA, Spitz N. Comprehensive Analysis of Clinically Significant Hepatitis B Virus Mutations in Relation to Genotype, Subgenotype and Geographic Region. Front Microbiol 2020; 11:616023. [PMID: 33381105 PMCID: PMC7767914 DOI: 10.3389/fmicb.2020.616023] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 11/25/2020] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus (HBV) is a highly variable DNA virus due to its unique life cycle, which involves an error-prone reverse transcriptase. The high substitution rate drives the evolution of HBV by generating genetic variants upon which selection operates. HBV mutants with clinical implications have been documented worldwide, indicating the potential for spreading and developing their own epidemiology. However, the prevalence of such mutants among the different HBV genotypes and subgenotypes has not been systematically analyzed. In the current study, we performed large-scale analysis of 6,479 full-length HBV genome sequences from genotypes A-H, with the aim of gaining comprehensive insights into the relationships of relevant mutations associated with immune escape, antiviral resistance and hepatocellular carcinoma (HCC) development with HBV (sub)genotypes and geographic regions. Immune escape mutations were detected in 10.7% of the sequences, the most common being I/T126S (1.8%), G145R (1.2%), M133T (1.2%), and Q129R (1.0%). HBV genotype B showed the highest rate of escape mutations (14.7%) while genotype H had no mutations (P < 0.001). HCC-associated mutations were detected in 33.7% of the sequences, with significantly higher frequency of C1653T, T1753V and A1762T/G1764A in genotype G than C (P < 0.001). The overall frequencies of lamivudine-, telbivudine-, adefovir-, and entecavir-resistant mutants were 7.3, 7.2, 0.5, and 0.2%, respectively, while only 0.05% showed reduced susceptibility to tenofovir. In particular, the highest frequency of lamivudine-resistant mutations was observed in genotype G and the lowest frequency in genotype E (32.5 and 0.3%; P < 0.001). The prevalence of HBV mutants was also biased by geographic location, with North America identified as one of the regions with the highest rates of immune escape, antiviral resistance, and HCC-associated mutants. The collective findings were discussed in light of natural selection and the known characteristics of HBV (sub)genotypes. Our data provide relevant information on the prevalence of clinically relevant HBV mutations, which may contribute to further improvement of diagnostic procedures, immunization programs, therapeutic protocols, and disease prognosis.
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Affiliation(s)
- Natalia M Araujo
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil
| | - Sheila A Teles
- Faculty of Nursing, Federal University of Goias, Goiânia, Brazil
| | - Natália Spitz
- Laboratory of Molecular Virology, Oswaldo Cruz Institute, FIOCRUZ, Rio de Janeiro, Brazil
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33
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Liu Y, May L, Liu X, Martin R, Svarovskaia E, Gaggar A, Mo H, Feierbach B. Developing a sensitive HBV genotyping assay for HBV DNA suppressed patients using both DNA and RNA sequencing. J Med Virol 2020; 92:3420-3425. [PMID: 32609910 DOI: 10.1002/jmv.26249] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 06/01/2020] [Accepted: 06/29/2020] [Indexed: 12/17/2022]
Abstract
Hepatitis B virus (HBV) genotypes impact treatment outcomes and disease progression. The current genotyping methods have limitations in patients with low HBV viral load. In this study, a more sensitive assay has been developed for determining the HBV genotype in HBV DNA suppressed patients. Fifty-five serum samples from 55 chronic hepatitis B patients (HBeAg-, n = 20; HBeAg+, n = 35) across genotypes A to H with long-term nucleos(t)ide analogs (NAs) treatment were collected. All samples had HBV DNA less than 29 IU/mL. Total nucleic acid (viral DNA and RNA) was extracted and a 341 bp amplicon located at HBV S gene overlapping with reverse transcriptase domain of polymerase (pol/RT) was amplified via real time (RT)-nested polymerase chain reaction (PCR) followed by population sequencing. HBV genotype was determined by phylogenetic analysis. The assay successfully amplified HBV S/RT gene from 53 of 55 (96.4%) patient serum samples. Phylogenetic analysis demonstrated that the genotypes of all the 53 PCR positive samples matched the historical genotypes as determined by INNO-LiPA or RT sequence from the corresponding baseline samples. This assay was able to accurately determine HBV genotype irrespective of baseline genotype, HBeAg status, or duration of viral suppression. The ability to determine genotype in virally suppressed patients may facilitate the evaluation of novel treatment agents for HBV in this patient population.
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Affiliation(s)
- Yang Liu
- Gilead Sciences, Inc., Foster City, California
| | - Lindsey May
- Gilead Sciences, Inc., Foster City, California
| | - Xinan Liu
- Gilead Sciences, Inc., Foster City, California
| | - Ross Martin
- Gilead Sciences, Inc., Foster City, California
| | | | - Anuj Gaggar
- Gilead Sciences, Inc., Foster City, California
| | - Hongmei Mo
- Gilead Sciences, Inc., Foster City, California
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34
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Jaspe RC, Loureiro CL, Chemin I, Pujol FH. Mutation pattern and methylation susceptibility of Hepatitis B virus American genotypes. Clin Res Hepatol Gastroenterol 2020; 44:973-976. [PMID: 32814675 DOI: 10.1016/j.clinre.2020.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 02/12/2020] [Accepted: 02/12/2020] [Indexed: 02/07/2023]
Affiliation(s)
- Rossana C Jaspe
- Laboratorio de Virología Molecular, CMBC, IVIC, Apdo 20632, 1020A Caracas, Venezuela
| | - Carmen L Loureiro
- Laboratorio de Virología Molecular, CMBC, IVIC, Apdo 20632, 1020A Caracas, Venezuela
| | - Isabelle Chemin
- INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France
| | - Flor H Pujol
- Laboratorio de Virología Molecular, CMBC, IVIC, Apdo 20632, 1020A Caracas, Venezuela.
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35
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Pujol F, Jaspe RC, Loureiro CL, Chemin I. Hepatitis B virus American genotypes: Pathogenic variants ? Clin Res Hepatol Gastroenterol 2020; 44:825-835. [PMID: 32553521 DOI: 10.1016/j.clinre.2020.04.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/19/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) chronic infection is responsible for almost 900.000 deaths each year, due to cirrhosis or hepatocellular carcinoma (HCC). Ten HBV genotypes have been described (A-J). HBV genotype F and H circulate in America. HBV genotypes have been further classified in subgenotypes. There is a strong correlation between the genetic admixture of the American continent and the frequency of genotypes F or H: a high frequency of these genotypes is found in countries with a population with a higher ratio of Amerindian to African genetic admixture. The frequency of occult HBV infection in Amerindian communities from Latin America seems to be higher than the one found in other HBV-infected groups, but its association with American genotypes is unknown. There is growing evidence that some genotypes might be associated with a faster evolution to HCC. In particular, HBV genotype F has been implicated in a frequent and rapid progression to HCC. However, HBV genotype H has been associated to a less severe progression of disease. This study reviews the diversity and frequency of autochthonous HBV variants in the Americas and evaluates their association to severe progression of disease. Although no significant differences were found in the methylation pattern between different genotypes and subgenotypes of the American types, basal core promoter mutations might be more frequent in some subgenotypes, such as F1b and F2, than in other American subgenotypes or genotype H. F1b and probably F2 may be associated with a severe presentation of liver disease as opposed to a more benign course for subgenotype F4 and genotype H. Thus, preliminary evidence suggests that not all of the American variants are associated with a rapid progression to HCC.
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Affiliation(s)
- Flor Pujol
- Laboratorio de Virología Molecular, CMBC, IVIC, Apdo 20632, Caracas 1020A, Venezuela.
| | - Rossana C Jaspe
- Laboratorio de Virología Molecular, CMBC, IVIC, Apdo 20632, Caracas 1020A, Venezuela
| | - Carmen L Loureiro
- Laboratorio de Virología Molecular, CMBC, IVIC, Apdo 20632, Caracas 1020A, Venezuela
| | - Isabelle Chemin
- INSERM U1052, CNRS 5286, Université de Lyon, Université Claude Bernard Lyon 1, centre Léon Bérard, centre de recherche en cancérologie de Lyon, 69000, Lyon, France
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36
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D'souza S, Lau KCK, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol 2020; 26:5759-5783. [PMID: 33132633 PMCID: PMC7579760 DOI: 10.3748/wjg.v26.i38.5759] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 09/03/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC) represents 90% of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV), hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins. DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.
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Affiliation(s)
- Simmone D'souza
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Keith CK Lau
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Carla S Coffin
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
| | - Trushar R Patel
- Department of Microbiology, Immunology, and Infectious Diseases, Cumming School of Medicine, University of Calgary, Calgary T2N 1N4, AB, Canada
- Department of Chemistry and Biochemistry, Alberta RNA Research and Training Institute, University of Lethbridge, Lethbridge T1K3M4, AB, Canada
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37
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Affiliation(s)
| | | | - Priya Abraham
- Department of Virology, Christian Medical College, Vellore, 632 004, India
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38
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Mojsiejczuk L, Torres C, Flichman D, Campos RH. Long-term evolution of hepatitis B virus genotype F: Strong association between viral diversification and the prehistoric settlement of Central and South America. J Viral Hepat 2020; 27:620-630. [PMID: 32052519 DOI: 10.1111/jvh.13273] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Revised: 01/30/2020] [Accepted: 02/04/2020] [Indexed: 12/13/2022]
Abstract
The genotype F (HBV-F) is an autochthonous Native American strain of the hepatitis B virus. In this study, we reconstruct the HBV-F long-term evolution under a hypothesis of co-divergence with humans in Central and South America, since their entry into the region 14.5-16 thousand years ago. The Bayesian phylogeographic reconstruction supported a virus-host co-expansion; however, two evolutionary scenarios would have been present. Whereas subgenotype F1 spreads along a Pacific coastal route and would have evolved associated with Central American and Andean cultures from the west of the continent, subgenotypes F2-F6 spread along the Atlantic coastline and inner pathways associated with communities inhabiting the tropical forest lowlands. Then, we propose a model for HBV-F evolution in which the selection of differential biological characteristics in these two main groups would be related to their evolution in host populations with different genetic backgrounds and dissimilar demographic conditions.
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Affiliation(s)
- Laura Mojsiejczuk
- Facultad de Farmacia y Bioquímica, Instituto de Investigaciones en Bacteriología y Virología Molecular (IBaViM), Universidad de Buenos Aires, Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Carolina Torres
- Facultad de Farmacia y Bioquímica, Instituto de Investigaciones en Bacteriología y Virología Molecular (IBaViM), Universidad de Buenos Aires, Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Diego Flichman
- Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina.,Instituto de Investigaciones Biomédicas en Retrovirus y SIDA (INBIRS), Universidad de Buenos Aires-CONICET, Buenos Aires, Argentina
| | - Rodolfo Héctor Campos
- Facultad de Farmacia y Bioquímica, Instituto de Investigaciones en Bacteriología y Virología Molecular (IBaViM), Universidad de Buenos Aires, Buenos Aires, Argentina.,Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
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39
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McNaughton AL, Revill PA, Littlejohn M, Matthews PC, Ansari MA. Analysis of genomic-length HBV sequences to determine genotype and subgenotype reference sequences. J Gen Virol 2020; 101:271-283. [PMID: 32134374 PMCID: PMC7416611 DOI: 10.1099/jgv.0.001387] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 01/08/2020] [Indexed: 12/11/2022] Open
Abstract
Hepatitis B virus (HBV) is a diverse, partially double-stranded DNA virus, with 9 genotypes (A-I), and a putative 10th genotype (J), characterized thus far. Given the broadening interest in HBV sequencing, there is an increasing requirement for a consistent, unified approach to HBV genotype and subgenotype classification. We set out to generate an updated resource of reference sequences using the diversity of all genomic-length HBV sequences available in public databases. We collated and aligned genomic-length HBV sequences from public databases and used maximum-likelihood phylogenetic analysis to identify genotype clusters. Within each genotype, we examined the phylogenetic support for currently defined subgenotypes, as well as identifying well-supported clades and deriving reference sequences for them. Based on the phylogenies generated, we present a comprehensive set of HBV reference sequences at the genotype and subgenotype level. All of the generated data, including the alignments, phylogenies and chosen reference sequences, are available online (https://doi.org/10.6084/m9.figshare.8851946) as a simple open-access resource.
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Affiliation(s)
- Anna L. McNaughton
- Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, UK
| | - Peter A. Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
- Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute for Infection and Immunity, Melbourne, Australia
- Department of Microbiology and Immunology, University of Melbourne, Melbourne, Australia
| | - Philippa C. Matthews
- Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, South Parks Road, Oxford OX1 3SY, UK
- Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK
- Oxford NIHR Biomedical Research Centre, John Radcliffe Hospital, Headley Way, Oxford OX3 9DU, UK
| | - M. Azim Ansari
- Wellcome Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK
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40
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Pineau P, Ruiz E, Deharo E, Bertani S. On hepatocellular carcinoma in South America and early-age onset of the disease. Clin Res Hepatol Gastroenterol 2019; 43:522-526. [PMID: 30482474 DOI: 10.1016/j.clinre.2018.10.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 10/26/2018] [Indexed: 02/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most predominant tumor types worldwide, being particularly prevalent in sub-Saharan Africa and East Asia. However, HCC is inexplicably underreported in South America, despite unsettling clinical epidemiological trends of the disease on this continent. Here, we review the current knowledge on HCC presentation in Peru. We emphasize the well-documented occurrence of an early-age nosological form of the disease in Andean descent populations. We further discuss the reasons for such HCC clinical presentation, as well as the implications for liver cancer screening, management, and prevention.
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Affiliation(s)
- Pascal Pineau
- Institut Pasteur, Unité organisation nucléaire et oncogenèse, Inserm, U 993, 75015 Paris, France.
| | - Eloy Ruiz
- Instituto nacional de enfermedades neoplasicas, Departamento de cirugía en abdomen, 34 Lima, Peru
| | - Eric Deharo
- Université de Toulouse, IRD, UPS, UMR 152 Pharmadev, 31000 Toulouse, France
| | - Stéphane Bertani
- Université de Toulouse, IRD, UPS, UMR 152 Pharmadev, 31000 Toulouse, France.
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41
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Lago BV, do Espirito-Santo MP, Costa VD, Marques VA, Villar LM, Lewis-Ximenez LL, Lampe E, Mello FCA. Genetic Diversity of the Hepatitis B Virus Subgenotypes in Brazil. Viruses 2019; 11:v11090860. [PMID: 31540166 PMCID: PMC6784006 DOI: 10.3390/v11090860] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 06/29/2019] [Accepted: 07/04/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) subgenotypes may be related to clinical outcomes and response to antiviral therapy. Most Brazilian studies on HBV subgenotypes are restricted to some regions and to specific population groups. Here, we provide an insight about genetic diversity of HBV subgenotypes in 321 serum samples from all five geographical regions, providing a representative overview of their circulation among chronic carriers. Overall, HBV/A1 was the most prevalent subgenotype, being found as the major one in all regions except in South Brazil. Among HBV/D samples, subgenotype D3 was the most prevalent, found in 51.5%, followed by D2 (27.3%) and D4 (21.2%). D2 and D3 were the most prevalent subgenotypes in South region, with high similarity with European strains. D4 was found in North and Northeast region and clustered with strains from Cape Verde and India. For HBV/F, the most frequent subgenotype was F2 (84.1%), followed by F4 (10.1%) and F1 (5.8%), closely related with strains from Venezuela, Argentina and Chile, respectively. Phylogeographic analyses were performed using an HBV full-length genome obtained from samples infected with genotypes rarely found in Brazil (B, C, and E). According to Bayesian inference, HBV/B2 and HBV/C2 were probably introduced in Brazil through China, and HBV/E from Guinea, all of them mostly linked to recent events of human migration. In conclusion, this study provided a comprehensive overview of the current circulation of HBV subgenotypes in Brazil. Our findings might contribute to a better understand of the dynamics of viral variants, to establish a permanent molecular surveillance on the introduction and dispersion patterns of new strains and, thus, to support public policies to control HBV dissemination in Brazil.
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Affiliation(s)
- Barbara V Lago
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ 21040-900, Brazil.
- Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), FIOCRUZ, Rio de Janeiro, RJ 21040-900, Brazil.
| | - Marcia P do Espirito-Santo
- Instituto de Tecnologia em Imunobiológicos (Bio-Manguinhos), FIOCRUZ, Rio de Janeiro, RJ 21040-900, Brazil.
| | - Vanessa D Costa
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ 21040-900, Brazil.
| | - Vanessa A Marques
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ 21040-900, Brazil.
| | - Livia M Villar
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ 21040-900, Brazil.
| | - Lia L Lewis-Ximenez
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ 21040-900, Brazil.
| | - Elisabeth Lampe
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ 21040-900, Brazil.
| | - Francisco C A Mello
- Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, RJ 21040-900, Brazil.
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42
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Limeres MJ, Gomez ER, Noseda DG, Cerrudo CS, Ghiringhelli PD, Nusblat AD, Cuestas ML. Impact of hepatitis B virus genotype F on in vitro diagnosis: detection efficiency of HBsAg from Amerindian subgenotypes F1b and F4. Arch Virol 2019; 164:2297-2307. [PMID: 31267215 DOI: 10.1007/s00705-019-04332-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 05/31/2019] [Indexed: 02/06/2023]
Abstract
The influence of the high genetic variability of hepatitis B virus (HBV) on the sensitivity of serological assays has received little attention so far. A major source of variability is related to viral genotypes and subgenotypes. Their possible influence on diagnosis and prophylaxis is poorly known and has mostly been evaluated for genotypes A, B, C and D. Robust data showing the detection efficiency of HBsAg from genotype F is lacking. This study examined the effect of virus-like particles containing HBsAg from genotypes A and F (particularly, F1b and F4) produced in Pichia pastoris in relation to the anti-HBs antibodies used in the immunoassays for in vitro diagnosis and compared it with that exerted by the G145R S-escape mutant. The results showed that HBsAg detection rates for subgenotypes F1b and F4 differed significantly from those obtained for genotype A and that subgenotype F1b had a major impact on the sensitivity of the immunoassays tested. Prediction of the tertiary structure of subgenotypes F1b and F4 revealed changes inside and outside the major hydrophilic region (aa 101-160) of the HBsAg compared to genotype A and the G145R variant. A phosphorylation site (target for protein kinase C) produced by the G145R substitution might prevent recognition by anti-HBs antibodies. In conclusion, the use of different genotypes or variants for diagnosis could improve the rate of detection of HBV infection. The incorporation of a genotype-F-derived HBsAg vaccine in areas where this genotype is endemic should be evaluated, since this might also affect vaccination efficacy.
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Affiliation(s)
- María J Limeres
- CONICET, Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Evangelina R Gomez
- Instituto de Agrobiotecnología y Biología Molecular, INTA-CONICET, Buenos Aires, Argentina
| | - Diego G Noseda
- Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús (IIB-INTECH), Universidad Nacional de San Martín (UNSAM)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | - Carolina S Cerrudo
- Departamento de Ciencia y Tecnología, Laboratorio de Ingeniería Genética y Biología Celular y Molecular, Área Virosis de Insectos (LIGBCM-AVI), Instituto de Microbiología Básica y Aplicada (IMBA), Universidad Nacional de Quilmes, Bernal, Provincia de Buenos Aires, Argentina
| | - Pablo D Ghiringhelli
- Departamento de Ciencia y Tecnología, Laboratorio de Ingeniería Genética y Biología Celular y Molecular, Área Virosis de Insectos (LIGBCM-AVI), Instituto de Microbiología Básica y Aplicada (IMBA), Universidad Nacional de Quilmes, Bernal, Provincia de Buenos Aires, Argentina
| | - Alejandro D Nusblat
- Facultad de Farmacia y Bioquímica, Instituto de Nanobiotecnología (NANOBIOTEC), Universidad de Buenos Aires, Buenos Aires, Argentina
| | - María L Cuestas
- CONICET, Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM), Universidad de Buenos Aires, Buenos Aires, Argentina.
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43
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Tsushima K, Tsuge M, Hiraga N, Uchida T, Murakami E, Makokha GN, Kurihara M, Nomura M, Hiyama Y, Fujino H, Ono A, Nakahara T, Yamauchi M, Abe-Chayama H, Kawaoka T, Miki D, Imamura M, Aikata H, Hayes CN, Chayama K. Comparison of intracellular responses between HBV genotype A and C infection in human hepatocyte chimeric mice. J Gastroenterol 2019; 54:650-659. [PMID: 30790056 DOI: 10.1007/s00535-019-01558-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 02/07/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS The clinical course and responsiveness to antiviral treatments differs among hepatitis B virus (HBV) genotypes. However, the cause of these differences is unclear. In the present study, we compared mRNA expression profiles in human hepatocyte chimeric mice infected with HBV genotypes A and C. METHODS Fifteen chimeric mice were prepared and divided into the following three groups: uninfected control mice, HBV genotype A-infected mice, and HBV genotype C-infected mice. Human hepatocytes were collected from these mouse livers and gene expression analyses were performed using next-generation RNA sequencing. RESULTS Although similar pathways were influenced by HBV infection, including inflammation mediated by chemokine and cytokine signaling, p53, and integrin signaling pathways, expression levels of up-regulated genes by HBV genotype A or C infection were quite different. In HBV genotype A-infected hepatocytes, 172 genes, including KRT23 and C10orf54, were significantly more highly expressed than in HBV genotype C-infected cells, whereas 10 genes, including SPX and IER3, were expressed at significantly lower levels. Genes associated with the p53 pathway and the inflammation mediated by chemokine and cytokine signaling pathway were more highly expressed in cells with HBV genotype A infection, whereas genes associated with CCKR signaling map and oxidative stress response were more highly expressed in cells with HBV genotype C infection. CONCLUSION Several differences in gene expression with respect to HBV genotype A and C infection were detected in human hepatocytes. These differences might be associated with genotypic difference in the clinical course or responsiveness to treatment.
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Affiliation(s)
- Ken Tsushima
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Masataka Tsuge
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Nobuhiko Hiraga
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Takuro Uchida
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Grace Naswa Makokha
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Mio Kurihara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Motonobu Nomura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Yuichi Hiyama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hatsue Fujino
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Masami Yamauchi
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hiromi Abe-Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.,Center for Medical Specialist Graduate Education and Research, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tomokazu Kawaoka
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Daiki Miki
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Michio Imamura
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Clair Nelson Hayes
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan.,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. .,Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, Japan.
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44
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Ren CC, Chen QY, Wang XY, Harrison TJ, Yang QL, Hu LP, Liu HB, He X, Jia HH, Fang ZL. Novel subgenotype D11 of hepatitis B virus in NaPo County, Guangxi, bordering Vietnam. J Gen Virol 2019; 100:828-837. [PMID: 30990399 DOI: 10.1099/jgv.0.001257] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B virus has been classified into 10 genotypes and 48 subgenotypes worldwide. We found previously, through polymerase chain reaction (PCR) amplification of a sample collected in 2011, that an HBsAg carrier was infected with two genotypes (B and D) of HBV. We carried out cloning, sequencing and phylogenetic analysis of the complete genomes and, for confirmation, analysed a sample collected from the same individual in 2018. Fifteen complete sequences were obtained from each sample. The carrier was infected in 2011 by genotypes B and D and by various recombinants, but only genotype D was present in 2018. The major and minor parents of the recombinants are genotypes B and D, respectively, although the recombination breakpoints vary among them. All 23 genotype D isolates form a cluster, branching out from other subgenotype D sequences and supported by a 100 % bootstrap value. Based on complete genome sequences, almost all of the estimated intragroup nucleotide divergence values between our isolates and HBV subgenotypes D1-D10 exceed 4 %. Compared to the other subgenotypes (D1-D10), 35 unique amino acids were present in our isolates. Our data provide evidence for a novel subgenotype, provisionally designated HBV subgenotype D11.
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Affiliation(s)
- Chuang-Chuang Ren
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China.,2School of Preclinical Medicine, Guangxi Medical University, UCL Medical School, 22 ShuangYong Road Nanning, Guangxi 530021, PR China
| | - Qin-Yan Chen
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China
| | - Xue-Yan Wang
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China
| | | | - Qing-Li Yang
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China
| | - Li-Ping Hu
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China
| | - Hua-Bing Liu
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China.,2School of Preclinical Medicine, Guangxi Medical University, UCL Medical School, 22 ShuangYong Road Nanning, Guangxi 530021, PR China
| | - Xiang He
- 4Guangdong Provincial Institute of Public Health, Guangdong Provincial Center for Disease Control and Prevention, Guangzhou 511430, PR China
| | - Hui-Hua Jia
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China.,2School of Preclinical Medicine, Guangxi Medical University, UCL Medical School, 22 ShuangYong Road Nanning, Guangxi 530021, PR China
| | - Zhong-Liao Fang
- 1Guangxi Zhuang Autonomous Region Center for Disease Prevention and Control, Guangxi Key Laboratory for the Prevention and Control of Viral Hepatitis, Nanning, Guangxi 530028, PR China
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45
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Indolfi G, Easterbrook P, Dusheiko G, Siberry G, Chang MH, Thorne C, Bulterys M, Chan PL, El-Sayed MH, Giaquinto C, Jonas MM, Meyers T, Walsh N, Wirth S, Penazzato M. Hepatitis B virus infection in children and adolescents. Lancet Gastroenterol Hepatol 2019; 4:466-476. [PMID: 30982722 DOI: 10.1016/s2468-1253(19)30042-1] [Citation(s) in RCA: 118] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2018] [Revised: 01/20/2019] [Accepted: 01/22/2019] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus (HBV) infection is a major cause of acute and chronic liver disease and associated morbidity and mortality worldwide. Vertical (mother-to-child) and horizontal early childhood transmission are the main routes of HBV transmission and are responsible for most chronic infections, including among adults who bear the greatest burden of morbidity and mortality. Universal hepatitis B immunisation at birth and in infancy is the key strategy for global elimination of HBV infection, and has been highly effective in reducing new vertical infections. However, global progress in scale-up of HBV testing and treatment has been slow in adults and children. In this Series paper, we summarise knowledge on the epidemiology, natural history, and treatment of chronic HBV infection in adolescents and children, and we highlight key differences from HBV infection in adults. The estimated global prevalence of HBV infection in children aged 5 years or younger is 1·3%. Most children are in the high-replication, low-inflammation phase of infection, with normal or only slightly raised aminotransferases; cirrhosis and hepatocellular carcinoma are rare. Although entecavir is approved and recommended for children aged 2-17 years, and tenofovir for those aged 12-18 years, a conservative approach to treatment initiation in children is recommended. Key actions to address current policy gaps include: validation of non-invasive tests for liver disease staging; additional immunopathogenesis studies in children with HBV infection; long-term follow-up of children on nucleoside or nucleotide analogue regimens to inform guidance on when to start treatment; evaluation of different treatment strategies for children with high rates of HBV replication; and establishment of paediatric treatment registries and international consortia to promote collaborative research.
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Affiliation(s)
- Giuseppe Indolfi
- Paediatric and Liver Unit, Meyer Children's University Hospital of Florence, Florence, Italy
| | - Philippa Easterbrook
- Global Hepatitis Programme and HIV Department, World Health Organization, Geneva, Switzerland.
| | - Geoffrey Dusheiko
- King's College Hospital, London, UK; University College London Medical School, London, UK
| | - George Siberry
- Office of the US Global AIDS Coordinator, US Department of State, Washington, DC, USA
| | - Mei-Hwei Chang
- Department of Paediatrics, National Taiwan University Hospital, Taipei, Taiwan
| | - Claire Thorne
- UCL Great Ormond Street Institute of Child Health, University College London, NIHR GOSH BRC, London, UK
| | - Marc Bulterys
- Global Hepatitis Programme and HIV Department, World Health Organization, Geneva, Switzerland
| | - Po-Lin Chan
- World Health Organization Regional Office for the Western Pacific, Manila, Philippines
| | - Manal H El-Sayed
- Department of Paediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Carlo Giaquinto
- Department of Women and Child Health, University of Padova, Padova, Italy
| | - Maureen M Jonas
- Division of Gastroenterology, Hepatology, and Nutrition, Boston Children's Hospital, Boston, MA, USA
| | - Tammy Meyers
- Department of Paediatrics and Child Health, Faculty of Health Sciences, University of the Witwatersrand, South Africa
| | - Nick Walsh
- Pan American Health Organization, World Health Organization Regional Office for the Americas, Washington, DC, USA
| | - Stefan Wirth
- Department of Paediatrics, Helios Medical Centre Wuppertal, Witten-Herdecke University, Witten, Germany
| | - Martina Penazzato
- Global Hepatitis Programme and HIV Department, World Health Organization, Geneva, Switzerland
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Hayashi S, Khan A, Simons BC, Homan C, Matsui T, Ogawa K, Kawashima K, Murakami S, Takahashi S, Isogawa M, Ikeo K, Mizokami M, McMahon BJ, Tanaka Y. An Association Between Core Mutations in Hepatitis B Virus Genotype F1b and Hepatocellular Carcinoma in Alaskan Native People. Hepatology 2019; 69:19-33. [PMID: 29893492 DOI: 10.1002/hep.30111] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2017] [Accepted: 05/18/2018] [Indexed: 12/15/2022]
Abstract
Hepatitis B virus (HBV) genotype F1b infection is strongly associated with hepatocellular carcinoma (HCC) in young Alaskan Native (AN) people. However, the mechanisms by which genotype F1b causes HCC are unclear. Here, we analyzed the clinical and virological significance of genotype F1b in long-term serial samples from 20 HCC patients with HBV infection. Complete sequence analyses revealed that all isolates were genotype F1b. In the HCC patients, T1938C and A2051C mutations in the core region had accumulated significantly with A1762T/G1764A mutations in the basal core promoter (BCP) region and G1896A mutation in the precore (PC) region. Several HBV clones containing the core mutations were examined for their replication efficiency and core stability in vitro. Clones containing the A2051C mutation replicated more efficiently than the wild type in association with enhanced stability of core protein dimerization. In chimeric mice with human hepatocytes carrying BCP/PC/2051 mutant but not with wild-type virus, liver fibrosis was induced in association with high levels of serum HBV DNA and hepatitis B surface antigen. Interestingly, microarray analysis and validation study showed that five genes associated with cell proliferation or carcinogenesis, v-myc avian myelocytomatosis viral oncogene homolog, Grb2-associated binding protein 2, bradykinin receptor B2, follistatin, and mitogen-activated protein kinase kinase kinase 8, were significantly up-regulated in human hepatocytes infected with genotype F1b, particularly the BCP/PC/2051 mutant, compared with other genotypes. Conclusion: We have identified an association between Alaska-specific core mutations and HCC development in AN people infected with genotype F1b; accumulation of these core mutations during the course of chronic infection with genotype F1b would contribute to HCC development in AN people earlier in life.
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Affiliation(s)
- Sanae Hayashi
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan
| | - Anis Khan
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan
| | - Brenna C Simons
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA
| | - Chriss Homan
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA
| | - Takeshi Matsui
- Center for Gastroenterology, Teine Keijinkai Hospital, Sapporo, Japan
| | - Kenji Ogawa
- Chemical Genetics Laboratory, RIKEN, 2-1 Hirosawa, Wako, Saitama, Japan
| | - Keigo Kawashima
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan
| | - Shuko Murakami
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Masanori Isogawa
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan
| | - Kazuho Ikeo
- Center for Information Biology, National Institute of Genetics, Mishima, Japan
| | - Masashi Mizokami
- The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Brian J McMahon
- Liver Disease and Hepatitis Program, Alaska Native Tribal Health Consortium, Anchorage, AK, USA
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Science, Nagoya, Japan
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McNaughton AL, D'Arienzo V, Ansari MA, Lumley SF, Littlejohn M, Revill P, McKeating JA, Matthews PC. Insights From Deep Sequencing of the HBV Genome-Unique, Tiny, and Misunderstood. Gastroenterology 2019; 156:384-399. [PMID: 30268787 PMCID: PMC6347571 DOI: 10.1053/j.gastro.2018.07.058] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 06/27/2018] [Accepted: 07/23/2018] [Indexed: 12/13/2022]
Abstract
Hepatitis B virus (HBV) is a unique, tiny, partially double-stranded, reverse-transcribing DNA virus with proteins encoded by multiple overlapping reading frames. The substitution rate is surprisingly high for a DNA virus, but lower than that of other reverse transcribing organisms. More than 260 million people worldwide have chronic HBV infection, which causes 0.8 million deaths a year. Because of the high burden of disease, international health agencies have set the goal of eliminating HBV infection by 2030. Nonetheless, the intriguing HBV genome has not been well characterized. We summarize data on the HBV genome structure and replication cycle, explain and quantify diversity within and among infected individuals, and discuss advances that can be offered by application of next-generation sequencing technology. In-depth HBV genome analyses could increase our understanding of disease pathogenesis and allow us to better predict patient outcomes, optimize treatment, and develop new therapeutics.
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Affiliation(s)
- Anna L McNaughton
- Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom
| | - Valentina D'Arienzo
- Nuffield Department of Medicine, NDM Research Building, Oxford, United Kingdom
| | - M Azim Ansari
- Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom
| | - Sheila F Lumley
- Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom; Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom
| | - Margaret Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute of Infection and Immunity, Melbourne, Australia; Department of Microbiology and Immunology, University of Melbourne. Melbourne, Australia
| | - Peter Revill
- Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at the Peter Doherty Institute of Infection and Immunity, Melbourne, Australia; Department of Microbiology and Immunology, University of Melbourne. Melbourne, Australia
| | - Jane A McKeating
- Nuffield Department of Medicine, NDM Research Building, Oxford, United Kingdom
| | - Philippa C Matthews
- Nuffield Department of Medicine, Peter Medawar Building for Pathogen Research, Oxford, United Kingdom; Department of Infectious Diseases and Microbiology, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, United Kingdom.
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48
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Cuenca-Gómez JÁ, Lozano-Serrano AB, Cabezas-Fernández MT, Soriano-Pérez MJ, Vázquez-Villegas J, Estévez-Escobar M, Cabeza-Barrera I, Salas-Coronas J. Chronic hepatitis B genotype E in African migrants: response to nucleos(t)ide treatment in real clinical practice. BMC Infect Dis 2018; 18:568. [PMID: 30428845 PMCID: PMC6236963 DOI: 10.1186/s12879-018-3469-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Accepted: 10/31/2018] [Indexed: 12/18/2022] Open
Abstract
Background Hepatitis B virus (HBV) genotype E is a poorly studied genotype that almost exclusively occurs in African people. It seems to harbour intrinsic potential oncogenic activity and virological characteristics of immune scape but a paucity of information is available on clinical and virological characteristic of HBV genotype E-infected patients as well as on the efficacy of anti-HBV drugs for such patients. The increasing flow of migrants from high endemic HBV sub-Saharan Africa, where genotype E is the predominant one, to Western countries makes improving such knowledge critical in order to deliver proper medical care. Methods Prospective observational study of naïve patients of sub-Saharan origin treated for chronic HBV genotype E infection at a Tropical Medicine clinic sited in Spain from February 2004 to January 2018. The aim of the study was to describe the response of chronic HBV genotype E infection to nucleos(t)ide analogues (NA), entecavir or tenofovir, in real clinical practice. Results During the study period, 2209 sub-Saharan patients were assisted at our Tropical Medicine Unit and 609 (27.6%) had chronic HBV (CHB) infection. Genotype information was available for 55 naïve patients initiating treatment with NA (entecavir or tenofovir), 43 (84.3%) of them being genotype E, although 15 were excluded because they did not meet study inclusion criteria. Thus, a total of 28 CHB genotype E patients were included and followed for 24 months at least. Twenty-one patients were in HBeAg-negative chronic hepatitis phase and 7 patients in HBeAg-positive chronic hepatitis phase. After one year of treatment, among those with good adherence, 89.4% (17/19) of the HBeAg-negative patients and 80% of the HBeAg-positive ones had undetectable viral loads. Response rates reached 100% in both groups after 15–18 months of follow-up. Out of the 7 HBeAg-positive patients, 6 (85.7%) presented HBeAg loss in a median time of 31.8 months. Neither serious adverse effects nor hepatocarcinoma cases happened during the study period. Conclusions HBV genotype may influence disease progression and antiviral response. Our study provides precious information on the efficacy and safety of NA treatment for CHB genotype E infection, a fairly unknown genotype with and increasing epidemiological impact.
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Affiliation(s)
- José Ángel Cuenca-Gómez
- Tropical Medicine Unit, Hospital de Poniente, Carretera de Almerimar s/n, PD: 07400, Almería, El Ejido, Spain.
| | - Ana Belén Lozano-Serrano
- Tropical Medicine Unit, Hospital de Poniente, Carretera de Almerimar s/n, PD: 07400, Almería, El Ejido, Spain
| | | | - Manuel Jesús Soriano-Pérez
- Tropical Medicine Unit, Hospital de Poniente, Carretera de Almerimar s/n, PD: 07400, Almería, El Ejido, Spain
| | | | | | - Isabel Cabeza-Barrera
- Tropical Medicine Unit, Hospital de Poniente, Carretera de Almerimar s/n, PD: 07400, Almería, El Ejido, Spain
| | - Joaquín Salas-Coronas
- Tropical Medicine Unit, Hospital de Poniente, Carretera de Almerimar s/n, PD: 07400, Almería, El Ejido, Spain
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Datta S, Dasgupta D, Ghosh A, Ghosh S, Manna A, Datta S, Chatterjee M, Chowdhury A, Banerjee S. Oncogenic potential of hepatitis B virus subgenotype D1 surpasses D3: significance in the development of hepatocellular carcinoma. Carcinogenesis 2018; 39:283-292. [PMID: 29228221 DOI: 10.1093/carcin/bgx145] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 12/06/2017] [Indexed: 12/15/2022] Open
Abstract
Despite widespread distribution of hepatitis B virus (HBV)-genotype D, the clinical implications of its ten subgenotypes (D1-D10) have not been well documented. Here, we have investigated the impact of two major circulating HBV/D subgenotypes, D1 and D3 in Eastern India towards pathogenesis of liver disease progression to hepatocellular carcinoma (HCC). HBV subgenotypes were determined using full-length genome sequences of HBV isolates from patients with chronic hepatitis B (CHB), liver cirrhosis (LC) and HCC. Impact of D1 and D3 on viral lifecycle and disease progression was assessed by several in vitro assays. Phylogenetic tree analysis revealed that HBV/D1 and HBV/D3 were the two predominating HBV subgenotypes circulating in Eastern India. Interestingly, the frequency of patients infected with HBV/D1 was noticed progressively rising from CHB to HCC through LC while the increasing frequency of HBV/D3 declined suddenly in HCC implicating HBV/D1 might have greater oncogenic potential than HBV/D3. Similar to higher viral load noted in HCC patients infected with HBV/D1 than HBV/D3, the larger amount of intracellular/extracellular viral DNA and secreted HBsAg levels in transfected cell lines also implicated that HBV/D1 might replicate faster than HBV/D3. Again, higher expression of marker genes related to endoplasmic reticulum stress, epithelial-mesenchymal transition, DNA double strand breaks, angiogenesis etc. and faster rate of cellular migration and anchorage independent growth cumulatively suggested that compared to HBV/D3, HBV/D1 generates more liver injuries which eventually culminates into HCC. Therefore, our results highlight the importance of determination of subgenotypes of HBV in CHB patients, so that high-risk individual can be monitor periodically that may help to detect HCC at early stages.
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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
| | - Debanjali Dasgupta
- 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
| | - Suchandrima Ghosh
- Centre for Liver Research, School of Digestive and Liver Diseases, Institute of Post Graduate Medical Education and Research, Kolkata, India
| | - Alak Manna
- Department of Pharmacology, 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
| | - Mitali Chatterjee
- Department of Pharmacology, 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
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50
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Chen L, Shi Y, Yang W, Zhang Y, Xie Q, Li Y, Li X, Li J, Zhang Z. Differences in Cpg Island Distribution Between Subgenotypes of the Hepatitis B Virus Genotype. Med Sci Monit 2018; 24:6781-6794. [PMID: 30253420 PMCID: PMC6180904 DOI: 10.12659/msm.910049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background Hepatitis B virus (HBV) genotypes show genomic variations, resulting in different CpG islands in each HBV genotypes or subgenotype. This study aimed to establish reference sequences for each HBV subgenotype of A–H genotypes and to analyze the characteristics of the CpG islands. Material/Methods There were 3,037 retrieved whole-genome sequences of HBV genotypes A–H from GenBank, 28 subgenotype reference sequences were established for these genotypes. CpG islands of the subgenotype reference sequences were analyzed, and 939 strains were selected from the 3,037 genomic sequences. Differences in CpG islands between subgenotypes were compared using the chi-squared and non-parametric tests. Results Of the 28 subgenotype reference sequences established, 11 subgenotype reference sequences lacked CpG island I, and only F4 contained a new CpG island. Of all selected strains, 48.35% (454/939) contained three traditional CpG islands I, II, and III (no new islands); 45.05% (423/939) lacked CpG island I; 38.98% (366/939) contained only CpG islands II and III; and 12.46% (117/939) contained new islands (genotypes A1, D7) (genotype G had no new islands). Strains with or without CpG island I, or new islands between subgenotypes of each HBV genotype were significantly different (P<0.05). Strains containing CpG islands I, II, and III and new islands among different subtypes in HBV genotypes A, C, and F were significantly different (P<0.05). Conclusions Different HBV genotypes and subgenotypes had characteristic CpG island patterns. Strains with or without CpG island I, or new islands among subgenotypes of each HBV genotype, were significantly different.
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Affiliation(s)
- Lin Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Yi Shi
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Wanrong Yang
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Yafei Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Qinxiu Xie
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Yunsong Li
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Xu Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei, Anhui, China (mainland)
| | - Zhenhua Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China (mainland).,School of Pharmacy, Anhui Medical University, Hefei, Anhui, China (mainland)
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