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1
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Padarath K, Deroubaix A, Kramvis A. The Complex Role of HBeAg and Its Precursors in the Pathway to Hepatocellular Carcinoma. Viruses 2023; 15:v15040857. [PMID: 37112837 PMCID: PMC10144019 DOI: 10.3390/v15040857] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 03/30/2023] Open
Abstract
Hepatitis B virus (HBV) is one of the seven known human oncogenic viruses and has adapted to coexist with a single host for prolonged periods, requiring continuous manipulation of immunity and cell fate decisions. The persistence of HBV infection is associated with the pathogenesis of hepatocellular carcinoma, and various HBV proteins have been implicated in promoting this persistence. The precursor of hepatitis e antigen (HBeAg), is translated from the precore/core region and is post-translationally modified to yield HBeAg, which is secreted in the serum. HBeAg is a non-particulate protein of HBV and can act as both a tolerogen and an immunogen. HBeAg can protect hepatocytes from apoptosis by interfering with host signalling pathways and acting as a decoy to the immune response. By evading the immune response and interfering with apoptosis, HBeAg has the potential to contribute to the hepatocarcinogenic potential of HBV. In particular, this review summarises the various signalling pathways through which HBeAg and its precursors can promote hepatocarcinogenesis via the various hallmarks of cancer.
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2
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Kumar R. Review on hepatitis B virus precore/core promoter mutations and their correlation with genotypes and liver disease severity. World J Hepatol 2022; 14:708-718. [PMID: 35646275 PMCID: PMC9099108 DOI: 10.4254/wjh.v14.i4.708] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Revised: 09/04/2021] [Accepted: 03/27/2022] [Indexed: 02/06/2023] Open
Abstract
Of 350 million people worldwide are chronically infected with hepatitis B virus (HBV) and are at risk of developing cirrhosis and hepatocellular carcinoma (HCC) later in life. HBV is the most diverse DNA virus, and its genome is composed of four open reading frames: Presurface antigen/surface antigen gene (preS/S), precore/core gene (preC/C), polymerase gene (P), and the X gene (X). HBV produces quasispecies naturally or in response to antiviral agents because of the absence of proofreading activity amid reverse transcription and a high replication rate. The virus has 10 genotypes (A to J) with different geographical distributions. There are various HBV mutations in the HBV genome, including preC/C mutations, preS/S mutations, P gene mutations, and X gene mutations. The core promoter region plays a vital part in the replication, morphogenesis and pathogenesis of the virus. The precore region also plays a crucial role in viral replication. Both core promoter and precore mutations rescue the virus from host immune surveillance and result in the formation of mutated strains that may have altered pathogenicity. preC/C mutations are associated with liver disease progression. Precore mutations stop hepatitis B e antigen (HBeAg) production and basal core promoter mutations downregulate HBeAg production. Mutations in the basal core promoter are also associated with increased HBV replication and an increased incidence of advanced liver diseases such as cirrhosis and HCC. The emergence of antiviral-resistant mutations is the main reason for treatment failure. This review focuses mainly on preC/C promoter mutations and their correlation with genotypes and liver disease severity. Thorough perception and knowledge of HBV genetic variety and mutants could be vital to discover techniques for the prognosis and control of HBV infection.
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Affiliation(s)
- Rajesh Kumar
- Department of School Education, Haryana Government, Panchkula 134109, Haryana, India
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3
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Li Q, Wang J, Lu M, Qiu Y, Lu H. Acute-on-Chronic Liver Failure From Chronic-Hepatitis-B, Who Is the Behind Scenes. Front Microbiol 2020; 11:583423. [PMID: 33365018 PMCID: PMC7750191 DOI: 10.3389/fmicb.2020.583423] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 11/13/2020] [Indexed: 12/12/2022] Open
Abstract
Acute-on-chronic liver failure (ACLF) is an acute syndrome accompanied with decompensation of cirrhosis, organ failure with high 28-day mortality rate. Systemic inflammation is the main feature of ACLF, and poor outcome is closely related with exacerbated systemic inflammatory responses. It is well known that severe systemic inflammation is an important event in chronic hepatitis B (CHB)-ACLF, which eventually leads to liver injury. However, the initial CHB-ACLF events are unclear; moreover, the effect of these events on host immunity as well as that of immune imbalance on CHB-ACLF progression are unknown. Here, we investigate the initial events of ACLF progression, discuss possible mechanisms underlying ACLF progression, and provide a new model for ACLF prediction and treatment. We review the characteristics of ACLF, and consider its plausible immune predictors and alternative treatment strategies.
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Affiliation(s)
- Qian Li
- Department of Infectious Diseases, Shanghai Public Health Clinical Center, Shanghai, China
| | - Jun Wang
- Center of Clinical Laboratory, The Fifth People's Hospital of Wuxi, Jiangnan University, Wuxi, China
| | - Mengji Lu
- Institute of Virology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany
| | - Yuanwang Qiu
- Department of Hepatology, The Fifth People's Hospital of Wuxi, Jiangnan University, Wuxi, China
| | - Hongzhou Lu
- Department of Infectious Diseases, Shanghai Public Health Clinical Center, Shanghai, China
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4
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Asgari S, Chaturvedi N, Scepanovic P, Hammer C, Semmo N, Giostra E, Müllhaupt B, Angus P, Thompson AJ, Moradpour D, Fellay J. Human genomics of acute liver failure due to hepatitis B virus infection: An exome sequencing study in liver transplant recipients. J Viral Hepat 2019; 26:271-277. [PMID: 30315682 DOI: 10.1111/jvh.13019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 09/05/2018] [Accepted: 09/10/2018] [Indexed: 12/12/2022]
Abstract
Acute liver failure (ALF) or fulminant hepatitis is a rare, yet severe outcome of infection with hepatitis B virus (HBV) that carries a high mortality rate. The occurrence of a life-threatening condition upon infection with a prevalent virus in individuals without known risk factors is suggestive of pathogen-specific immune dysregulation. In the absence of established differences in HBV virulence, we hypothesized that ALF upon primary infection with HBV could be due to rare deleterious variants in the human genome. To search for such variants, we performed exome sequencing in 21 previously healthy adults who required liver transplantation upon fulminant HBV infection and 172 controls that were positive for anti-HBc and anti-HBs but had no clinical history of jaundice or liver disease. After a series of hypothesis-driven filtering steps, we searched for putatively pathogenic variants that were significantly associated with case-control status. We did not find any causal variant or gene, a result that does not support the hypothesis of a shared monogenic basis for human susceptibility to HBV-related ALF in adults. This study represents a first attempt at deciphering the human genetic contribution to the most severe clinical presentation of acute HBV infection in previously healthy individuals.
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Affiliation(s)
- Samira Asgari
- School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Swiss Institute of Bioinformatics, Lausanne, Switzerland.,Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Nimisha Chaturvedi
- School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Petar Scepanovic
- School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Christian Hammer
- School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Swiss Institute of Bioinformatics, Lausanne, Switzerland
| | - Nasser Semmo
- Department for BioMedical Research, Hepatology, University of Bern, Bern, Switzerland
| | - Emiliano Giostra
- Department of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland
| | - Beat Müllhaupt
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Peter Angus
- Gastroenterology and Hepatology Department, Austin Health and the University of Melbourne, Melbourne, Victoria, Australia
| | - Alexander J Thompson
- Department of Gastroenterology, St Vincent's Hospital, University of Melbourne, Melbourne, Australia
| | - Darius Moradpour
- Service of Gastroenterology and Hepatology, Lausanne University Hospital, Lausanne, Switzerland
| | - Jacques Fellay
- School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.,Swiss Institute of Bioinformatics, Lausanne, Switzerland.,Precision Medicine Unit, Lausanne University Hospital, Lausanne, Switzerland
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5
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Analysis of HBV basal core promoter/precore gene variability in patients with HBV drug resistance and HIV co-infection in Northwest Ethiopia. PLoS One 2018; 13:e0191970. [PMID: 29408943 PMCID: PMC5800642 DOI: 10.1371/journal.pone.0191970] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 01/15/2018] [Indexed: 12/13/2022] Open
Abstract
Background We recently reported complex hepatitis B virus (HBV) drug resistant and concomitant vaccine escape hepatitis B surface antigen (HBsAg) variants during human immunodeficiency virus (HIV) co-infection and antiretroviral therapy (ART) exposure in Ethiopia. As a continuation of this report using the HBV positive sera from the same study participants, the current study further analyzed the HBV basal core promoter (BCP)/precore (PC) genes variability in patients with HBV drug resistance (at tyrosine-methionine-aspartate-aspartate (YMDD) reverse transcriptase (RT) motifs) and HIV co-infection in comparison with HBV mono-infected counterparts with no HBV drug resistant gene variants. Materials and methods A total of 143 participants of HBV-HIV co-infected (n = 48), HBV mono-infected blood donors (n = 43) and chronic liver disease (CLD) patients (n = 52) were included in the study. The BCP/PC genome regions responsible for HBeAg expression from the EcoRI site (nucleotides 1653–1959) were sequenced and analyzed for the BCP/PC mutant variants. Results Among the major mutant variants detected, double BCP mutations (A1762T/G1764A) (25.9%), Kozak sequences mutations (nt1809-1812) (51.7%) and the classical PC mutations such as A1814C/C1816T (15.4%), G1896A (25.2%) and G1862T (44.8%) were predominant mutant variants. The prevalence of the double BCP mutations was significantly lower in HIV co-infected patients (8.3%) compared with HBV mono-infected blood donors (32.6%) and CLD patients (36.5%). However, the Kozak sequences BCP mutations and the majority of PC mutations showed no significant differences among the study groups. Moreover, except for the overall BCP/PC mutant variants, co-prevalence rates of each major BCP/PC mutations and YMDDRT motif associated lamivudine (3TC)/entecavir (ETV) resistance mutations showed no significant differences when compared with the rates of BCP/PC mutations without YMDD RT motif drug resistance gene mutations. Unlike HIV co-infected group, no similar comparison made among HBV mono-infected blood donors and CLD patients since none of them developed the YMDD RT motif associated 3TC/ETV resistance mutations. However, HBV mono-infected blood donors and CLD patients who had no any drug resistance gene variants developed comparable G1862T (60.6% vs. 65.1%) and G1896A (24.2% vs. 11.6%) PC gene mutations. Conclusion No correlation observed between the BCP/PC genome variability and the YMDD RT motif associated HBV drug resistance gene variants during HIV co-infection. Nevertheless, irrespective of HIV co-infection status, the higher records of the BCP/PC gene variability in this study setting indicate a high risk of potential HBeAg negative chronic HBV infection in Northwest Ethiopia.
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Bhoola NH, Kramvis A. Expression of wild-type or G1862T mutant HBe antigen of subgenotype A1 of hepatitis B virus and the unfolded protein response in Huh7 cells. J Gen Virol 2017; 98:1422-1433. [PMID: 28678685 DOI: 10.1099/jgv.0.000793] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The G1862T mutation, which occurs most frequently in subgenotype A1 of the hepatitis B virus (HBV), results in a valine to phenylalanine substitution at the -3 position of the signal peptide cleavage site at the amino end of the precore/core (preC/C) precursor protein. The objective of this study was to functionally characterize the G1862T mutation relative to its wild-type counterpart in subgenotype A1. Huh7 cells were transfected with subgenotype A1 replication-competent plasmids, with and without G1862T. Secretion of HBsAg and HBeAg, preC/C/HBeAg expression in the secretory pathway, activation of the unfolded protein response (UPR) and subsequent activation of apoptosis were monitored. The introduction of G1862T did not affect HBsAg expression. Cells transfected with the G1862T subgenotype A1 plasmid showed decreased expression of intracellular HBcAg and of nuclear preC/C/HBeAg and extracellular HBeAg, when compared to cells transfected with its wild-type counterpart as a result of the accumulation of the mutant protein in the endoplasmic reticulum (ER) and ER-Golgi intermediate compartment (ERGIC) . This accumulation of preC/C/HBeAg protein in the ER led to the earlier activation of the three UPR pathways, but not to an increase in apoptosis. Therefore, it is evident that the presence of G1862T in subgenotype A1 does not completely abolish HBeAg expression, but affects the rate of HBeAg maturation, its passage through the secretory pathway and activation of the UPR. Increase in ER stress can result in liver damage, which has been shown to be a contributing factor to hepatocarcinogenesis and may explain why G1862T is frequently found in subgenotype A1 from liver disease patients.
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Affiliation(s)
- Nimisha Harshadrai Bhoola
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, South Africa
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, South Africa
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7
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Mello FMMAD, Kuniyoshi ASO, Lopes AF, Gomes-Gouvêa MS, Bertolini DA. Hepatitis B virus genotypes and mutations in the basal core promoter and pre-core/core in chronically infected patients in southern Brazil: a cross-sectional study of HBV genotypes and mutations in chronic carriers. Rev Soc Bras Med Trop 2015; 47:701-8. [PMID: 25626648 DOI: 10.1590/0037-8682-0158-2014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2014] [Accepted: 11/11/2014] [Indexed: 01/04/2023] Open
Abstract
INTRODUCTION In Brazil, little data exist regarding the distribution of genotypes in relation to basal core promoter (BCP) and precore/core mutations among chronic hepatitis B virus (HBV) carriers from different regions of the country. The aim of this study was to identify HBV genotypes and the frequency of mutations at the BCP and precore/core region among the prevalent genotypes in chronic carriers from southern Brazil. METHODS Nested-polymerase chain reaction (nested-PCR) products amplified from the S-polymerase gene, BCP and precore/core region from 54 samples were sequenced and analyzed. RESULTS Phylogenetic analysis of the S-polymerase gene sequences showed that 66.7% (36/54) of the patients were infected with genotype D (D1, D2, D3), 25.9% (14/54) with genotype A (A1, A2), 5.6% (3/54) with subgenotype C2, and 2% (1/54) with genotype E. A comparison of virological characteristics showed significant differences between genotypes A, C and D. The comparison between HBeAg status and the G1896A stop codon mutation in patients with genotype D revealed a relationship between HBV G1896A precore mutants and genotype D and hepatitis B e antigen (HBeAg) seroconversion. Genotype D had a higher prevalence of the G1896A mutation and the presence of a thymine at position 1858. Genotype A was associated with a higher prevalence of the G1862T mutation and the presence of a cytosine at position 1858. CONCLUSIONS HBV genotype D (D3) is predominant in HBV chronic carriers from southern Brazil. The presence of mutations in the BCP and precore/core region was correlated with the HBV genotype and HBeAg negative status.
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Affiliation(s)
| | | | - André Fanhani Lopes
- Laboratório de Virologia Clínica, Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá, Maringá, PR
| | - Michele Soares Gomes-Gouvêa
- Laboratório de Gastroenterologia Tropical do Instituto de Medicina Tropical, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil
| | - Dennis Armando Bertolini
- Laboratório de Virologia Clínica, Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá, Maringá, PR
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8
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Yang G, Han M, Chen F, Xu Y, Chen E, Wang X, Liu Y, Sun J, Hou J, Ning Q, Wang Z. Hepatitis B virus genotype B and mutations in basal core promoter and pre-core/core genes associated with acute-on-chronic liver failure: a multicenter cross-sectional study in China. Hepatol Int 2014; 8:508-516. [DOI: 10.1007/s12072-014-9554-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Saha D, Pal A, Biswas A, Panigrahi R, Sarkar N, Das D, Sarkar J, Guha SK, Saha B, Chakrabarti S, Chakravarty R. Molecular characterization of HBV strains circulating among the treatment-naive HIV/HBV co-infected patients of eastern India. PLoS One 2014; 9:e90432. [PMID: 24587360 PMCID: PMC3938687 DOI: 10.1371/journal.pone.0090432] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 01/29/2014] [Indexed: 02/07/2023] Open
Abstract
Previously we reported that the exposure to hepatitis B virus (HBV) infection serves as a major threat among the treatment naive HIV infected population of eastern India. Hence, molecular characterization of these strains is of utmost importance in order to identify clinically significant HBV mutations. A total of 85 treatment naive HIV/HBV co-infected participants were included of whom the complete basal core promoter/precore region, the core and the whole envelope gene could be successfully sequenced for 59, 57 and 39 isolates respectively. Following phylogenetic analysis, it was found that HBV/D was the predominant genotype with HBV/D2 (38.5%) being the most prevalent subgenotype followed by HBV/A1. The major mutations affecting HBeAg expression includes the A1762T/G1764A (13.6%), G1896A (22%) and G1862T mutation (33.9%) which was predominantly associated with HBV/A1. Moreover, the prevalence of G1896A was considerably high among the HBeAg negative HIV/HBV co-infected subjects compared to HBV mono-infection. The main amino acid substitutions within the MHC class II restricted T-cell epitope of HBcAg includes the T12S (15.8%) and T67N (12.3%) mutation and the V27I (10.5%) mutation in the MHC class I restricted T-cell epitope. PreS1/S2 deletion was detected in 3 isolates with all harboring the BCP double mutation. Furthermore, the frequently occurring mutations in the major hydrophilic loop of the S gene include the T125M, A128V and M133I/L. Therefore, this study is the first from India to report useful information on the molecular heterogeneity of the HBV strains circulating among the treatment naive HIV/HBV co-infected population and is thus clinically relevant.
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Affiliation(s)
- Debraj Saha
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Ananya Pal
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Avik Biswas
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Rajesh Panigrahi
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana, United States of America
| | - Neelakshi Sarkar
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Dipanwita Das
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
| | - Jayeeta Sarkar
- Calcutta School of Tropical Medicine, Kolkata, West Bengal, India
| | | | - Bibhuti Saha
- Calcutta School of Tropical Medicine, Kolkata, West Bengal, India
| | - Sekhar Chakrabarti
- National Institute of Cholera and Enteric Diseases, Kolkata, West Bengal, India
| | - Runu Chakravarty
- ICMR Virus Unit, Kolkata, ID & BG Hospital Campus, Kolkata, West Bengal, India
- * E-mail:
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Chen L, Zheng CX, Lin MH, Huang ZX, Chen RH, Li QG, Li Q, Chen P. Distinct quasispecies characteristics and positive selection within precore/core gene in hepatitis B virus HBV associated acute-on-chronic liver failure. J Gastroenterol Hepatol 2013; 28:1040-6. [PMID: 23278564 DOI: 10.1111/jgh.12109] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/18/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM The cause of hepatitis B virus associated acute-on-chronic liver failure (ACLF) remains unclear. Quasispecies can contribute to virus persistence and pathogenesis. We used a bioinformatics-based molecular evolution approach to compare quasispecies characteristics and positive selection sites within HBV precore/core gene between ACLF and chronic hepatitis B (CHB) patients. METHODS HBV precore/core gene were amplified from 11 ACLF and 10 CHB patients harboring HBV genotype B; following DNA cloning and sequencing quasispecies complexity, diversity, and positive selection sites within the precore/core gene were determined by bioinformatics analysis, and compared between the patient groups. RESULTS Both quasispecies complexity (P=0.022 at nucleotide level and 0.008 at amino acid level) and diversity (P<0.05) were found to be significantly greater in ACLF than in CHB. The frequency of G1896/A mutation in ACLF (175/298 clones, 58.7%) was also significantly higher than in CHB (100/230 clones, 43.5%) (P=0.0005). Moreover, analysis of positive selection revealed that significantly more patients with such sites were present in ACLF than in CHB (8/11 VS 2/10, P=0.03); the majority of these positive selection sites lay within HLA-restricted epitopes. CONCLUSIONS The ACLF patients showed distinct quasispecies characteristics with higher complexity and diversity within the HBV precore/core gene. The increased HBV quasispecies complexity and diversity, together with a distinct set of positive selection sites, is likely associated with the development of ACLF.
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Affiliation(s)
- Li Chen
- Department of Hepatology, Infectious Disease Hospital of Fujian Medical University, Fuzhou, China
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11
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Hakami A, Ali A, Hakami A. Effects of hepatitis B virus mutations on its replication and liver disease severity. Open Virol J 2013; 7:12-8. [PMID: 23400390 PMCID: PMC3565227 DOI: 10.2174/1874357901307010012] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2012] [Revised: 11/26/2012] [Accepted: 11/27/2012] [Indexed: 02/07/2023] Open
Abstract
Hepatitis B virus (HBV), nowadays, is one of the major human pathogens worldwide. Approximately, 400 million people worldwide have chronic HBV infection. Only 5% of persons infected during adulthood develop chronic infection. The reverse is true for those infected at birth or in early childhood, i.e. more than 90% of these persons progress to chronic infection. Currently, eight different genotypes o f HBV have been identified, differing in nucleotide sequence by greater than 8%. In addition, numerous subgenotypes have a l s o been recognized based on the nucleotide sequence variability of 4- 8%. It has invariably been found that these genotypes and mutations play a pivotal role in the liver disease aggravation and virus replication. The precore mutations (G1896A) and the double mutation (T1762/A1764) in the basal core promoter are important mutations that alter expression of the hepatitis B e antigen (HBeAg). The HBeAg is important for establishing viral persistence. The precore G1896A mutation abrogates the expression of HBeAg. Numerous other mutations alter the disease severity and progression. It is predictive that the infected patient has high risk of hepatocellular carcinoma if the genotype C is incriminated or if HBV possesses basal core promoter double mutation. Association of the remaining genotypes have been noted but with less degree than genotype C. Phenotypic assays of the different HBV protein markers with different molecular techniques illustrate the replication efficiency of the virus in cell lines. This review will discuss various mutations into their association with liver disease severity and progression as well as virus replication.
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Affiliation(s)
- Abdulrahim Hakami
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha 61481, Saudi Arabia
| | - Abdelwahid Ali
- Department of Clinical Microbiology, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia
| | - Ahmed Hakami
- Department of Clinical Microbiology, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia
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12
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Makondo E, Bell TG, Kramvis A. Genotyping and molecular characterization of hepatitis B virus from human immunodeficiency virus-infected individuals in southern Africa. PLoS One 2012; 7:e46345. [PMID: 23029487 PMCID: PMC3460816 DOI: 10.1371/journal.pone.0046345] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Accepted: 08/30/2012] [Indexed: 12/12/2022] Open
Abstract
Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) are hyperendemic in sub-Saharan Africa. The HBV genotypes prevailing in HIV-infected Africans are unknown. Our aim was to determine the HBV genotypes in HIV-infected participants and to identify clinically significant HBV mutations. From 71 HBV DNA+ve HIV-infected participants, 49 basic core promoter/precore (BCP/PC) and 29 complete S regions were successfully sequenced. Following phylogenetic analysis of 29 specimens in the complete S region, 28 belonged to subgenotype A1 and one to D3. Mutations affecting HBeAg expression at the transcriptional (1762T1764A), translational (Kozak 1809–1812, initiation 1814–1816, G1896A with C1858T), or post translational levels (G1862T), were responsible for the high HBeAg-negativity observed. The G1862T mutation occurred only in subgenotype A1 isolates, which were found in one third (7/21) of HBsAg−ve participants, but in none of the 18 HBsAg+ve participants (p<0.05). Pre-S deletion mutants were detected in four HBsAg+ve and one HBsAg−ve participant/s. The following mutations occurred significantly more frequently in HBV isolated in this study than in strains of the same cluster of the phylogenetic tree: ps1F25L, ps1V88L/A; ps2Q10R, ps2 R48K/T, ps2A53V and sQ129R/H, sQ164A/V/G/D, sV168A and sS174N (p<0.05). ps1I48V/T occurred more frequently in females than males (p<0.05). Isolates with sV168A occurred more frequently in participants with viral loads >200 IU per ml (p<0.05) and only sS174N occurred more frequently in HBsAg−ve than in HBsAg+ve individuals (p<0.05). Prior to initiation of ART, ten percent, 3 of 29 isolates sequenced, had drug resistance mutations rtV173L, rtL180M+rtM204V and rtV214A, respectively. This study has provided important information on the molecular characteristics of HBV in HIV-infected southern Africans prior to ART initiation, which has important clinical relevance in the management of HBV/HIV co-infection in our unique setting.
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Affiliation(s)
| | | | - Anna Kramvis
- Hepatitis Virus Diversity Research Programme, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
- * E-mail:
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13
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Yan T, Li K, Li F, Su H, Mu J, Tong S, Patel M, Xia J, Wands JR, Wang H. T1846 and A/G1913 are associated with acute on chronic liver failure in patients infected with hepatitis B virus genotypes B and C. J Med Virol 2012; 83:996-1004. [PMID: 21503912 DOI: 10.1002/jmv.22067] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The aim of this study was to determine whether mutations in the hepatitis B virus (HBV) genome are associated with the onset of acute on chronic liver failure (ACLF). For the longitudinal study, full-length HBV genomes were cloned and sequenced from four ACLF patients and compared with sequences from matching samples collected before ACLF. For the cross-sectional study, 166 serum samples were obtained, including 49 samples from patients with ACLF. The results of longitudinal study showed that C53T, A1846T, and G1896A were the most common mutations in association with ACLF. In the cross-sectional study 61.2% patients with ACLF presented with T1846, which was higher than patients with chronic hepatitis B (CHB) (11.1%), liver cirrhosis (LC) (31.1%), and hepatocellular carcinoma (HCC) (33.3%). Prevalence of A/G1913 was 42.9% in patients with ACLF, also higher than patients with CHB (2.2%), LC (17.8%), and HCC (11.1%). There were no differences in HBV genotype and patients' HBeAg status among patients with ACLF, LC, and HCC. However, prevalence of T1846 was much higher in patients infected with genotype B (57.1%) than genotype C (30.4%). A/G1913 was higher in HBeAg negative patients (28%) than HBeAg positive patients (13.2%). Results of a multivariable analysis showed that T1846 and A/G1913 were independent factors for ACLF (OR = 3.373 and 4.244, respectively). Interestingly, T1846 destroys an ATG codon of a small open reading frame in the preC region, which may increase core protein expression. We conclude that T1846 and A/G1913 in the preC/C gene are closely associated with ACLF.
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Affiliation(s)
- Tao Yan
- Intensive Care Center, 302 Military Hospital, Beijing, China
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Shi W, Carr MJ, Dunford L, Zhu C, Hall WW, Higgins DG. Identification of novel inter-genotypic recombinants of human hepatitis B viruses by large-scale phylogenetic analysis. Virology 2012; 427:51-9. [PMID: 22374235 DOI: 10.1016/j.virol.2012.01.030] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Revised: 01/14/2012] [Accepted: 01/26/2012] [Indexed: 02/08/2023]
Abstract
Recombination plays an important role in the evolutionary history of Hepatitis B virus (HBV). We performed a phylogenetic analysis of 3403 full-length HBV genome sequences isolated from humans to define the genotype. The genome sequences were divided into 13 sub-datasets, each approximately 250 bp in length. Genotype designations obtained from the sub-datasets that differed from the genotype defined by the whole genome were assigned as putative recombinants. Our results showed that 3379 out of 3403 sequences belonged to the previously described and putative genotypes A to J respectively, with 315 sequences defined in this analysis. The remaining 24 viruses had sequence divergence of less than 8% with both genotypes B and C and were provisionally assigned genotype "BC". 1047 out of 3403 sequences were identified to be putative recombinants, of which 72 were identified to be novel recombinants. Notably, all viruses of the herein described genotype "BC" were identified to be B/C recombinants.
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Affiliation(s)
- Weifeng Shi
- The Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland.
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15
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Inoue J, Ueno Y, Wakui Y, Fukushima K, Kondo Y, Kakazu E, Ninomiya M, Niitsuma H, Shimosegawa T. Enhanced replication of hepatitis B virus with frameshift in the precore region found in fulminant hepatitis patients. J Infect Dis 2011; 204:1017-1025. [PMID: 21881116 DOI: 10.1093/infdis/jir485] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The genotype B of hepatitis B virus (HBV) was reported to associate with fulminant hepatitis (FH). We aimed to clarify the characteristics of HBV obtained from FH patients in an area of Japan where genotype B HBV is prevalent. METHODS Using serum samples of 16 HBV-associated FH patients, partial HBV sequences were determined. The effects of HBV mutation/insertion/deletion were evaluated using an in vitro HBV replication system. RESULTS Of the 16 HBV isolates, 31% belonged to subgenotype B1/Bj, 38% were subgenotype B2/Ba, and 31% were subgenotype C2/Ce. Notably, the single nucleotide insertion/deletion that resulted in a frameshift of the precore protein was found exclusively in 60% of B1/Bj strains. An in vitro study showed that all of the frameshift mutants had significantly higher amounts of HBV DNA than did the wild type. One of the isolates had a novel insertion of A between nucleotides 1900 and 1901, which resulted in a 3-nucleotide change within the Kozak sequence of the core protein and enhanced the core protein expression in vitro. CONCLUSIONS The frameshift insertion/deletion in the precore region enhanced HBV replication and might be associated with the development of FH by the subgenotype B1/Bj HBV.
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Affiliation(s)
- Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Xiao L, Zhou B, Gao H, Ma S, Yang G, Xu M, Abbott WGH, Chen J, Sun J, Wang Z, Hou J. Hepatitis B virus genotype B with G1896A and A1762T/G1764A mutations is associated with hepatitis B related acute-on-chronic liver failure. J Med Virol 2011; 83:1544-1550. [PMID: 21739444 DOI: 10.1002/jmv.22159] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The existence of statistical associations between hepatitis B-related acute-on-chronic liver failure and both hepatitis B virus (HBV) genotype and mutations in the basal core promoter (BCP) and precore (PC) regions needs to be confirmed. A total of 322 patients with a chronic HBV infection, including 77 with hepatitis B-related acute-on-chronic liver failure, 109 with hepatocellular carcinoma (HCC) and 136 with chronic hepatitis B (CHB) were enrolled. The HBV genotype and the presence of mutations in the BCP/PC regions were determined by direct sequencing, and the frequencies were compared in the three patient groups. Overall, 198/322 (61.5%) were infected with genotype B and 124/322 (38.5%) with genotype C. Genotype B was significantly more frequent in patients with acute-on-chronic liver failure than CHB (92.2% vs. 60.3%, P < 0.001). As a contrast, genotype C was more common in patients with HCC than CHB (58.7% vs. 39.7%, P = 0.003). In genotype B patients, the A1762T/G1764A, A1846T, and G1896A mutations were significantly more prevalent in patients with acute-on-chronic liver failure than CHB (50.7% vs. 28.0%, P = 0.004; 59.2% vs. 34.1%, P = 0.002; 69.0% vs. 41.5%, P = 0.001, respectively). In multivariate analysis, the risk factors for acute-on-chronic liver failure were genotype B, A1762T/G1764A, and G1896A. In conclusion, CHB patients with genotype B, G1896A, and A1762T/G1764A had a higher tendency to develop liver failure than patients with genotype C. Therefore, HBV genotyping and detecting G1896A and A1762T/G1764A mutations might have important clinical implications as predictive risk factors for hepatitis B-related acute-on-chronic liver failure.
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Affiliation(s)
- Lei Xiao
- Hepatology Unit and Key Lab for Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Association of hepatitis B virus mutations in basal core promoter and precore regions with severity of liver disease: an investigation of 793 Chinese patients with mild and severe chronic hepatitis B and acute-on-chronic liver failure. J Gastroenterol 2011; 46:391-400. [PMID: 20848146 PMCID: PMC7088102 DOI: 10.1007/s00535-010-0315-4] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2010] [Accepted: 08/15/2010] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To investigate the features of hepatitis B virus (HBV) basal core promoter/precore (BCP/PC) mutations and genotypes in a large number of mild/severe chronic hepatitis B (CHB-M/CHB-S), and acute-on-chronic liver failure (ACLF) patients and analyze the clinical implications of the virologic features. PATIENTS AND METHODS Sera of 793 (325 CHB-M, 170 CHB-S, and 298 ACLF) patients admitted to or who had visited Beijing 302 Hospital from January 2005 to December 2008 were collected and successfully amplified for the HBV BCP/PC and a 1225-bp-long S/Pol (nt 54-1278) gene regions. Biochemical and serological parameters and HBV DNA level were routinely performed. Viral DNA was extracted and subjected to a nested PCR. Genotypes/subgenotypes were determined based on complete genomic sequence or on analysis of the 1225-bp-long S/Pol-gene sequence. HBV genotyping was performed by direct PCR sequencing followed by molecular evolutionary analysis of the viral sequences. A P value of <0.05 (two-sided) was considered to be statistically significant. CONCLUSIONS Our findings suggest that CHB patients infected with BCP/PC mutant viruses are more susceptible to severe hepatitis and ACLF than those with the BCP/PC wild-type virus and that ACLF patients with PC mutant viruses have an increased risk of death. As such, the HBV PC mutation is a potential predictive indicator of ACLF outcome.
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Ren X, Xu Z, Liu Y, Li X, Bai S, Ding N, Zhong Y, Wang L, Mao P, Zoulim F, Xu D. Hepatitis B virus genotype and basal core promoter/precore mutations are associated with hepatitis B-related acute-on-chronic liver failure without pre-existing liver cirrhosis. J Viral Hepat 2010; 17:887-95. [PMID: 20070500 PMCID: PMC2998700 DOI: 10.1111/j.1365-2893.2009.01254.x] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The study was undertaken to investigate the features and clinical implications of hepatitis B virus (HBV) genotypes, basal core promoter (BCP) and precore (PC) mutations in hepatitis B-related acute-on-chronic liver failure (HB-ACLF). Samples from 75 patients with HB-ACLF and without pre-existing liver cirrhosis and 328 age-matched patients with chronic hepatitis B (CHB) were analyzed. HBV genotype and BCP/PC mutations were determined by direct sequencing. Mutations at 8 sites of the BCP/PC region were compared between the two groups of patients. A significantly higher ratio of genotype B to C was found in patients with HB-ACLF than in patients with CHB (30.7-69.3% vs 16.5-82.6%, P < 0.01). Single mutations including T1753V (C/A/G), A1762T, G1764A, G1896A and G1899A and triple mutations T1753V/A1762T/G1764A and A1762T/G1764A/C1766T (or T1768A) were more frequently detected in patients with HB-ACLF than in patients with CHB. Correspondingly, BCP/PC wild-type sequences were absent in patients with HB-ACLF in contrast to 27.1% in patients with CHB. The BCP/PC mutations were found to be associated with increased HBeAg negativity, higher alanine aminotransferase level and lower viral load. Patients with HB-ACLF infected with the PC mutant virus had a higher mortality. The findings suggest that patients with CHB infected with genotype B with BCP/PC mutations were more likely to develop HB-ACLF than those with genotype C with wild-type BCP/PC regions, and patients with HB-ACLF with the PC mutation had increased risk of a fatal outcome.
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Affiliation(s)
- X Ren
- Viral Hepatitis Research Laboratory, Institute of Infectious DiseasesBeijing 302 Hospital, Beijing, China
| | - Z Xu
- Viral Hepatitis Research Laboratory, Institute of Infectious DiseasesBeijing 302 Hospital, Beijing, China
| | - Y Liu
- Viral Hepatitis Research Laboratory, Institute of Infectious DiseasesBeijing 302 Hospital, Beijing, China
| | - X Li
- Viral Hepatitis Research Laboratory, Institute of Infectious DiseasesBeijing 302 Hospital, Beijing, China
| | - S Bai
- Viral Hepatitis Research Laboratory, Institute of Infectious DiseasesBeijing 302 Hospital, Beijing, China
| | - N Ding
- Viral Hepatitis Research Laboratory, Institute of Infectious DiseasesBeijing 302 Hospital, Beijing, China
| | - Y Zhong
- Viral Hepatitis Research Laboratory, Institute of Infectious DiseasesBeijing 302 Hospital, Beijing, China
| | - L Wang
- Viral Hepatitis Research Laboratory, Institute of Infectious DiseasesBeijing 302 Hospital, Beijing, China
| | - P Mao
- Viral Hepatitis Research Laboratory, Institute of Infectious DiseasesBeijing 302 Hospital, Beijing, China
| | - F Zoulim
- INSERM, U871 and Department of Hepatology and Gastroenterology, Hospices Civils de LyonHôtel Dieu, Lyon, France
| | - D Xu
- Viral Hepatitis Research Laboratory, Institute of Infectious DiseasesBeijing 302 Hospital, Beijing, China,*Correspondence: Dongping Xu, Viral Hepatitis Research Laboratory, Institute of Infectious Diseases, Beijing 302 Hospital, Beijing, China. E-mail:
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Inoue J, Ueno Y, Nagasaki F, Wakui Y, Kondo Y, Fukushima K, Niitsuma H, Shimosegawa T. Enhanced intracellular retention of a hepatitis B virus strain associated with fulminant hepatitis. Virology 2009; 395:202-209. [PMID: 19850315 DOI: 10.1016/j.virol.2009.09.028] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2009] [Revised: 06/22/2009] [Accepted: 09/23/2009] [Indexed: 12/17/2022]
Abstract
A plasmid carrying 1.3-fold HBV genome was constructed from a HBV strain that caused five consecutive cases of fulminant hepatitis (pBFH2), and HepG2 cells were transfected with pBFH2 or its variants. The pBFH2 construct with A1762T/G1764A, G1862T, and G1896A showed the largest amount of core particle-associated intracellular HBV DNA, but no significant increase of extracellular HBV DNA in comparison with the wild construct, suggesting that these mutations might work together for retention of the replicative intermediates in the cells. The retention might relate to the localization of hepatitis B core antigen (HBcAg) in the nucleus of HepG2, which was observed by confocal fluorescence microscopy. HBcAg immunohistochemical examination of liver tissue samples obtained from the consecutive fulminant hepatitis patients showed stronger staining in the nucleus than acute hepatitis patients. In conclusion, the fulminant HBV strain caused retention of the core particles and the core particle-associated HBV DNA in the cells.
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Affiliation(s)
- Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aoba, Sendai 980-8574, Japan.
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20
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Inoue J. Factors involved in the development of fulminant hepatitis B: Are the mutations of hepatitis B virus implicated? Hepatol Res 2009; 39:1053-5. [PMID: 19878349 DOI: 10.1111/j.1872-034x.2009.00609.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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21
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Chandra PK, Biswas A, Datta S, Banerjee A, Panigrahi R, Chakrabarti S, De BK, Chakravarty R. Subgenotypes of hepatitis B virus genotype D (D1, D2, D3 and D5) in India: differential pattern of mutations, liver injury and occult HBV infection. J Viral Hepat 2009; 16:749-56. [PMID: 19457142 DOI: 10.1111/j.1365-2893.2009.01129.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatitis B genotype D (HBV/D) is the most widespread genotype and exists as at least five subgenotypes (HBV/D1-D5). However, little is known about the association of virological characteristics with clinical differences among HBV/D subgenotypes. To investigate the virological characteristics of these subgenotypes and their clinical implications, we selected a cohort of 109 genotype D infected individuals from the state of West Bengal, India, including 68 HBsAg positive patients and 41 with occult HBV infection. Among the HBsAg positive subjects 28 had chronic hepatitis B virus infection, 40 were asymptomatic carriers based on clinical examination, liver function test and ultrasonograph results. Overall, HBV/D1 was found in 17%, HBV/D2 in 29%, HBV/D3 in 34% and HBV/D5 in 20% of the cases. HBV/D1 was significantly associated with chronic liver disease (P = 0.01), and in this subgenotype A1896 (PreC mutations) were most common. Although BCP mutations (A/C1753 and T1762/A1764) were found to be frequently associated with HBV/D2 (33% and 33%) and D5 (47% and 59%), no apparent clinical correlation was observed. On the other hand, occult HBV infection was significantly associated with HBV/D3 infection, along with low level of BCP and PreC mutations and several non-synonymous substitutions in the catalytic reverse transcriptase (RT) domain of polymerase gene. Similar nucleotide substitutions in the surface (S) gene region were observed from both northern and eastern Indian HBV/D3 isolates. In conclusion, HBV/D subgenotypes differ in their mutational patterns in the S, polymerase and the BCP/PreC regions that may influence their clinical outcomes.
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22
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Chen CY, Crowther C, Kew MC, Kramvis A. A valine to phenylalanine mutation in the precore region of hepatitis B virus causes intracellular retention and impaired secretion of HBe-antigen. Hepatol Res 2008; 38:580-92. [PMID: 18201182 DOI: 10.1111/j.1872-034x.2007.00315.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
AIM Hepatitis B virus (HBV) e antigen (HBeAg) is translated from precore mRNA as a precore/core protein, which is post-translationally modified to give rise to the protein that is secreted into the serum. The G1862T mutation in HBV occurs in the bulge of the encapsidation signal within the pregenomic RNA. When the precore mRNA is translated, this mutation results in a valine to phenylalanine substitution at the -3 position to the signal peptide cleavage site at the amino end of the precursor protein. The aim of this study was to determine whether this mutation could affect HBV replication and/or HBeAg expression. METHODS Following transfection of Huh 7 cells, HBV replication was followed using real time polymerase reaction (PCR) and expression of HBeAg expression was monitored using confocal microscopy. RESULTS HBV replication was reduced when this mutation was introduced into genotype D but not into genotype A replication-competent constructs. Using mutant HBeAg-expressing plasmids, we demonstrated a 54% reduction in HBeAg secretion relative to the wild type. Confocal microscopy demonstrated that the mutant HBeAg accumulated in the endoplasmic reticulum, endoplasmic reticulum intermediate compartment and Golgi. These aggregates of mutant protein increased in size following treatment of the cells with a proteasome inhibitor, MG132, and had the hallmark features of aggresomes. They attracted ubiquitin, heat shock proteins and proteasomes and were isolated from the cytosol by the intermediate filaments, vimentin and cytokeratin. CONCLUSION The formation of aggresomes, as a result of the G1862T mutation, may play a contributory role in HBV-induced liver disease.
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Affiliation(s)
- Chien Yu Chen
- MRC/University Molecular Hepatology Research Unit, Department of Medicine, University of the Witwatersrand, Johannesburg, South Africa
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23
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A fatal case of acute hepatitis B developed in a toluene abuser. Clin J Gastroenterol 2008; 1:64-68. [DOI: 10.1007/s12328-008-0009-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2008] [Accepted: 03/31/2008] [Indexed: 11/29/2022]
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Abstract
Subgenotypes of hepatitis B virus (HBV) were first recognized after a unique segment of genotype A was identified when sequencing the preS2/S region of southern African HBV isolates. Originally named subgroup A', subsequently called subgroup Aa (for Africa) or subgenotype A1, this subgenotype is found in South Africa, Malawi, Uganda, Tanzania, Somalia, Yemen, India, Nepal, the Philippines and Brazil. The relatively higher mean nucleotide divergence of subgenotype A1 suggests that it has been endemic and has a long evolutionary history in the populations where it prevails. Distinctive sequence characteristics could account for the high hepatitis B e-antigen (HBeAg) negativity and low HBV DNA levels in carriers of this subgenotype. Substitutions or mutations can reduce HBeAg expression at three levels: (i) 1762T1764A atthe transcriptional level; (ii) substitutions at nt 1809-1812 at the translational level; and (iii) 1862T at the post-translational level. Co-existence of 1762T1764A and nt 1809-1812 mutations reduces HBeAg expression in an additive manner. In addition, subgenotype A1 has unique sequence alterations in the transcriptional regulatory elements and the polymerase coding region. The distinct sequence characteristics of subgenotype A1 may contribute to the 4.5-fold increased risk of heptocellular carcinoma in HBV carriers infected with genotype A, which is entirely attributable to subgenotype A1.
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Affiliation(s)
- Anna Kramvis
- MRC/University Molecular Hepatology Research Unit, Department of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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25
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Chandra PK, Banerjee A, Datta S, Chakravarty R. G1862T mutation among hepatitis B virus-infected individuals: association with viral genotypes and disease outcome in Kolkata, Eastern India. Intervirology 2007; 50:173-80. [PMID: 17259736 DOI: 10.1159/000098960] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2006] [Accepted: 07/27/2006] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE To study the prevalence of G1862T mutation in hepatitis B virus (HBV) isolates among Eastern Indian patients and its relationship with genotypes, HBeAg status and disease manifestation. METHODS HBV DNA was isolated from patients, amplified by nested PCR and sequenced directly. RESULTS Of the 102 patients, 32 were HBeAg positive and 70 HBeAg negative; 55, 24 and 23 isolates were infected with genotypes D, A and C, respectively. G1862T was detected in 18 samples, 15 (83%) of them belonged to genotype A (subgenotype HBV/A1), 3 (17%) to genotype D. This mutation was more frequent in HBeAg-negative than in HBeAg-positive patients (21 vs. 9%), whereas in HBV/A1 it was as common in HBeAg-positive as in HBeAg-negative patients and significantly associated with T1762/A1764 mutation. The mean viral load was lower in patients with G1862T mutation. Furthermore, this mutation was common in various clinical outcomes. CONCLUSION In our community, G1862T mutation was predominantly found in HBV/A1 isolates irrespective of HBeAg status. Moreover this mutation could not be correlated to the clinical outcome. These findings indicate that the G1862T mutation is probably a part of the natural variability of HBV/A1.
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Chauhan R, Kazim SN, Bhattacharjee J, Sakhuja P, Sarin SK. Basal core promoter, precore region mutations of HBV and their association with e antigen, genotype, and severity of liver disease in patients with chronic hepatitis B in India. J Med Virol 2006; 78:1047-54. [PMID: 16789012 DOI: 10.1002/jmv.20661] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Spontaneous mutations of hepatitis B virus (HBV) could influence the severity of liver disease. Since the basal core promoter (BCP) and the precore (Pc) regions are important for viral replication, these regions were examined for naturally occurring mutations and were correlated with the genotype, e antigen status, and severity of liver disease. In 82 patients with histologically confirmed chronic hepatitis B, the BCP and Pc regions were sequenced and aligned with known wild-type sequences. Sequence based HBV genotyping was done and HBV DNA was quantified. Thirty-three (40%) patients had decompensated chronic liver disease and the remaining patients had chronic hepatitis B. Forty-six (56%) patients were HBeAg positive. HBV genotype A was found in 28%, D in 65%, and B/C in 7.3%. The Pc G1896A mutation was more common in HBeAg-negative (33% vs. 2%, P < 0.01) patients and was genotype D specific. The Pc G1862T mutation was detected more often in HBeAg-positive than HBeAg-negative (37% vs. 11%, P < 0.01) patients and was genotype A specific (P < 0.01). BCP mutations at the 1,762/64 nucleotide positions were common in HBeAg negative than positive (36% vs. 13%, P < 0.05) and were equally common in different genotypes. TA 1-3 region mutations of the BCP were significantly higher in HBeAg-negative as compared to HBeAg-positive patients (78% vs. 26%, P < 0.01). BCP mutations had significantly higher HBV DNA levels. It is concluded that Pc G1862T mutant is Genotype A-specific but is not always associated with e antigen. The TA 1-3 rich mutations of BCP region are also associated with the absence of e antigen in Indian patients.
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Affiliation(s)
- Ranjit Chauhan
- Department of Gastroenterology, and Advanced Center for Liver Diseases, G.B. Pant Hospital, New Delhi, India
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Szmaragd C, Foster GR, Manica A, Bartholomeusz A, Nichols RA, Balloux F. Genome-wide characterisation of hepatitis B mutations involved in clinical outcome. Heredity (Edinb) 2006; 97:389-97. [PMID: 16896341 DOI: 10.1038/sj.hdy.6800882] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Infection with the hepatitis B virus (HBV) leads to different disease outcomes, which can be broadly divided into three categories: acute mild infection, 'fulminant' and chronic hepatitis (long-term persistent form of the infection). The factors that influence the development of these different disease states are poorly understood and may include viral polymorphisms. To investigate this possibility, we analysed 116 published complete HBV genomes for which we knew disease outcome and had access to associated information on patients (age, sex and geographic origin). Our best statistical model correctly classified 72% of the cases and retained age and sex of the patient, as well as 29 candidate mutations. With the exception of one mutation in the X gene, all were located in the viral polymerase, suggesting this gene plays a critical role in clinical outcome. Our results highlight the importance of the genetics of HBV strains in the evolution of the disease and demonstrate that disease outcome can be predicted to a surprisingly large extent with a limited number of host and viral factors.
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Affiliation(s)
- C Szmaragd
- Theoretical and Molecular Population Genetics group, Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK
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Huang LH, Jiang YM, Dai YX. Influence of mutation in hepatitis B virus precore region on immune response of patients with chronic severe hepatitis B. Shijie Huaren Xiaohua Zazhi 2006; 14:1921-1923. [DOI: 10.11569/wcjd.v14.i19.1921] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the role of mutation at site 1896 in hepatitis B virus (HBV) precore region in the pathogenesis of chronic severe hepatitis B and its influence on the immune response of patients.
METHODS: The production of interferon-γ (IFN-γ) and interleukin-4 (IL-4) by Th1/Th2 and Tc1/Tc2 cells in the peripheral blood from 31 patients with chronic heavy hepatitis were assessed by flow cytometry. The serum concentration of IL-4 and IFN-γ were examined by solid-phase sandwich enzyme-linked immunosorbent assay (ELISA). HBV DNA was amplified by nested polymerase chain reaction and the precore/core fragment was directly sequenced.
RESULTS: The mutation at site 1896 in HBV precore region appeared in 8 of 31 (25.8%) patients with chronic severe hepatitis. Of the 8 patients, 4 (50%) were confirmed with the mutation at site 1913. However, of the 23 patients without the mutation at site 1896, 1 case was detected with the mutation at site 1913. The level of Tc1 was significantly higher in the patients with G1896A mutation than that in those without G1896A mutation (t = 2.407, P = 0.023). The levels of serum IFN-γ and IL-4 were not markedly different between the patients with and without G1896A mutation (P > 0.05). The mortality rate was also similar between the two groups.
CONCLUSION: Tc1 level is significantly enhanced due to G1896A mutation and plays an important role in the pathogenesis of chronic severe hepatitis B.
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Guarnieri M, Kim KH, Bang G, Li J, Zhou Y, Tang X, Wands J, Tong S. Point mutations upstream of hepatitis B virus core gene affect DNA replication at the step of core protein expression. J Virol 2006; 80:587-95. [PMID: 16378961 PMCID: PMC1346833 DOI: 10.1128/jvi.80.2.587-595.2006] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The pregenomic RNA directs replication of the hepatitis B virus (HBV) genome by serving both as the messenger for core protein and polymerase and as the genome precursor following its packaging into the core particle. RNA packaging is mediated by a stem-loop structure present at its 5' end designated the epsilon signal, which includes the core gene initiator AUG. The precore RNA has a slightly extended 5' end to cover the entire precore region and, consequently, directs the translation of a precore/core protein, which is secreted as e antigen (HBeAg) following removal of precore-derived signal peptide and the carboxyl terminus. A naturally occurring G1862T mutation upstream of the core AUG affects the bulge of the epsilon signal and generates a "forbidden" residue at the -3 position of the signal peptide cleavage site. Transfection of this and other mutants into human hepatoma cells failed to prove their inhibition of HBeAg secretion but rather revealed great impairment of genome replication. This replication defect was associated with reduced expression of core protein and could be overcome by a G1899A covariation, or by nonsense or frameshift mutation in the precore region. All these mutations antagonized the G1862T mutation on core protein expression. Cotransfection of the G1862T mutant with a replication-deficient HBV genome that provides core protein in trans also restored genome replication. Consistent with our findings in cell culture, HBV genotype A found in African/Asian patients has T1862 and is associated with much lower viremia titers than the European subgroup of genotype A.
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Affiliation(s)
- Michael Guarnieri
- The Liver Research Center and Brown Medical School, Providence, RI 02903, USA
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Karayiannis P, Carman WF, Thomas HC. Molecular Variations in the Core Promoter, Precore and Core Regions of Hepatitis B Virus, and their Clinical Significance. VIRAL HEPATITIS 2005:242-262. [DOI: 10.1002/9780470987131.ch15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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31
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Kew MC, Kramvis A, Yu MC, Arakawa K, Hodkinson J. Increased hepatocarcinogenic potential of hepatitis B virus genotype A in Bantu-speaking sub-saharan Africans. J Med Virol 2005; 75:513-21. [PMID: 15714494 DOI: 10.1002/jmv.20311] [Citation(s) in RCA: 115] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Genotypes A, D, and E of the hepatitis B virus (HBV) circulate in southern Africa, with genotype A predominating. Their hepatocarcinogenic potential in Bantu-speaking sub-saharan Africans is, however, unknown. Using a case/control format, we investigated the hepatocarcinogenic potential of these genotypes and subgenotype A1 of genotype A, which accounts for the great majority of genotype A isolates. HBV isolates from 111 unselected Bantu-speaking sub-saharan Africans with hepatocellular carcinoma (HCC) and 111 matched asymptomatic chronic carriers, serving as controls, were genotyped using the method of [Lindh et al. (1997): J Infect Dis 175:1285-1293]. Subgenotypes of genotype A were determined using an in-house restriction fragment length polymorphism assay. Genotype A was present in 96 (86.5%) of patients with HCC and 76 (68.5%) of the carriers, giving a 4.5-fold (95% confidence limits: 1.86, 10.90) increased risk of HCC in carriers infected with genotype A compared with those infected with non-A genotypes. HCC patients infected with genotype A were significantly younger than those infected with non-A genotypes (P = 0.02). The distributions between these two groups according to sex, geographic background, and tribe were not significantly different. Subgenotype A1 was present in all of the 77 cancer patients and 69 of 70 carriers analyzed, yielding a relative risk of 4.21 (95% confidence limits: 1.73,10.23) of HCC in those infected with subgenotype A1 compared with those infected with non-A genotypes. Genotype A has a greater hepatocarcinogenic potential than non-A genotypes in Bantu-speaking sub-saharan Africans and this is entirely attributable to subgenotype A1.
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Affiliation(s)
- Michael C Kew
- MRC/CANSA/University Molecular Hepatology Research Unit, Department of Medicine, Medical School, University of the Witwatersrand, 7 York Road, Parktown 2193, Johannesburg, South Africa.
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Wai CT, Fontana RJ, Polson J, Hussain M, Shakil AO, Han SH, Davern TJ, Lee WM, Lok ASF. Clinical outcome and virological characteristics of hepatitis B-related acute liver failure in the United States. J Viral Hepat 2005; 12:192-8. [PMID: 15720535 DOI: 10.1111/j.1365-2893.2005.00581.x] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The role of hepatitis B virus (HBV) genotypes in the outcome of acute HBV infection is unclear. In this study, we aimed to evaluate the clinical and virological features of patients with hepatitis B-related acute liver failure (HBV-ALF) in the US. Clinical and laboratory features of consecutive patients with HBV-ALF from the US ALF Study Group were analysed. Prevalence of HBV genotypes, precore stop (G1896A) and core promoter dual (T1762A, A1764T) variants among patients with HBV-ALF were compared with a cohort of 530 patients with chronic HBV infection. Thirty-four HBV-ALF patients were studied: mean age 41 years, 56% men, 25 had detectable HBV-DNA. HBV genotypes A, B, C and D were found in 36, 24, 8 and 32% patients, respectively. Precore stop and core promoter dual variants were detected in 32 and 44% of patients, respectively. Twenty-three (68%) patients survived: 14 after liver transplant, nine without transplant. Older age was the only independent factor associated with poor outcome. Compared with patients with chronic HBV infection, patients with ALF were more likely to be non-Asians (88% vs 44%, P = 0.005) and to have genotype D (32% vs 10%, P < 0.01). A higher prevalence of HBV genotype D persisted even after matching for race and HBeAg status (32% vs 16%, P = 0.007). We concluded that HBV genotype D was more frequently found in patients with HBV-ALF than those with chronic HBV infection in the US. Further studies are needed to determine if HBV genotypes play a role in the outcome of acute HBV infection.
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Affiliation(s)
- C-T Wai
- Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA
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Zeng GB, Wen SJ, Wang ZH, Yan L, Sun J, Hou JL. A novel hepatitis B virus genotyping system by using restriction fragment length polymorphism patterns of S gene amplicons. World J Gastroenterol 2004; 10:3132-6. [PMID: 15457558 PMCID: PMC4611256 DOI: 10.3748/wjg.v10.i21.3132] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: Traditional hepatitis B virus (HBV) genotyping methods using restriction fragment length polymorphism (RFLP) can reliably identify genotypes A to F. As HBV genotypes G and H have been recently identified, this study was to establish an accurate and simple genotyping method for all eight HBV genotypes (A to H).
METHODS: Two hundred and forty HBV small S sequences obtained from GeneBank were analysed for restriction enzyme sites that would be genotype-specific. Restriction patterns following digestion with restriction enzymes BsrI, StyI, DpnI, HpaII, and EaeI, were determined to identify all eight HBV genotypes. Mixed genotype infections were confirmed by cloning and further RFLP analysis.
RESULTS: The new genotyping method could identify HBV genotypes A to H. Genotypes B and C could be determined by a single step digestion with BsrI and StyI in parallel. This was particularly useful in the Far East where genotypes B and C are predominant. Serum samples from 187 Chinese HBV carriers were analysed with this genotyping system, and the genotype distribution was 1.1% (2), 51.9% (97), 40.6% (76) and 4.8% (9) for genotypes A, B, C, and D, respectively. Mixed genotypes were found in only 3 patients (1.6%). Sequence data analysis confirmed the validity of this new method.
CONCLUSION: This HBV genotyping system can identify all eight HBV genotypes. It is accurate and simple, and can be widely used for studies on HBV genotyping.
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Affiliation(s)
- Guo-Bing Zeng
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
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Tanaka Y, Hasegawa I, Kato T, Orito E, Hirashima N, Acharya SK, Gish RG, Kramvis A, Kew MC, Yoshihara N, Shrestha SM, Khan M, Miyakawa Y, Mizokami M. A case-control study for differences among hepatitis B virus infections of genotypes A (subtypes Aa and Ae) and D. Hepatology 2004; 40:747-755. [PMID: 15349915 DOI: 10.1002/hep.20365] [Citation(s) in RCA: 129] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
There are two subtypes of hepatitis B virus genotype A (HBV/A) and they are provisionally designated Aa ("a" standing for Africa/Asia) and Ae ("e" for Europe). In a case-control study, 78 HBV/Aa, 78HBV/Ae, and 78HBV/D carriers from several countries were compared. The prevalence of HBe antigen (HBeAg) in serum was significantly lower in carriers of HBV/Aa than in carriers of HBV/Ae (31% vs. 49%; P = .033), with a difference more obvious in the carriers aged 30 years or younger (34% vs. 67%; P = .029). HBV DNA levels in the carriers of HBV/Aa (median, 3.46 log copies/mL; 95% CI, 2.93-3.95) were significantly lower than those of carriers of HBV/Ae (6.09 log copies/mL; 95% CI, 4.24-7.64) or of carriers of HBV/D (5.48 log copies/mL; 95% CI, 4.06-7.02), regardless of the HBeAg status (P < .001). The most specific and frequent substitutions in 54 HBV/Aa isolates were double substitutions for T1809 (100%) and T1812 (96%) immediately upstream of the precore initiation codon, which would interfere with the translation of HBeAg in HBV/Aa infections. They were not detected in 57 HBV/Ae or 61 HBV/D isolates examined. The double mutation in the core promoter (T1762/A1764) was more frequent in both HBV/Aa (50%) and HBV/Ae (44%) than in HBV/D isolates (25%; P < .01), whereas the precore mutation (A1896) occurred in HBV/D isolates only (48%; P < .0001). In conclusion, the clearance of HBeAg from serum may occur by different mechanisms in HBV/Aa, HBV/Ae, and HBV/D infections, which may influence clinical manifestations in the Western countries where both genotypes A and D are prevalent.
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Affiliation(s)
- Yasuhito Tanaka
- Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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35
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Wai CT, Fontana RJ. Clinical significance of hepatitis B virus genotypes, variants, and mutants. Clin Liver Dis 2004; 8:321-52, vi. [PMID: 15481343 DOI: 10.1016/j.cld.2004.02.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Emerging evidence suggests that hepatitis B virus (HBV) genotypes may influence the rate of spontaneous and interferon-induced hepatitis B e antigen (HBeAg) seroconversion as well as the natural history of liver disease. In contrast, the dinical significance of precore and core promoter variants associated with HBeAg negative liver disease is less certain in light of the many competing host and virologic factors noted in reported studies. HBV surface mutants are primarily associated with prior vaccine or hepatitis B immune globulin exposure and do not appear to have untoward virulence or association with occult HBV infection. Polymerase mutants with reduced drug sensitivity and phenotypic resistance are commonly detected in patients receiving prolonged antiviral therapy and have a variable impact on disease outcomes. The introduction of additional nucleoside/nucleotide analog agents will likely lead to the development of further unique polymerase mutants with varying pathogenicity and cross-resistance to existing drugs.
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Affiliation(s)
- Chun-Tao Wai
- Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, 3912 Taubman Center, Ann Arbor, MI 48109-0362, USA
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Sugauchi F, Kumada H, Acharya SA, Shrestha SM, Gamutan MTA, Khan M, Gish RG, Tanaka Y, Kato T, Orito E, Ueda R, Miyakawa Y, Mizokami M. Epidemiological and sequence differences between two subtypes (Ae and Aa) of hepatitis B virus genotype A. J Gen Virol 2004; 85:811-820. [PMID: 15039524 DOI: 10.1099/vir.0.79811-0] [Citation(s) in RCA: 116] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Complete nucleotide sequences of 19 hepatitis B virus (HBV) isolates of genotype A (HBV/A) were determined and analysed along with those of 20 previously reported HBV/A isolates. Of the 19 HBV/A isolates, six including three from Japan and three from the USA clustered with the 14 HBV/A isolates from Western countries. The remaining 13 isolates including four from The Philippines, two from India, three from Nepal and four from Bangladesh clustered with the six HBV/A isolates reported from The Philippines, South Africa and Malawi. Due to distinct epidemiological distributions, genotype A in the 20 HBV isolates was classified into subtype Ae (e for Europe), and that in the other 19 into subtype Aa (a for Asia and Africa) provisionally. The 19 HBV/Aa isolates had a sequence variation significantly greater than that of the 20 HBV/Ae isolates (2.5+/-0.3 % vs 1.1+/-0.6 %, P<0.0001); they differed by 5.0+/-0.4 % (4.1-6.4 %). The double mutation (T1762/A1764) in the core promoter was significantly more frequent in HBV/Aa isolates than in HBV/Ae isolates (11/19 or 58 % vs 5/20 or 25 %, P<0.01). In the pregenome encapsidation (epsilon) signal, a point mutation from G to A or T at nt 1862 was detected in 16 of the 19 (84 %) HBV/Aa isolates but not in any of the 20 HBV/Ae isolates, which may affect virus replication and translation of hepatitis B e antigen. Subtypes Aa and Ae of genotype A deserve evaluation for any clinical differences between them, with a special reference to hepatocellular carcinoma prevalent in Africa.
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Affiliation(s)
- Fuminaka Sugauchi
- Departments of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
- Departments of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiromitsu Kumada
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
| | - Subrat A Acharya
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
| | | | | | - Mobin Khan
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Robert G Gish
- Hepatology and Gastroenterology, California Pacific Medical Center, San Francisco, USA
| | - Yasuhito Tanaka
- Departments of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takanobu Kato
- Departments of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Etsuro Orito
- Departments of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Ryuzo Ueda
- Departments of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | | | - Masashi Mizokami
- Departments of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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