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• W2892432796 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. 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. Valentina D’ArienzoView Large Image Figure ViewerDownload Hi-res image Download (PPT)M. Azim AnsariView Large Image Figure ViewerDownload Hi-res image Download (PPT)Sheila F. LumleyView Large Image Figure ViewerDownload Hi-res image Download (PPT)Margaret LittlejohnView Large Image Figure ViewerDownload Hi-res image Download (PPT)Peter RevillView Large Image Figure ViewerDownload Hi-res image Download (PPT)Jane A. McKeatingView Large Image Figure ViewerDownload Hi-res image Download (PPT)Philippa C. MatthewsView Large Image Figure ViewerDownload Hi-res image Download (PPT) Hepatitis B virus (HBV) was first identified in the 1960s by Baruch Blumberg, who went on to win the Nobel prize for this discovery.1London W.T. Sutnick A.I. Blumberg B.S. Australia antigen and acute viral hepatitis.Ann Intern Med. 1969; 70: 55-59Crossref PubMed Google Scholar, 2Blumberg B.S. Alter H.J. Visnich S. A “new” antigen in leukemia sera.JAMA. 1965; 191: 541-546Crossref PubMed Google Scholar The virus is a leading cause of liver disease worldwide: an estimated 250–260 million individuals are chronically infected, and approximately one third of the world’s population has serologic evidence of exposure.3World Health Organization Preventing perinatal hepatitis B virus transmission : a guide for introducing and strengthening hepatitis B birth dose vaccination.http://apps.who.int/iris/bitstream/10665/208278/1/Google Scholar HBV is a global public health problem with endemic levels of infection in Southeast Asia and Africa, where prevalence rates are at least 8% in many populations.4Schweitzer A. Horn J. Mikolajczyk R.T. et al.Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013.Lancet. 2015; 386: 1546-1555Abstract Full Text Full Text PDF PubMed Scopus (716) Google Scholar, 5Matthews P.C. Geretti A.M. Goulder P.J.R. et al.Epidemiology and impact of HIV coinfection with hepatitis B and hepatitis C viruses in Sub-Saharan Africa.J Clin Virol. 2014; 61: 20-33Abstract Full Text Full Text PDF PubMed Google Scholar However, HBV is under-represented in terms of resource allocation, political advocacy, and research.6O’Hara G.A. McNaughton A.L. Maponga T. et al.Hepatitis B virus as a neglected tropical disease.PLoS Negl Trop Dis. 2017; 11: e0005842PubMed Google Scholar Chronic HBV infection leads to liver inflammation, with long-term risks of cirrhosis and hepatocellular carcinoma (HCC).7Akinyemiju T. Abera S. Ahmed M. et al.The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level.JAMA Oncol. 2017; 3: 1683-1691Crossref PubMed Scopus (3) Google Scholar, 8Bertuccio P. Turati F. Carioli G. et al.Global trends and predictions in hepatocellular carcinoma mortality.J Hepatol. 2017; 67: 302-309Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar In contrast to the decrease in mortality from human immunodeficiency virus (HIV), tuberculosis, and malaria, HBV-associated mortality is increasing.9World Health OrganizationWorld Health Organization global hepatitis report 2017.http://apps.who.int/iris/bitstream/10665/255016/1/Google Scholar The United Nations Sustainable Development Goals set the challenge of eliminating HBV infection as a public health threat by 2030.10United NationsUnited Nations sustainable development goals 2012.http://www.un.org/sustainabledevelopment/sustainabGoogle Scholar, 11Griggs D. Stafford-Smith M. Gaffney O. et al.Policy: sustainable development goals for people and planet.Nature. 2013; 495: 305-307Crossref PubMed Scopus (555) Google Scholar However, substantial barriers to elimination include gaps in vaccine coverage, long periods between vaccination and its effects on population prevalence,12McNaughton A. Lourenço J. Hattingh L. et al.Utilising a cohort study of hepatitis B virus (HBV) vaccine-mediated immunity in South African children to model infection dynamics: can we meet global targets for elimination by 2030? Biorxiv 2017.https://www.biorxiv.org/content/early/2018/09/24/162594Google Scholar and lack of a cure. Other challenges include the virus’s resistance to drugs (and to a lesser extent vaccines),13Locarnini S. The hepatitis B virus and antiviral drug resistance: causes, patterns, and mechanisms.in: Mayers D.L. Antimicrobial drug resistance: mechanisms of drug resistance. Humana Press, Totowa, NJ2009: 519-530Crossref Google Scholar, 14Romanò L. Paladini S. Galli C. et al.Hepatitis B vaccination.Hum Vaccin Immunother. 2015; 11: 53-57Crossref PubMed Scopus (11) Google Scholar HIV coinfection, stigma, poverty, lack of education, and limited access to diagnostic tests.6O’Hara G.A. McNaughton A.L. Maponga T. et al.Hepatitis B virus as a neglected tropical disease.PLoS Negl Trop Dis. 2017; 11: e0005842PubMed Google Scholar HBV infection is treated with interferon and nucleos(t)ide analogue reverse transcriptase (RT) inhibitors—primarily tenofovir or entecavir—which can limit liver damage by suppressing viral replication.15European Association for Study of LiverEASL 2017 clinical practice guidelines on the management of hepatitis B virus infection.J Hepatol. 2017; 67: 370-398Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar However, interferon therapy is associated with unpleasant side effects and cures only a small percentage of patients. Nucleos(t)ide analogue RT inhibitors decrease viremia but have no consistent effect on clearance. Therefore, rebound viremia after cessation is common. There is a great need to cure HBV infection if we are to achieve elimination targets; curative therapy for HBV is an important goal for individual patients and the international public health agenda.16Tseng T.C. Kao J.H. Elimination of hepatitis B: is it a mission possible?.BMC Med. 2017; 15: 53Crossref PubMed Scopus (11) Google Scholar Curing HBV infection requires a detailed and robust understanding of the genetic sequence, structure, and diversity of HBV. Scientific investment is required to develop panels of diverse infectious clones that replicate in cell lines and in animals, to support drug resistance-screening programs.17Sozzi V. Walsh R. Littlejohn M. et al.In vitro studies show that sequence variability contributes to marked variation in hepatitis B virus replication, protein expression, and function observed across genotypes.J Virol. 2016; 90: 10054-10064Crossref PubMed Scopus (10) Google Scholar Detailed insights into immune control and clearance can be gained from identifying sites of immune selection pressure in the virus genome.18Klenerman P. McMichael A. AIDS/HIV: finding footprints among the trees.Science. 2007; 315: 1505-1507Crossref PubMed Scopus (0) Google Scholar This approach has helped identify immune correlates of HIV control over the past decade.18Klenerman P. McMichael A. AIDS/HIV: finding footprints among the trees.Science. 2007; 315: 1505-1507Crossref PubMed Scopus (0) Google Scholar, 19Kawashima Y. Pfafferott K. Frater J. et al.Adaptation of HIV-1 to human leukocyte antigen class I.Nature. 2009; 458: 641-645Crossref PubMed Scopus (312) Google Scholar Increasing our understanding of virus genetics can improve management of patients—in stratification, selection of therapy, identification of drug- and vaccine-resistant strains, and development of new approaches to monitoring.20Rajoriya N. Combet C. Zoulim F. et al.How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualized approach?.J Hepatol. 2017; 67: 1281-1297Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar HBV sequence data largely consist of consensus sequences of individual viral genes derived by Sanger sequencing. However, next-generation sequencing (NGS) platforms are rapidly becoming more accessible and affordable, in addition to new bioinformatic approaches to handle the resulting datasets.21Quick J. Grubaugh N.D. Pullan S.T. et al.Multiplex PCR method for MinION and Illumina sequencing of Zika and other virus genomes directly from clinical samples.Biorxiv. 2017; 12: 098913Google Scholar, 22Bui T.T.T. Tran T.T. Nghiem M.N. et al.Molecular characterization of hepatitis B virus in Vietnam.BMC Infect Dis. 2017; 17: 601Crossref PubMed Scopus (0) Google Scholar, 23Lin Y.Y. Hsieh C.H. Chen J.H. et al.De novo assembly of highly polymorphic metagenomic data using in situ generated reference sequences and a novel BLAST-based assembly pipeline.BMC Bioinformatics. 2017; 18: 223Crossref PubMed Scopus (1) Google Scholar In addition to enabling whole-genome sequencing, NGS offers a powerful method for detection of minor variants relevant to the identification of drug resistance,24Rodriguez C. Chevaliez S. Bensadoun P. et al.Characterization of the dynamics of hepatitis B virus resistance to adefovir by ultra-deep pyrosequencing.Hepatology. 2013; 58: 890-901Crossref PubMed Scopus (42) Google Scholar, 25Solmone M. Vincenti D. Prosperi M.C.F. et al.Use of massively parallel ultradeep pyrosequencing to characterize the genetic diversity of hepatitis B virus in drug-resistant and drug-naive patients and to detect minor variants in reverse transcriptase and hepatitis B S antigen.J Virol. 2009; 83: 1718-1726Crossref PubMed Scopus (0) Google Scholar, 26Shirvani-Dastgerdi E. Winer B.Y. Celià-Terrassa T. et al.Selection of the highly replicative and partially multidrug resistant rtS78T HBV polymerase mutation during TDF-ETV combination therapy.J Hepatol. 2017; 67: 246-254Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar studies of quasispecies dynamics,27Homs M. Caballero A. Gregori J. et al.Clinical application of estimating hepatitis b virus quasispecies complexity by massive sequencing: correlation between natural evolution and on-treatment evolution.PLoS One. 2014; 9: e112306Crossref PubMed Scopus (0) Google Scholar and characterization of complex viral populations.28Caballero A. Gregori J. Homs M. et al.Complex genotype mixtures analyzed by deep sequencing in two different regions of hepatitis B virus.PLoS One. 2015; 10: e0144816Crossref PubMed Scopus (1) Google Scholar Together with improved curation and publication of clinical metadata, these accurate, full-length, ultra-deep HBV sequence data provide increasing opportunities for developing new insights into HBV evolution, diversity, pathogenesis, immune control, and treatment outcomes. To provide a solid foundation for interpretation of new sequence datasets, we assimilate available data on HBV genome structure, function, and diversity and summarize gains made using NGS platforms. HBV is the prototype virus of the Hepadnaviridae family—small spherical viruses with icosahedral symmetry that combine a partial double-stranded (ds) DNA genome and virus-encoded RT. Within the Baltimore virus classification system, which classifies viruses based on their genomic composition and replication cycles,29Baltimore D. Expression of animal virus genomes.Bacteriol Rev. 1971; 35: 235-241Crossref PubMed Google Scholar the Hepadnaviridae are classified as group VII (sometimes referred to as pararetroviruses)—they are the only animal viruses of this group. Until recently, the family was divided into 2 genera: the Orthohepadnavirus species (which infect mammals, including primates and bats) and the Avihepadnavirus species (which infect birds). However, the recent discovery of putative hepadnaviruses that infect fish30Hahn C.M. Iwanowicz L.R. Cornman R.S. et al.Characterization of a novel hepadnavirus in the white sucker (Catostomus commersonii) from the Great Lakes Region of the United States.J Virol. 2015; 89: 11801-11811Crossref PubMed Scopus (0) Google Scholar and amphibians31Dill J.A. Camus A.C. Leary J.H. et al.Distinct viral lineages from fish and amphibians reveal the complex evolutionary history of hepadnaviruses.J Virol. 2016; 90: 7920-7933Crossref PubMed Scopus (16) Google Scholar indicates that the viral family might be larger than initially believed (Figure 1A).32Benson D.A. Cavanaugh M. Clark K. et al.GenBank. Nucleic Acids Res. 2013; 41: 36-42Crossref PubMed Scopus (0) Google Scholar, 33Kumar S. Stecher G. Tamura K. MEGA7: Molecular Evolutionary Genetics Analysis Version 7.0 for bigger datasets.Mol Biol Evol. 2016; 33: 1870-1874Crossref PubMed Google Scholar Based on sequence diversity, HBV is divided into 9 genotypes and 1 putative genotype (Figure 1B). Hepadnaviruses have some of the smallest known viral genomes, ranging from 3.0 to 3.3 kb; the HBV genome is approximately 3.2 kb34International Committee on Taxonomy of VirusesICTV Ninth Report; Family: Hepadnaviridae 2009.https://talk.ictvonline.org/ictv-reports/ictv_9th_report/reverse-transcribing-dna-and-rna-viruses-2011/w/rt_viruses/155/hepadnaviridaeGoogle Scholar (Figure 1C). The circular partially double stranded HBV genome encodes 4 genes— polymerase (P), surface (S; pre-S1 and pre-S2), precore/core (C) and the X protein, encoded by discrete open reading frames (ORFs; Figure 2A).35Angelo P. Different patterns of codon usage in the overlapping polymerase and surface genes of hepatitis B virus suggest a de novo origin by modular evolution.J Gen Virol. 2015; 96: 3577-3586Crossref PubMed Scopus (3) Google Scholar, 36Kay A. Zoulim F. Hepatitis B virus genetic variability and evolution.Virus Res. 2007; 127: 164-176Crossref PubMed Scopus (0) Google Scholar, 37Liu C. Fan G. Wang Z. et al.Allosteric conformational changes of human HBV core protein transform its assembly.Sci Rep. 2017; 7: 1404Crossref PubMed Scopus (2) Google Scholar, 38Dryden K.A. Wieland S.F. Whitten-Bauer C. et al.Native hepatitis B virions and capsids visualized by electron cryomicroscopy.Mol Cell. 2006; 22: 843-850Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar HBV produces 5 viral RNA transcripts of varying lengths, which are translated into 7 distinct proteins (Figure 2A and B). This basic genomic organization is common to all hepadnaviruses, although the X gene is absent from most Avihepadnavirus species (with the exception of a vestigial X gene in duck hepadnaviruses).39Lin B. Anderson D.A. A vestigial X open reading frame in duck hepatitis B virus.Intervirology. 2000; 43: 185-190Crossref PubMed Scopus (7) Google Scholar The compact nature of hepadnavirus genomes, which have multiple overlapping reading frames, results in approximately two thirds of nucleotides encoding more than 1 functional element.40Simmonds P. The origin and evolution of hepatitis viruses in humans.J Gen Virol. 2001; 82: 693-712Crossref PubMed Google Scholar This genome structure encompasses virus genes and regulatory regions and restricts redundancy within coding regions (Figure 2A). One specific example is the N-terminal region of the precore protein, which is highly conserved among Orthohepadnavirus species, likely owing to constraints from the overlapping encapsidating signal (epsilon) sequence.41Revill P. Yuen L. Walsh R. et al.Bioinformatic analysis of the hepadnavirus e-antigen and its precursor identifies remarkable sequence conservation in all orthohepadnaviruses peter.J Med Virol. 2010; 82: 105-115Crossref Scopus (18) Google Scholar The negative-sense genomic DNA strand (complementary to the mRNA transcript) is the complete strand—it is held in a circular conformation by an overlap at the 5′ end of the genome (ranging from 50 bp in Avihepadnavirus species to 240 bp in Orthohepadnavirus species). Partially double stranded relaxed circular (RC-DNA) in HBV virions is converted into covalently closed circular DNA (cccDNA) inside the hepatocyte nucleus by the viral polymerase filling in the partially single-stranded region of the genome (Figure 2B). Biogenesis of cccDNA, including the exact mechanism of DNA repair of the partially single-stranded DNA region of the RC-DNA, is not fully understood. It is likely that cell enzymes such as tyrosyl-DNA phosphodiesterase 2 contribute to cccDNA formation through cleavage of the HBV P from RC-DNA.42Lucifora J. Salvetti A. Marniquet X. et al.Detection of the hepatitis B virus (HBV) covalently-closed-circular DNA (cccDNA) in mice transduced with a recombinant AAV-HBV vector.Antiviral Res. 2017; 145: 14-19Crossref PubMed Scopus (9) Google Scholar, 43Nassal M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B.Gut. 2015; 64: 1972-1984Crossref PubMed Scopus (191) Google Scholar The viral cccDNA is extremely stable and persists in the nucleus as a viral minichromosome44Revill P. Locarnini S. Antiviral strategies to eliminate hepatitis B virus covalently closed circular DNA (cccDNA).Curr Opin Pharmacol. 2016; 30: 144-150Crossref PubMed Scopus (7) Google Scholar for the lifespan of the cell, providing the transcriptional template for all RNA species that are translated into viral proteins (Figure 2B). In addition to persisting as a minichromosome in the form of cccDNA, hepadnavirus DNA also integrates into the host genome.45Tu T. Budzinska M. Shackel N. et al.HBV DNA integration: molecular mechanisms and clinical implications.Viruses. 2017; 9https://doi.org/10.3390/v9040075Crossref Scopus (27) Google Scholar In woodchucks, integration usually occurs within Myc proto-oncogenes, eventually causing HCC in almost all infected animals.45Tu T. Budzinska M. Shackel N. et al.HBV DNA integration: molecular mechanisms and clinical implications.Viruses. 2017; 9https://doi.org/10.3390/v9040075Crossref Scopus (27) Google Scholar In humans, HBV integration can occur in different sites within the genome, and the consequences are less clear, although chronic HBV infection is associated with liver cancer.46Jiang Z. Jhunjhunwala S. Liu J. et al.The effects of hepatitis B virus integration into the genomes of hepatocellular carcinoma patients.Genome Res. 2012; 22: 593-601Crossref PubMed Scopus (0) Google Scholar After integration of HBV DNA into the host genome, only the S gene typically remains under the control of its native promoter,45Tu T. Budzinska M. Shackel N. et al.HBV DNA integration: molecular mechanisms and clinical implications.Viruses. 2017; 9https://doi.org/10.3390/v9040075Crossref Scopus (27) Google Scholar leaving these integrated genomes as a source of HBV surface antigen (HBsAg) production.47Wooddell C.I. Yuen M.F. Chan H.L. et al.RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg.Sci Transl Med. 2017; 9https://doi.org/10.1126/scitranslmed.aan0241Crossref PubMed Scopus (48) Google Scholar During infection, infectious viral particles containing HBV genomes are secreted from infected hepatocytes, in addition to smaller subviral particles and long tubular filamentous particles. These particles are empty shells formed from the HBsAg—they lack a capsid and virus genome and are therefore noninfectious.48Chai N. Chang H.E. Nicolas E. et al.Properties of subviral particles of hepatitis B virus.J Virol. 2008; 82: 7812-7817Crossref PubMed Scopus (0) Google Scholar The particles typically outnumber infectious virions by as much as 100,000-fold48Chai N. Chang H.E. Nicolas E. et al.Properties of subviral particles of hepatitis B virus.J Virol. 2008; 82: 7812-7817Crossref PubMed Scopus (0) Google Scholar and are believed to be involved in immune evasion by binding neutralizing antibodies49Ganem D. Assembly of hepadnaviral virions and subviral particles.Curr Top Microbiol Immunol. 1991; 168: 61-83Crossref PubMed Google Scholar and potentially promoting T-cell anergy.50Reignat S. Webster G.J.M. Brown D. et al.Escaping high viral load exhaustion.J Exp Med. 2002; 195: 1089-1101Crossref PubMed Scopus (0) Google Scholar Similar particles have been documented in the woodchuck HBV model,51Tennant B.C. Gerin J.L. The woodchuck model of hepatitis B virus infection.ILAR J. 2001; 42: 89-102Crossref PubMed Google Scholar indicating a common role in Orthohepadnavirus infections. Nine different HBV genotypes (A–I) have been defined by >8% divergence at the nucleotide level; a 10th putative genotype (J) was characterized after isolation from 1 individual.52Kramvis A. Genotypes and genetic variability of hepatitis B virus.Intervirology. 2014; 57: 141-150Crossref PubMed Scopus (115) Google Scholar, 53Tatematsu K. Tanaka Y. Kurbanov F. et al.A genetic variant of hepatitis b virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype.J. J Virol. 2009; 83: 10538-10547Crossref PubMed Scopus (0) Google Scholar The HBV genotypes are further divided into at least 35 subtypes by >4% divergence, with wide variation observed in the numbers of subtypes described per genotype (Table 1).20Rajoriya N. Combet C. Zoulim F. et al.How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualized approach?.J Hepatol. 2017; 67: 1281-1297Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 54Schaefer S. Hepatitis B virus taxonomy and hepatitis B virus genotypes.World J Gastroenterol. 2007; 13: 14-21Crossref PubMed Google Scholar, 55Tong S. Revill P. Overview of hepatitis B viral replication and genetic variability.J Hepatol. 2016; 64: S4-S16Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 56Olinger C.M. Jutavijittum P. Hübschen J.M. et al.Possible new hepatitis B virus genotype, southeast Asia.Emerg Infect Dis. 2008; 14: 1777-1780Crossref PubMed Scopus (0) Google ScholarTable 1HBV Subtypes and Genotype FeaturesGenotypeSubtypesGeographic distributionGenome length (bp)Distinguishing features of HBV sequenceaInsertions and deletions relative to 3215-bp genome length.AA1–A4Africa, Europe32216-bp insertion in core gene; G1896AbG1896A mutation introduces a premature stop codon in the precore, resulting in loss of HBeAg expression. mutations rare; BCP mutationscBasal core promoter mutations at A1762T and G1764A result in decreased HBeAg expression. commonBB1–B5Japan, China, Southeast Asia3215B1 and B5 are pure strains, whereas B2, B3, and B4 are recombinants with genotype C in the core regionCC1–C16Southeast Asia, Australia3215BCP mutationsbG1896A mutation introduces a premature stop codon in the precore, resulting in loss of HBeAg expression. commonDD1–D7Worldwide, Middle East, West Africa318233-bp deletion in pre-S1ENo subtypes describedWest Africa32123-bp deletion in pre-S1FF1–F4North and South America3215G1896AbG1896A mutation introduces a premature stop codon in the precore, resulting in loss of HBeAg expression. mutations rareGNo subtypes describedCentral America and Europe324836-bp insertion in core and 3-bp deletion in pre-S1; insertion results in a high level of core expression; stop codons at positions 2 and 28 (G1896AbG1896A mutation introduces a premature stop codon in the precore, resulting in loss of HBeAg expression.) of the precore protein render it unable to express HBeAg; often found in coinfection with other genotypes that express HBeAgHNo subtypes describedCentral America3215G1896AbG1896A mutation introduces a premature stop codon in the precore, resulting in loss of HBeAg expression. mutations rareII1–I2 (putativedFew sequences of genotype I have been characterized, although the genetic distance between isolates suggests there might be 2 subtypes.56)Southeast Asia3215Evolved as a recombinant of genotypes A, C, and G56Olinger C.M. Jutavijittum P. Hübschen J.M. et al.Possible new hepatitis B virus genotype, southeast Asia.Emerg Infect Dis. 2008; 14: 1777-1780Crossref PubMed Scopus (0) Google ScholarJ (putative)No subtypes describedJapan3182Single isolate identified in elderly Japanese patient with HCC; highly divergent from other human HBV strains; likely a genotype C–gibbon Orthohepadnavirus recombinant53Tatematsu K. Tanaka Y. Kurbanov F. et al.A genetic variant of hepatitis b virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype.J. J Virol. 2009; 83: 10538-10547Crossref PubMed Scopus (0) Google ScholarNOTE. Further details about genotypes and subtypes can be found in Rajoriya et al20Rajoriya N. Combet C. Zoulim F. et al.How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualized approach?.J Hepatol. 2017; 67: 1281-1297Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and Tong and Revill.55Tong S. Revill P. Overview of hepatitis B viral replication and genetic variability.J Hepatol. 2016; 64: S4-S16Abstract Full Text Full Text PDF PubMed Scopus (83) Google ScholarBCP, basal core promoter; HBeAg, hepatitis B e antigen.a Insertions and deletions relative to 3215-bp genome length.b G1896A mutation introduces a premature stop codon in the precore, resulting in loss of HBeAg expression.c Basal core promoter mutations at A1762T and G1764A result in decreased HBeAg expression.d Few sequences of genotype I have been characterized, although the genetic distance between isolates suggests there might be 2 subtypes.56Olinger C.M. Jutavijittum P. Hübschen J.M. et al.Possible new hepatitis B virus genotype, southeast Asia.Emerg Infect Dis. 2008; 14: 1777-1780Crossref PubMed Scopus (0) Google Scholar Open table in a new tab NOTE. Further details about genotypes and subtypes can be found in Rajoriya et al20Rajoriya N. Combet C. Zoulim F. et al.How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualized approach?.J Hepatol. 2017; 67: 1281-1297Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and Tong and Revill.55Tong S. Revill P. Overview of hepatitis B viral replication and genetic variability.J Hepatol. 2016; 64: S4-S16Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar BCP, basal core promoter; HBeAg, hepatitis B e antigen. There are substantial differences among genotypes in geographic distribution, transmission mode, and clinical outcomes, including emergence of drug resistance and response to therapy20Rajoriya N. Combet C. Zoulim F. et al.How viral genetic variants and genotypes influence disease and treatment outcome of chronic hepatitis B. Time for an individualized approach?.J Hepatol. 2017; 67: 1281-1297Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 57Guettouche T. Hnatyszyn H.J. Chronic hepatitis B and viral genotype: the clinical significance of determining HBV genotypes.Antiviral Ther. 2005; 10: 593-604PubMed Google Scholar (Table 1). However, the data are incomplete—particularly from low- and middle-income countries.6O’Hara G.A. McNaughton A.L. Maponga T. et al." @default.
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• W2892432796 title "Insights From Deep Sequencing of the HBV Genome—Unique, Tiny, and Misunderstood" @default.
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