|
1
|
García-García S, Caballero-Garralda A, Tabernero D, Cortese MF, Gregori J, Rodriguez-Algarra F, Quer J, Riveiro-Barciela M, Homs M, Rando-Segura A, Pacin-Ruiz B, Vila M, Ferrer-Costa R, Pumarola T, Buti M, Rodriguez-Frias F. Hepatitis B Virus Variants with Multiple Insertions and/or Deletions in the X Open Reading Frame 3' End: Common Members of Viral Quasispecies in Chronic Hepatitis B Patients. Biomedicines 2022; 10:1194. [PMID: 35625929 PMCID: PMC9139148 DOI: 10.3390/biomedicines10051194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/18/2022] [Accepted: 05/19/2022] [Indexed: 11/16/2022] Open
Abstract
Deletions in the 3' end region of the hepatitis B virus (HBV) X open reading frame (HBX) may affect the core promoter (Cp) and have been frequently associated with hepatocellular carcinoma (HCC). The aim of this study was to investigate the presence of variants with deletions and/or insertions (Indels) in this region in the quasispecies of 50 chronic hepatitis B (CHB) patients without HCC. We identified 103 different Indels in 47 (94%) patients, in a median of 3.4% of their reads (IQR, 1.3-8.4%), and 25% (IQR, 13.1-40.7%) of unique sequences identified in each quasispecies (haplotypes). Of those Indels, 101 (98.1%) caused 44 different altered stop codons, the most commonly observed were at positions 128, 129, 135, and 362 (putative position). Moreover, 39 (37.9%) Indels altered the TATA-like box (TA) sequences of Cp; the most commonly observed caused TA2 + TA3 fusion, creating a new putative canonical TATA box. Four (8%) patients developed negative clinical outcomes after a median follow-up of 9.4 (8.7-12) years. In conclusion, we observed variants with Indels in the HBX 3' end in the vast majority of our CHB patients, some of them encoding alternative versions of HBx with potential functional roles, and/or alterations in the regulation of transcription.
Collapse
Affiliation(s)
- Selene García-García
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (S.G.-G.); (A.C.-G.); (A.R.-S.); (B.P.-R.); (M.V.); (R.F.-C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.G.); (J.Q.); (M.R.-B.); (M.B.)
- Biochemistry and Molecular Biology Department, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain
| | - Andrea Caballero-Garralda
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (S.G.-G.); (A.C.-G.); (A.R.-S.); (B.P.-R.); (M.V.); (R.F.-C.)
- Echevarne Laboratory, Department of Biochemistry, 08037 Barcelona, Spain
| | - David Tabernero
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (S.G.-G.); (A.C.-G.); (A.R.-S.); (B.P.-R.); (M.V.); (R.F.-C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.G.); (J.Q.); (M.R.-B.); (M.B.)
| | - Maria Francesca Cortese
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (S.G.-G.); (A.C.-G.); (A.R.-S.); (B.P.-R.); (M.V.); (R.F.-C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.G.); (J.Q.); (M.R.-B.); (M.B.)
| | - Josep Gregori
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.G.); (J.Q.); (M.R.-B.); (M.B.)
- Liver Diseases-Viral Hepatitis, Liver Unit, Vall d’Hebron Institute of Research (VHIR), Vall d’Hebron University Hospital, 08035 Barcelona, Spain
| | - Francisco Rodriguez-Algarra
- Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK;
| | - Josep Quer
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.G.); (J.Q.); (M.R.-B.); (M.B.)
- Biochemistry and Molecular Biology Department, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain
- Liver Diseases-Viral Hepatitis, Liver Unit, Vall d’Hebron Institute of Research (VHIR), Vall d’Hebron University Hospital, 08035 Barcelona, Spain
| | - Mar Riveiro-Barciela
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.G.); (J.Q.); (M.R.-B.); (M.B.)
- Liver Unit, Department of Internal Medicine, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
| | - Maria Homs
- Anoia Primary Care Service, Territorial Management of Central Catalonia, Catalan Institute of Health, 08700 Igualada, Spain;
- Health Promotion in Rural Areas Research Group, Territorial Management of Central Catalonia, Catalan Institute of Health, 08272 Sant Fruitós de Bages, Spain
| | - Ariadna Rando-Segura
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (S.G.-G.); (A.C.-G.); (A.R.-S.); (B.P.-R.); (M.V.); (R.F.-C.)
- Department of Microbiology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain;
| | - Beatriz Pacin-Ruiz
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (S.G.-G.); (A.C.-G.); (A.R.-S.); (B.P.-R.); (M.V.); (R.F.-C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.G.); (J.Q.); (M.R.-B.); (M.B.)
- Biochemistry and Molecular Biology Department, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain
| | - Marta Vila
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (S.G.-G.); (A.C.-G.); (A.R.-S.); (B.P.-R.); (M.V.); (R.F.-C.)
| | - Roser Ferrer-Costa
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (S.G.-G.); (A.C.-G.); (A.R.-S.); (B.P.-R.); (M.V.); (R.F.-C.)
| | - Tomas Pumarola
- Department of Microbiology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain;
| | - Maria Buti
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.G.); (J.Q.); (M.R.-B.); (M.B.)
- Liver Unit, Department of Internal Medicine, Vall d’Hebron University Hospital, 08035 Barcelona, Spain
| | - Francisco Rodriguez-Frias
- Liver Pathology Unit, Departments of Biochemistry and Microbiology, Vall d’Hebron University Hospital, 08035 Barcelona, Spain; (S.G.-G.); (A.C.-G.); (A.R.-S.); (B.P.-R.); (M.V.); (R.F.-C.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain; (J.G.); (J.Q.); (M.R.-B.); (M.B.)
- Biochemistry and Molecular Biology Department, Universitat Autònoma de Barcelona (UAB), 08193 Bellaterra, Spain
| |
Collapse
|
|
2
|
Precore/core mutations of hepatitis B virus genotype D arising in different states of infection. Clin Exp Hepatol 2022; 8:21-28. [PMID: 35415256 PMCID: PMC8984791 DOI: 10.5114/ceh.2022.114253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 01/19/2022] [Indexed: 11/17/2022] Open
Abstract
Aim of the study Precore/core variations and liver disease progression have been suggested. In this study, we aimed to determine the frequency of precore/core mutations in hepatitis B virus (HBV)-infected patients at various clinical stages. Material and methods In total, 73 HBV-infected patients including 26 inactive carriers (IC), 20 chronic active (CA), and 27 patients with liver cirrhosis/hepatocellular carcinoma (C/HCC) were randomly selected. The HBV DNA was extracted from the sera and subjected to nested PCR for amplification of precore/core region. The PCR product was then sequenced by the Sanger method. Results The stop codon of W28*(G1896A) was determined as the most prevalent mutation (55%) of the precore region. The comparison of groups also demonstrated that core substitutions at residues of S21, E40 and I105 (< 0.05) correlated with the development of the inactive carrier state. Furthermore, the total substitutions in Th epitopes (117-131) were significantly higher in the C/HCC group than the IC and CA groups (p = 0.001). Conclusions Our results indicated a high frequency of W28* mutation in HBV studied patients. Moreover, variations including S21, E40 and I105 and R151 that were mapped onto cellular epitopes might be related to inactive state development.
Collapse
|
|
3
|
Jeong H, Kim DH, Choi YM, Choi H, Kim D, Kim BJ. rt269I Type of Hepatitis B Virus (HBV) Polymerase versus rt269L Is More Prone to Mutations within HBV Genome in Chronic Patients Infected with Genotype C2: Evidence from Analysis of Full HBV Genotype C2 Genome. Microorganisms 2021; 9:601. [PMID: 33803998 PMCID: PMC7999911 DOI: 10.3390/microorganisms9030601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/08/2021] [Accepted: 03/10/2021] [Indexed: 12/03/2022] Open
Abstract
Recently, it has been reported that the rt269I type of hepatitis B virus (HBV) polymerase (Pol) versus the rt269L type is more significantly related to lower viral replication and HBeAg negative infections in chronic hepatitis B (CHB) patients of genotype C2. In this study, we compared mutation rates within HBV genomes between rt269L and rt269I using a total of 234 HBV genotype C2 full genome sequences randomly selected from the HBV database (115 of rt269L and 119 of rt269I type). When we applied the Benjamini and Hochberg procedure for multiple comparisons, two parameters, dN and d, at the amino acids level in the Pol region were significantly higher in the rt269I type than in the rt269L type. Although it could not reach statistical significance from the Benjamini and Hochberg procedure, nonsynonymous (NS) mutations in the major hydrophilic region (MHR) or "a" determinant in the surface antigens (HBsAg ORF) related to host immune escape or vaccine escape are more frequently generated in rt269I strains than in rt269L. We also found that there are a total of 19 signature single nucleotide polymorphisms (SNPs), of which 2 and 17 nonsynonymous mutation types were specific to rt269L and rt269I, respectively: Of these, most are HBeAg negative infections (preC-W28*, X-V5M and V131I), lowered HBV DNA or virion production (C-I97F/L, rtM204I/V) or preexisting nucleot(s)ide analog resistance (NAr) (rtN139K/H, rtM204I/V and rtI224V) or disease severity (preC-W28*, C-I97F/L, C-Q182K/*, preS2-F141L, S-L213I/S, V/L5M, T36P/S/A, V131I, rtN139K/H, rtM204I/V and rtI224V). In conclusion, our data showed that rt269I types versus rt269L types are more prone to overall genome mutations, particularly in the Pol region and in the MHR or "a" determinant in genotype C2 infections and are more prevalent in signature NS mutations related to lowered HBV DNA replication, HBsAg and HBeAg secretion and potential NAr variants and hepatocellular carcinoma (HCC), possibly via type I interferon (IFN-I)-mediated enhanced inflammation. Our data suggest that rt269L types could contribute to liver disease progression via the generation of immune escape or enhanced persistent infection in chronic patients of genotype C2.
Collapse
Affiliation(s)
- Hyein Jeong
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Institute, College of Medicine, Seoul National University, Seoul 03080, Korea; (H.J.); (D.H.K.); (Y.-M.C.)
| | - Dong Hyun Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Institute, College of Medicine, Seoul National University, Seoul 03080, Korea; (H.J.); (D.H.K.); (Y.-M.C.)
| | - Yu-Min Choi
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Institute, College of Medicine, Seoul National University, Seoul 03080, Korea; (H.J.); (D.H.K.); (Y.-M.C.)
| | - HyeLim Choi
- Department of Biomedical Sciences, and Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 03080, Korea; (H.C.); (D.K.)
| | - Donghyun Kim
- Department of Biomedical Sciences, and Microbiology and Immunology, College of Medicine, Seoul National University, Seoul 03080, Korea; (H.C.); (D.K.)
| | - Bum-Joon Kim
- Department of Biomedical Sciences, Microbiology and Immunology, and Liver Institute, College of Medicine, Seoul National University, Seoul 03080, Korea; (H.J.); (D.H.K.); (Y.-M.C.)
| |
Collapse
|
|
4
|
The evolution and clinical impact of hepatitis B virus genome diversity. Nat Rev Gastroenterol Hepatol 2020; 17:618-634. [PMID: 32467580 DOI: 10.1038/s41575-020-0296-6] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/20/2020] [Indexed: 02/06/2023]
Abstract
The global burden of hepatitis B virus (HBV) is enormous, with 257 million persons chronically infected, resulting in more than 880,000 deaths per year worldwide. HBV exists as nine different genotypes, which differ in disease progression, natural history and response to therapy. HBV is an ancient virus, with the latest reports greatly expanding the host range of the Hepadnaviridae (to include fish and reptiles) and casting new light on the origins and evolution of this viral family. Although there is an effective preventive vaccine, there is no cure for chronic hepatitis B, largely owing to the persistence of a viral minichromosome that is not targeted by current therapies. HBV persistence is also facilitated through aberrant host immune responses, possibly due to the diverse intra-host viral populations that can respond to host-mounted and therapeutic selection pressures. This Review summarizes current knowledge on the influence of HBV diversity on disease progression and treatment response and the potential effect on new HBV therapies in the pipeline. The mechanisms by which HBV diversity can occur both within the individual host and at a population level are also discussed.
Collapse
|
|
5
|
Al-Qahtani AA, Al-Anazi MR, Nazir N, Abdo AA, Sanai FM, Al-Hamoudi WK, Alswat KA, Al-Ashgar HI, Khan MQ, Albenmousa A, El-Shamy A, Alanazi SK, Dela Cruz D, Bohol MFF, Al-Ahdal MN. The Correlation Between Hepatitis B Virus Precore/Core Mutations and the Progression of Severe Liver Disease. Front Cell Infect Microbiol 2018; 8:355. [PMID: 30406036 PMCID: PMC6204459 DOI: 10.3389/fcimb.2018.00355] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Accepted: 09/18/2018] [Indexed: 12/13/2022] Open
Abstract
Viral mutations acquired during the course of chronic hepatitis B virus (HBV) infection are known to be associated with the progression and severity of HBV-related liver disease. This study of HBV-infected Saudi Arabian patients aimed to identify amino acid substitutions within the precore/core (preC/C) region of HBV, and investigate their impact on disease progression toward hepatocellular carcinoma (HCC). Patients were categorized according to the severity of their disease, and were divided into the following groups: inactive HBV carriers, active HBV carriers, liver cirrhosis patients, and HCC patients. Two precore mutations, W28* and G29D, and six core mutations, F24Y, E64D, E77Q, A80I/T/V, L116I, and E180A were significantly associated with the development of cirrhosis and HCC. Six of the seven significant core mutations that were identified in this study were located within immuno-active epitopes; E77Q, A80I/T/V, and L116I were located within B-cell epitopes, and F24Y, E64D, and V91S/T were located within T-cell epitopes. Multivariate risk analysis confirmed that the core mutations A80V and L116I were both independent predictors of HBV-associated liver disease progression. In conclusion, our data show that mutations within the preC/C region, particularly within the immuno-active epitopes, may contribute to the severity of liver disease in patients with chronic hepatitis. Furthermore, we have identified several distinct preC/C mutations within the study population that affect the clinical manifestation and progression of HBV-related disease. The specific identity of HBV mutations that are associated with severe disease varies between different ethnic populations, and so the specific preC/C mutations identified here will be useful for predicting clinical outcomes and identifying the HBV-infected patients within the Saudi population that are at high risk of developing HCC.
Collapse
Affiliation(s)
- Ahmed A Al-Qahtani
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Department of Microbiology and Immunology, Alfaisal University School of Medicine, Riyadh, Saudi Arabia
| | - Mashael R Al-Anazi
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Nyla Nazir
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Ayman A Abdo
- Section of Gastroenterology, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
| | - Faisal M Sanai
- Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia.,Gastroenterology Unit, Department of Medicine, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Waleed K Al-Hamoudi
- Section of Gastroenterology, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
| | - Khalid A Alswat
- Section of Gastroenterology, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Liver Disease Research Center, King Saud University, Riyadh, Saudi Arabia
| | - Hamad I Al-Ashgar
- Gastroenterology Unit, Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Mohammed Q Khan
- Gastroenterology Unit, Department of Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Ali Albenmousa
- Department of Gastroenterology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Ahmed El-Shamy
- Department of Pharmaceutical and Biomedical Sciences, California Northstate University, Elk Grove, CA, United States
| | - Salah K Alanazi
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Damian Dela Cruz
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Marie Fe F Bohol
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Mohammed N Al-Ahdal
- Department of Infection and Immunity, Research Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.,Department of Microbiology and Immunology, Alfaisal University School of Medicine, Riyadh, Saudi Arabia
| |
Collapse
|
|
6
|
Liu WC, Wu IC, Lee YC, Lin CP, Cheng JH, Lin YJ, Yen CJ, Cheng PN, Li PF, Cheng YT, Cheng PW, Sun KT, Yan SL, Lin JJ, Yang JC, Chang KC, Ho CH, Tseng VS, Chang BCH, Wu JC, Chang TT. Hepatocellular carcinoma-associated single-nucleotide variants and deletions identified by the use of genome-wide high-throughput analysis of hepatitis B virus. J Pathol 2017; 243:176-192. [PMID: 28696069 DOI: 10.1002/path.4938] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2016] [Revised: 05/31/2017] [Accepted: 07/04/2017] [Indexed: 12/26/2022]
Abstract
This study investigated hepatitis B virus (HBV) single-nucleotide variants (SNVs) and deletion mutations linked with hepatocellular carcinoma (HCC). Ninety-three HCC patients and 108 non-HCC patients were enrolled for HBV genome-wide next-generation sequencing (NGS) analysis. A systematic literature review and a meta-analysis were performed to validate NGS-defined HCC-associated SNVs and deletions. The experimental results identified 60 NGS-defined HCC-associated SNVs, including 41 novel SNVs, and their pathogenic frequencies. Each SNV was specific for either genotype B (n = 24) or genotype C (n = 34), except for nt53C, which was present in both genotypes. The pathogenic frequencies of these HCC-associated SNVs showed a distinct U-shaped distribution pattern. According to the meta-analysis and literature review, 167 HBV variants from 109 publications were categorized into four levels (A-D) of supporting evidence that they are associated with HCC. The proportion of NGS-defined HCC-associated SNVs among these HBV variants declined significantly from 75% of 12 HCC-associated variants by meta-analysis (Level A) to 0% of 10 HCC-unassociated variants by meta-analysis (Level D) (P < 0.0001). PreS deletions were significantly associated with HCC, in terms of deletion index, for both genotypes B (P = 0.030) and C (P = 0.049). For genotype C, preS deletions involving a specific fragment (nt2977-3013) were significantly associated with HCC (HCC versus non-HCC, 6/34 versus 0/32, P = 0.025). Meta-analysis of preS deletions showed significant association with HCC (summary odds ratio 3.0; 95% confidence interval 2.3-3.9). Transfection of Huh7 cells showed that all of the five novel NGS-defined HCC-associated SNVs in the small surface region influenced hepatocarcinogenesis pathways, including endoplasmic reticulum-stress and DNA repair systems, as shown by microarray, real-time polymerase chain reaction and western blot analysis. Their carcinogenic mechanisms are worthy of further research. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Wen-Chun Liu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.,Infectious Disease and Signalling Research Centre, National Cheng Kung University, Tainan, Taiwan, ROC
| | - I-Chin Wu
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.,Infectious Disease and Signalling Research Centre, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Yen-Chien Lee
- Department of Oncology, Tainan Hospital, Ministry of Health and Welfare, Tainan, Taiwan, ROC.,Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | | | - Ji-Hong Cheng
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Yih-Jyh Lin
- Department of Surgery, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan, ROC
| | - Chia-Jui Yen
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.,Infectious Disease and Signalling Research Centre, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Pin-Nan Cheng
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.,Infectious Disease and Signalling Research Centre, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Pei-Fu Li
- Institute of Medical Informatics, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Yi-Ting Cheng
- Institute of Medical Informatics, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Pei-Wen Cheng
- Department of Information and Learning Technology, Science and Engineering College, National University of Tainan, Tainan, Taiwan, ROC
| | - Koun-Tem Sun
- Department of Information and Learning Technology, Science and Engineering College, National University of Tainan, Tainan, Taiwan, ROC
| | - Shu-Ling Yan
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Jia-Jhen Lin
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Jui-Chu Yang
- Human Biobank, Research Centre of Clinical Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, ROC
| | - Kung-Chao Chang
- Human Biobank, Research Centre of Clinical Medicine, National Cheng Kung University Hospital, Tainan, Taiwan, ROC
| | - Cheng-Hsun Ho
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.,Infectious Disease and Signalling Research Centre, National Cheng Kung University, Tainan, Taiwan, ROC
| | - Vincent S Tseng
- Department of Computer Science, National Chiao Tung University, Hsinchu, Taiwan, ROC
| | | | - Jaw-Ching Wu
- Institute of Clinical Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, ROC.,Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Ting-Tsung Chang
- Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.,Infectious Disease and Signalling Research Centre, National Cheng Kung University, Tainan, Taiwan, ROC
| |
Collapse
|
|
7
|
Salarnia F, Besharat S, Zhand S, Javid N, Khodabakhshi B, Moradi A. Mutations in Hepatitis-B X-Gene Region: Chronic Hepatitis-B versus Cirrhosis. J Clin Diagn Res 2017; 11:OC31-OC34. [PMID: 28511432 DOI: 10.7860/jcdr/2017/22570.9498] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Accepted: 11/28/2016] [Indexed: 12/21/2022]
Abstract
INTRODUCTION Specific mutations in Hepatitis-B Virus (HBV) genome would proceed the development of chronic hepatitis B to more serious consequences like cirrhosis and end-stage liver disease. AIM This study was designed to detect deletion and insertion mutational patterns in the X-gene region in a population of chronic HBV and related cirrhosis patients. MATERIALS AND METHODS Sixty eight chronic HBV patients and 34 HBV-related cirrhotics were recruited from the eligible cases (N=50) referred to the academic hospitals of Gorgan city, Northeast of Iran, between Jan 2011 to Dec 2013. The HBx region was amplified by semi-nested PCR using serum samples and analyzed by sequencing. RESULTS Our findings showed deletions and insertions in the C-terminal of HBx of the cirrhotic group and 8 bp found in two chronic HBV cases (2.9%). We detected 15 types of deletions in cirrhotic cases such as 1762-1768, 1763-1770, 1769-1773 and T1771/A1775. CONCLUSION We found that the frequencies of deletion and insertion mutations in C-terminal of X-gene were more seen in cirrhotic patients comparing to chronic HBV cases in our area of study.
Collapse
Affiliation(s)
- Farzaneh Salarnia
- Researcher, Infectious Disease Research Center, Golestan University of Medical Sciences, Gorgan, Golestan, Iran
| | - Sima Besharat
- Assistant Professor, PhD, Golestan Research Center of Gastroentrology and Hepatology, Golestan University of Medical Sciences, Gorgan, Golestan, Iran
| | - Sare Zhand
- PhD Candidate, Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Golestan, Iran
| | - Naeme Javid
- Researcher, Department of Microbiology, Golestan University of Medical Sciences, Gorgan, Golestan, Iran
| | - Behnaz Khodabakhshi
- Associate Professor, Golestan Research Center of Gastroentrology and Hepatology, Golestan University of Medical Sciences, Gorgan, Golestan, Iran
| | - Abdolvahab Moradi
- Professor, Golestan Research Center of Gastroentrology and Hepatology, Golestan University of Medical Sciences, Gorgan, Golestan, Iran
| |
Collapse
|
|
8
|
Twagirumugabe T, Swaibu G, Walker TD, Lindh M, Gahutu JB, Bergström T, Norder H. Hepatitis B virus strains from Rwandan blood donors are genetically similar and form one clade within subgenotype A1. BMC Infect Dis 2017; 17:32. [PMID: 28056881 PMCID: PMC5217631 DOI: 10.1186/s12879-016-2149-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 12/21/2016] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Rwanda is a central African country with about 12 million inhabitants. The 1994 genocide against the Tutsi destroyed much of the infrastructure, including the health system. Although this has improved significantly, many challenges remain to be addressed. In this study, the prevalence of serological markers of past and ongoing hepatitis B virus (HBV) infection and HBV vaccine related immunity was investigated in samples from blood donors from all regions of Rwanda. METHODS The results from hepatitis B surface antigen (HBsAg) analyses of all (45,061) blood donations collected countrywide in 2014 from 13,637 first time and 31,424 repeat blood donors were compiled. Samples from 581 HBsAg negative blood donors were selected for further analysis for antibodies against HBV, anti-HBs and anti-HBc. Additional 139 samples from HBsAg positive donors were analyzed for HBeAg/anti-HBe (132 samples) and for HBV DNA. The S-gene was amplified by PCR, products sequenced, and phylogenetic analysis was performed. RESULTS HBsAg was found in 4.1% of first time donors with somewhat higher prevalence among those from the Central and Eastern regions than from other parts of the country. Indications of past infection was found in 21% of the HBsAg negative donors, 4.3% had only anti-HBs suggesting HBV vaccination. HBeAg was detected in 28 (21%), anti-HBe in 97 (73%), and both HBeAg and anti-HBe in 4 of 132 HBsAg positive donors. HBV DNA was found in 85 samples, and the complete S-gene was sequenced in 58 of those. Phylogenetic analysis of the sequences revealed that all HBV strains belonged to subgenotype A1, and formed one clade in the phylogenetic tree. In addition, 12 strains from first time donors had a unique 18 amino acid deletion in the N-terminal part of the pre-S2 region. CONCLUSION This study indicated that the prevalence of hepatitis B is intermediate in Rwanda and that the vaccination coverage is relatively low in young adults. All surveyed Rwandan blood donors were infected with similar subgenotype A1 strains, and a high frequency of those with anti-HBe had detectable HBV DNA. Several strains had in addition a unique pre-S2 deletion, the virulence of which needs to be further studied.
Collapse
Affiliation(s)
- Theogene Twagirumugabe
- Department of Microbiology & Clinical Virology, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Guldhedsgatan 10B, 41346 Gothenburg, Sweden
- School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda
| | - Gatare Swaibu
- Rwanda Biomedical Center-National Center for Blood and Transfusion (RBC-NCBT), Kigali, Rwanda
| | - Timothy David Walker
- School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda
| | - Magnus Lindh
- Department of Microbiology & Clinical Virology, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Guldhedsgatan 10B, 41346 Gothenburg, Sweden
| | - Jean Bosco Gahutu
- School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda
| | - Tomas Bergström
- Department of Microbiology & Clinical Virology, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Guldhedsgatan 10B, 41346 Gothenburg, Sweden
| | - Heléne Norder
- Department of Microbiology & Clinical Virology, Institute of Biomedicine at Sahlgrenska Academy, University of Gothenburg, Guldhedsgatan 10B, 41346 Gothenburg, Sweden
| |
Collapse
|
|
9
|
Kim H, Lee SA, Do SY, Kim BJ. Precore/core region mutations of hepatitis B virus related to clinical severity. World J Gastroenterol 2016; 22:4287-4296. [PMID: 27158197 PMCID: PMC4853686 DOI: 10.3748/wjg.v22.i17.4287] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 03/10/2016] [Accepted: 04/07/2016] [Indexed: 02/06/2023] Open
Abstract
Despite the availability of an effective vaccine, hepatitis B virus (HBV) infection remains a major health problem, with more than 350 million chronically infected people worldwide and over 1 million annual deaths due to cirrhosis and liver cancer. HBV mutations are primarily generated due both to a lack of proofreading capacity by HBV polymerase and to host immune pressure, which is a very important factor for predicting disease progression and therapeutic outcomes. Several types of HBV precore/core (preC/C) mutations have been described to date. The host immune response against T cells drives mutation in the preC/C region. Specifically, preC/C mutations in the MHC class II restricted region are more common than in other regions and are significantly related to hepatocellular carcinoma. Certain mutations, including preC G1896A, are also significantly related to HBeAg-negative chronic infection. This review article mainly focuses on the HBV preC/C mutations that are related to disease severity and on the HBeAg serostatus of chronically infected patients.
Collapse
|
|
10
|
Tong S, Revill P. Overview of hepatitis B viral replication and genetic variability. J Hepatol 2016; 64:S4-S16. [PMID: 27084035 PMCID: PMC4834849 DOI: 10.1016/j.jhep.2016.01.027] [Citation(s) in RCA: 303] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 01/18/2016] [Accepted: 01/25/2016] [Indexed: 02/06/2023]
Abstract
Chronic infection with hepatitis B virus (HBV) greatly increases the risk for liver cirrhosis and hepatocellular carcinoma (HCC). HBV isolates worldwide can be divided into ten genotypes. Moreover, the immune clearance phase selects for mutations in different parts of the viral genome. The outcome of HBV infection is shaped by the complex interplay of the mode of transmission, host genetic factors, viral genotype and adaptive mutations, as well as environmental factors. Core promoter mutations and mutations abolishing hepatitis B e antigen (HBeAg) expression have been implicated in acute liver failure, while genotypes B, C, subgenotype A1, core promoter mutations, preS deletions, C-terminal truncation of envelope proteins, and spliced pregenomic RNA are associated with HCC development. Our efforts to treat and prevent HBV infection are hampered by the emergence of drug resistant mutants and vaccine escape mutants. This paper provides an overview of the HBV life cycle, followed by review of HBV genotypes and mutants in terms of their biological properties and clinical significance.
Collapse
Affiliation(s)
- Shuping Tong
- Liver Research Center, Rhode Island Hospital, The Alpert Warren School of Medicine, Brown University, Providence, RI, USA; Key Laboratory of Medical Molecular Virology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Peter Revill
- Research and Molecular Development, Victorian Infectious Diseases Reference Laboratory, Doherty Institute, Melbourne, VIC, Australia ()
| |
Collapse
|
|
11
|
Gededzha MP, Muzeze M, Burnett RJ, Amponsah-Dacosta E, Mphahlele MJ, Selabe SG. Complete genome analysis of hepatitis B virus in human immunodeficiency virus infected and uninfected South Africans. J Med Virol 2016; 88:1560-6. [PMID: 26890489 DOI: 10.1002/jmv.24502] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/14/2016] [Indexed: 12/21/2022]
Abstract
Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infections are highly endemic in South Africa. Data on the complete genome sequences of HBV in HIV-positive patients in South Africa are scanty. This study characterized the complete HBV genome isolated from both HIV-positive and negative patients at the Dr George Mukhari Academic Hospital (DGMAH), Pretoria. Serum samples from nine (five HIV-positive and four HIV-negative) patients attending the DGMAH from 2007 to 2011 were serologically tested, amplified, and sequenced for complete genome. Phylogenetic tree was constructed using MEGA6.0. Mutations were analyzed by comparing the sequences with genotype-matched GenBank references. Eight patients were HBsAg positive, with only one from the HIV positive group being negative. Phylogenetic analysis of the complete genome sequences classified them into five genotypes; A1 (n = 4), A2 (n = 1), C1 (n = 2), D1 (n = 1), and D3 (n = 1). Deletions up to 35 nucleotides in length were identified in this study. No drug resistance mutations were identified in the P ORF, while the L217R mutation was identified in one subgenotype A2 sequence. The double (A1762T/G1764A) and triple (T1753C/A1762T/G1764A) mutations in the Basal core promoter were identified in four and two sequences, respectively. In the core region, mutation G1888A was identified in four of the subgenotype A1 sequences. In conclusion, this study has added to the limited South African data on HBV genotypes and mutations in HBV/HIV co-infected and HBV mono-infected patients, based on complete HBV genome analysis. Subgenotype A1 was predominant, and no drug-resistant mutants were detected in the study. J. Med. Virol. 88:1560-1566, 2016. © 2016 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Maemu P Gededzha
- Department of Virology, HIV and Hepatitis Research Unit, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
| | - Muxe Muzeze
- Department of Virology, HIV and Hepatitis Research Unit, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
| | - Rosemary J Burnett
- Department of Virology, HIV and Hepatitis Research Unit, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
| | - Edina Amponsah-Dacosta
- Department of Virology, HIV and Hepatitis Research Unit, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
| | | | - Selokela G Selabe
- Department of Virology, HIV and Hepatitis Research Unit, Sefako Makgatho Health Sciences University and National Health Laboratory Service, Pretoria, South Africa
| |
Collapse
|
|
12
|
Buti M, Tabernero D, Mas A, Homs M, Prieto M, Rodríguez-Frías F, Casafont F, Casillas R, González A, Miras M, Herrero JI, Castells L, Esteban R. Hepatitis B virus quasispecies evolution after liver transplantation in patients under long-term lamivudine prophylaxis with or without hepatitis B immune globulin. Transpl Infect Dis 2015; 17:208-220. [PMID: 25641570 DOI: 10.1111/tid.12360] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 12/23/2014] [Accepted: 01/18/2015] [Indexed: 12/22/2022]
Abstract
AIMS To investigate an optimal long-term prophylactic strategy for prevention of hepatitis B virus (HBV) recurrence after liver transplantation, we conducted a randomized study of 29 transplant recipients receiving a short course of hepatitis B immune globulin (HBIg) + lamivudine (LAM), followed by randomization to long-term prophylaxis with LAM with or without HBIg. METHODS The efficacy and safety, and impact on survival and HBV recurrence of these 2 prophylactic regimens were compared over a mean period of 10 years. In patients with viral recurrence, the HBV quasispecies in the surface/polymerase region were studied by ultra-deep pyrosequencing (UDPS). RESULTS The 10-year survival rate was 76% and was not affected by the type of prophylaxis. Four patients had hepatitis B surface antigen (HBsAg) recurrence within the first 48 months after orthotopic liver transplantation (OLT). HBsAg-positive and -negative patients showed similar mean survival times, with no differences between the 2 regimens. Low HBV DNA levels were transiently detected in 32% of HBsAg-negative patients. UDPS showed major changes after OLT in the HBV quasispecies of patients with viral recurrence, which may be explained by a "bottleneck" effect of OLT together with prophylactic therapy. CONCLUSION Long-term survival after OLT in end-stage chronic hepatitis B patients was good with both prophylactic strategies. However, low, transient HBV DNA levels were detected even in the absence of HBsAg, showing the importance of continuing HBV prophylaxis.
Collapse
Affiliation(s)
- M Buti
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Liver Unit, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona (UAB), Barcelona, Spain
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
13
|
Littlejohn M, Davies J, Yuen L, Edwards R, Sozzi T, Jackson K, Cowie B, Tong S, Davis J, Locarnini S. Molecular virology of hepatitis B virus, sub-genotype C4 in northern Australian Indigenous populations. J Med Virol 2014; 86:695-706. [PMID: 24497078 DOI: 10.1002/jmv.23888] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2013] [Indexed: 12/18/2022]
Abstract
Indigenous Australians experience a significant health burden from chronic hepatitis B infection; however, the strain of hepatitis B virus (HBV) found among Indigenous Australians has not been well characterized. Blood samples were collected from 65 Indigenous Australians with chronic HBV infection from across the Top End of Australia's Northern Territory. Phylogenetic analysis of HBV from these samples revealed that 100% of the isolates were genotype C, sub-genotype C4, expressing the serotype ayw3. This strain is a divergent group within the HBV/C genotype, and has only been described in Indigenous Australians. Evidence of recombination was suggested by discordant phylogenetic clustering of the C4 sequences when comparing the full genome to the surface region and confirmed by recombination analysis which showed the surface gene region to be most closely related to genotype J, while the remaining regions of the genome were most similar to genotype C sequences. Mutational analysis revealed the presence of multiple mutations that have been linked with more rapid liver disease progression and an increased risk of hepatocellular carcinoma. These mutations were detected in the majority of sequences examined. Variants associated with vaccine failure were detected as the predominant viral quasi-species in 3/35 samples. In summary, the HBV C4 variant found in this population has a high potential to cause advanced liver disease and to escape vaccination programs. Further in vitro functional and natural history studies are warranted in order to determine the clinical and public health consequences of infection with the HBV C4 variant in these communities.
Collapse
Affiliation(s)
- M Littlejohn
- Victorian Infectious Diseases Reference Laboratory, Melbourne, VIC, Australia
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
14
|
Ouneissa R, Bahri O, Ben Yahia A, Touzi H, Azouz MM, Ben Mami N, Triki H. Evaluation of PCR-RFLP in the Pre-S Region as Molecular Method for Hepatitis B Virus Genotyping. HEPATITIS MONTHLY 2013; 13:e11781. [PMID: 24348634 PMCID: PMC3842526 DOI: 10.5812/hepatmon.11781] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Revised: 08/01/2013] [Accepted: 10/06/2013] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a public health problem in developing countries. HBV genotypes play major role in the evolution of infection since they were involved in different clinical presentations and response to treatment. OBJECTIVES This study was conducted to evaluate the efficiency of restriction fragment length polymorphism (RFLP) analysis for HBV genotyping. PATIENTS AND METHODS We investigated 98 samples collected from patients chronically infected with HBV. HBV genotypes were determined by analysis of patterns obtained after amplification in Pre-S region and digestion of the amplicon by two endonucleases AvaII and DpnII. Obtained results were confirmed by partial sequencing in the same region. RESULTS Two different HBV genotypes were detected in this study, Genotype D (in 95. 9%) and Genotype A (in 4.1%). Seventy-four samples (75.5%) were successfully genotyped with RFLP analysis and all classified as genotype D. The remaining 24 samples (24.5%) which were un-genotyped by RFLP analysis, were classified by partial sequencing of the pre-S region as HBV genotype D (20 samples, 20.4%) and genotype A (4 samples, 4.1%). Atypical profiles were significantly associated with advanced liver disease (P = 0.001) as well as older age (P < 0.05). CONCLUSIONS Several previous studies used PCR-RFLP to genotype HBV; however, we showed the high risk to obtain atypical profiles, especially in advanced stages of chronic infection, with as results difficulties to genotype the virus. These profiles resulted from the accumulation of mutations during natural course of infection resulting in a modification in restriction sites for enzymes. So, we recommended completing the investigation by partial sequencing to confirm obtained results.
Collapse
Affiliation(s)
- Rim Ouneissa
- Laboratory of Clinical Virology, Institute Pasteur de Tunis, Tunis, Tunisia
| | - Olfa Bahri
- Laboratory of Clinical Virology, Institute Pasteur de Tunis, Tunis, Tunisia
- Corresponding author: Olfa Bahri, Laboratory of Clinical Virology, Institute Pasteur de Tunis, Tunis, BP 1002, Tunisia. Tel: +216-98334999, Fax: +216-71791833, E-mail:
| | - Ahlem Ben Yahia
- Laboratory of Clinical Virology, Institute Pasteur de Tunis, Tunis, Tunisia
| | - Henda Touzi
- Laboratory of Clinical Virology, Institute Pasteur de Tunis, Tunis, Tunisia
| | | | - Nabyl Ben Mami
- Department of Gastroenterology, Hospital La Rabta, Tunis, Tunisia
| | - Henda Triki
- Laboratory of Clinical Virology, Institute Pasteur de Tunis, Tunis, Tunisia
| |
Collapse
|
|
15
|
Brichler S, Lagathu G, Chekaraou MA, Le Gal F, Edouard A, Dény P, Césaire R, Gordien E. African, Amerindian and European hepatitis B virus strains circulate on the Caribbean Island of Martinique. J Gen Virol 2013; 94:2318-2329. [PMID: 23884366 DOI: 10.1099/vir.0.055459-0] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Ten Hepatitis B virus (HBV) genotypes, as well as numerous subgenotypes, have been described in well-characterized ethnogeographical populations. Martinique has been at a crossroads between Africa, Europe, India and the Americas because of the slave trade (17th-19th centuries), followed by an important immigration of Indian and West African workers. In this work, we aimed to study the molecular epidemiology of HBV infection in Martinique according to this unique settlement pattern. To that end, blood samples from 86 consecutive HBV-infected patients from the main hospitals of the island, were retrospectively analysed. Direct sequencing of the pre-S1 or pre-C-C region or complete genome sequencing, followed by phylogenetic analyses were performed. HBV genotypes were: HBV/A1 (68.6 %), HBV/A2 (10.5 %), HBV/D, mainly HBV/D3 and HBV/D4 (8.1 %), HBV/F (3.5 %), and also HBV/E (2.3 %), two strains isolated from two West-African patients. Moreover, 74 % of the HBeAg-negative strains harboured classical pre-C-C mutations, and most HBV/A1 strains also containing specific mutations. Finally, various patterns of deletion mutants in pre-S and pre-C-C regions were found. In conclusion, our findings point to historical and migration-related issues in HBV-genotype distribution suggesting that HBV/A1, but not HBV/E, was imported from Africa during the slave trade, and further supporting the hypothesis that HBV/E has emerged recently in West Africa (<150 years). Potential origins of 'European' HBV/A2 and HBV/D3, 'Amerindian' HBV/F, and HBV/D4 strains are also discussed. Such HBV genetic diversity, beyond its epidemiological interest, may have a clinical impact on the natural history of HBV infection in Martinique.
Collapse
Affiliation(s)
- Ségolène Brichler
- Service de Bactériologie, Virologie-Hygiène, Assistance Publique-Hôpitaux de Paris; Hôpitaux Universitaires de Paris Seine Saint-Denis, Site Avicenne, Bobigny; Laboratoire Associé au Centre National de Référence des Hépatites B, C et Delta, Université Paris Nord, Sorbonne Paris Cité, France
| | - Gisèle Lagathu
- Service de Bactériologie, Virologie du Centre Hospitalier Régional et Universitaire de Rennes, Pontchaillou, France
| | - Mariama Abdou Chekaraou
- Service de Bactériologie, Virologie-Hygiène, Assistance Publique-Hôpitaux de Paris; Hôpitaux Universitaires de Paris Seine Saint-Denis, Site Avicenne, Bobigny; Laboratoire Associé au Centre National de Référence des Hépatites B, C et Delta, Université Paris Nord, Sorbonne Paris Cité, France
| | - Frédéric Le Gal
- Service de Bactériologie, Virologie-Hygiène, Assistance Publique-Hôpitaux de Paris; Hôpitaux Universitaires de Paris Seine Saint-Denis, Site Avicenne, Bobigny; Laboratoire Associé au Centre National de Référence des Hépatites B, C et Delta, Université Paris Nord, Sorbonne Paris Cité, France
| | - André Edouard
- Service d'Hépato-Gastro-Entérologie, Centre Hospitalier Universitaire de Fort-de-France, Martinique, France
| | - Paul Dény
- Centre de Recherche sur le Cancer, Équipe 16, INSERM U1052, CNRS UMR 5286, Lyon, France.,Service de Bactériologie, Virologie-Hygiène, Assistance Publique-Hôpitaux de Paris; Hôpitaux Universitaires de Paris Seine Saint-Denis, Site Avicenne, Bobigny; Laboratoire Associé au Centre National de Référence des Hépatites B, C et Delta, Université Paris Nord, Sorbonne Paris Cité, France
| | - Raymond Césaire
- Laboratoire de Virologie, Centre Hospitalier Universitaire de Fort-de-France, Martinique; EA 4537, Université Antilles-Guyane, France
| | - Emmanuel Gordien
- Service de Bactériologie, Virologie-Hygiène, Assistance Publique-Hôpitaux de Paris; Hôpitaux Universitaires de Paris Seine Saint-Denis, Site Avicenne, Bobigny; Laboratoire Associé au Centre National de Référence des Hépatites B, C et Delta, Université Paris Nord, Sorbonne Paris Cité, France
| |
Collapse
|
|
16
|
Parikh N, Nonnemacher MR, Pirrone V, Block T, Mehta A, Wigdahl B. Substance abuse, HIV-1 and hepatitis. Curr HIV Res 2013; 10:557-71. [PMID: 22973853 DOI: 10.2174/157016212803306023] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Revised: 07/16/2012] [Accepted: 09/05/2012] [Indexed: 02/06/2023]
Abstract
During the course of human immunodeficiency virus type 1 (HIV-1) disease, the virus has been shown to effectively escape the immune response with the subsequent establishment of latent viral reservoirs in specific cell populations within the peripheral blood (PB) and associated lymphoid tissues, bone marrow (BM), brain, and potentially other end organs. HIV-1, along with hepatitis B and C viruses (HBV and HCV), are known to share similar routes of transmission, including intravenous drug use, blood transfusions, sexual intercourse, and perinatal exposure. Substance abuse, including the use of opioids and cocaine, is a significant risk factor for exposure to HIV-1 and the development of acquired immune deficiency syndrome, as well as HBV and HCV exposure, infection, and disease. Thus, coinfection with HIV-1 and HBV or HCV is common and may be impacted by chronic substance abuse during the course of disease. HIV- 1 impacts the natural course of HBV and HCV infection by accelerating the progression of HBV/HCV-associated liver disease toward end-stage cirrhosis and quantitative depletion of the CD4+ T-cell compartment. HBV or HCV coinfection with HIV-1 is also associated with increased mortality when compared to either infection alone. This review focuses on the impact of substance abuse and coinfection with HBV and HCV in the PB, BM, and brain on the HIV-1 pathogenic process as it relates to viral pathogenesis, disease progression, and the associated immune response during the course of this complex interplay. The impact of HIV-1 and substance abuse on hepatitis virus-induced disease is also a focal point.
Collapse
Affiliation(s)
- Nirzari Parikh
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
| | | | | | | | | | | |
Collapse
|
|
17
|
Zhang D, Dong P, Zhang K, Deng L, Bach C, Chen W, Li F, Protzer U, Ding H, Zeng C. Whole genome HBV deletion profiles and the accumulation of preS deletion mutant during antiviral treatment. BMC Microbiol 2012; 12:307. [PMID: 23272650 PMCID: PMC3549285 DOI: 10.1186/1471-2180-12-307] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Accepted: 12/22/2012] [Indexed: 12/23/2022] Open
Abstract
Background Hepatitis B virus (HBV), because of its error-prone viral polymerase, has a high mutation rate leading to widespread substitutions, deletions, and insertions in the HBV genome. Deletions may significantly change viral biological features complicating the progression of liver diseases. However, the clinical conditions correlating to the accumulation of deleted mutants remain unclear. In this study, we explored HBV deletion patterns and their association with disease status and antiviral treatment by performing whole genome sequencing on samples from 51 hepatitis B patients and by monitoring changes in deletion variants during treatment. Clone sequencing was used to analyze preS regions in another cohort of 52 patients. Results Among the core, preS, and basic core promoter (BCP) deletion hotspots, we identified preS to have the highest frequency and the most complex deletion pattern using whole genome sequencing. Further clone sequencing analysis on preS identified 70 deletions which were classified into 4 types, the most common being preS2. Also, in contrast to the core and BCP regions, most preS deletions were in-frame. Most deletions interrupted viral surface epitopes, and are possibly involved in evading immuno-surveillance. Among various clinical factors examined, logistic regression showed that antiviral medication affected the accumulation of deletion mutants (OR = 6.81, 95% CI = 1.296 ~ 35.817, P = 0.023). In chronic carriers of the virus, and individuals with chronic hepatitis, the deletion rate was significantly higher in the antiviral treatment group (Fisher exact test, P = 0.007). Particularly, preS2 deletions were associated with the usage of nucleos(t)ide analog therapy (Fisher exact test, P = 0.023). Dynamic increases in preS1 or preS2 deletions were also observed in quasispecies from samples taken from patients before and after three months of ADV therapy. In vitro experiments demonstrated that preS2 deletions alone were not responsible for antiviral resistance, implying the coordination between wild type and mutant strains during viral survival and disease development. Conclusions We present the HBV deletion distribution patterns and preS deletion substructures in viral genomes that are prevalent in northern China. The accumulation of preS deletion mutants during nucleos(t)ide analog therapy may be due to viral escape from host immuno-surveillance.
Collapse
Affiliation(s)
- Dake Zhang
- Laboratory of Disease Genomics and Individualized Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Lim L, Tran BM, Vincan E, Locarnini S, Warner N. HBV-related hepatocellular carcinoma: the role of integration, viral proteins and miRNA. Future Virol 2012. [DOI: 10.2217/fvl.12.113] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The development of hepatocellular carcinoma during chronic hepatitis B infection is a multifactorial process thought to be a consequence of several direct and indirect mechanisms. In this review we discuss how viral proteins and cycles of ongoing liver damage and regeneration, coupled with HBV DNA integration and aberrant miRNA expression may enhance the risk for the development of hepatocellular carcinoma.
Collapse
Affiliation(s)
- Lucy Lim
- Victorian Infectious Diseases Reference Laboratories, North Melbourne, Victoria, Australia
- Austin Liver Transplant Unit, Heidelberg, Victoria, Australia
| | - Bang Manh Tran
- Victorian Infectious Diseases Reference Laboratories, North Melbourne, Victoria, Australia
- Cancer Biology Laboratory, Department of Anatomy & Neuroscience, The University of Melbourne, Parkville, Victoria, Australia
| | - Elizabeth Vincan
- Victorian Infectious Diseases Reference Laboratories, North Melbourne, Victoria, Australia
- Cancer Biology Laboratory, Department of Anatomy & Neuroscience, The University of Melbourne, Parkville, Victoria, Australia
| | - Stephen Locarnini
- Victorian Infectious Diseases Reference Laboratories, North Melbourne, Victoria, Australia
| | - Nadia Warner
- Victorian Infectious Diseases Reference Laboratories, North Melbourne, Victoria, Australia
| |
Collapse
|
|
19
|
Homs M, Buti M, Tabernero D, Quer J, Sanchez A, Corral N, Esteban R, Rodriguez-Frias F. Quasispecies dynamics in main core epitopes of hepatitis B virus by ultra-deep-pyrosequencing. World J Gastroenterol 2012; 18:6096-6105. [PMID: 23155338 PMCID: PMC3496886 DOI: 10.3748/wjg.v18.i42.6096] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Revised: 07/25/2012] [Accepted: 07/28/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the variability of the main immunodominant motifs of hepatitis B virus (HBV) core gene by ultra-deep-pyrosequencing (UDPS). METHODS Four samples (2 genotype A and 2 genotype D) from 4 treatment-naïve patients were assessed for baseline variability. Two additional samples from one patient (patient 4, genotype D) were selected for analysis: one sample corresponded to a 36-mo treatment-free period from baseline and the other to the time of viral breakthrough after 18 mo of lamivudine treatment. The HBV region analyzed covered amino acids 40 to 95 of the core gene, and included the two main epitopic regions, Th50-69 and B74-84. UDPS was carried out in the Genome Sequencer FLX system (454 Life Sciences, Roche). After computer filtering of UDPS data based on a Poisson statistical model, 122,813 sequences were analyzed. The most conserved position detected by UDPS was analyzed by site-directed mutagenesis and evaluated in cell culture. RESULTS Positions with highest variability rates were mainly located in the main core epitopes, confirming their role as immune-stimulating regions. In addition, the distribution of variability showed a relationship with HBV genotype. Patient 1 (genotype A) presented the lowest variability rates and patient 2 (genotype A) had 3 codons with variability higher than 1%. Patient 3 and 4 (both genotype D) presented 5 and 8 codons with variability higher than 1%, respectively. The median baseline frequencies showed that genotype A samples had higher variability in epitopic positions than in the other positions analyzed, approaching significance (P = 0.07, sample 1 and P = 0.05, sample 2). In contrast, there were no significant differences in variability between the epitopic and other positions in genotype D cases. Interestingly, patient 1 presented a completely mutated motif from amino acid 64 to 67 (E₆₄LMT₆₇), which is commonly recognized by T helper cells. Additionally, the variability observed in all 4 patients was particularly associated with the E₆₄LMT₆₇ motif. Codons 78 and 79 were highly conserved in all samples, in keeping with their involvement in the interaction between the HBV virion capsid and the surface antigens (HBsAg). Of note, codon 76 was even more conserved than codons 78 and 79, suggesting a possible role in HBsAg interactions or even in hepatitis B e antigen conformation. Sequential analysis of samples from patient 4 (genotype D) illustrated the dynamism of the HBV quasispecies, with strong selection of one minor baseline variant coinciding with a decrease in core variability during the treatment-free and lamivudine-treated period. The drop in variability seemed to result from a "steady state" situation of the HBV quasispecies after selection of the variant with greatest fitness. CONCLUSION Host immune pressure seems to be the main cause of HBV core evolution. UDPS analysis is a useful technique for studying viral quasispecies.
Collapse
|
|
20
|
Kim DW, Lee SA, Hwang ES, Kook YH, Kim BJ. Naturally occurring precore/core region mutations of hepatitis B virus genotype C related to hepatocellular carcinoma. PLoS One 2012; 7:e47372. [PMID: 23071796 PMCID: PMC3468518 DOI: 10.1371/journal.pone.0047372] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2012] [Accepted: 09/12/2012] [Indexed: 12/12/2022] Open
Abstract
Previous studies have proved the presence of several distinct types of mutations in hepatitis B virus (HBV) infections, which are related to the progression of liver disease. However, few reports have detailed the mutation frequencies and mutation patterns in the precore/core (preC/C) region, which are based on the clinical status and HBeAg serostatus. Our aim in this study is to investigate the relationships between the preC/C mutations and clinical severity or HBeAg serostatus from patients chronically infected with HBV genotype C. A total of 70 Korean chronic patients, including 35 with hepatocellular carcinoma (HCC), participated in this study. HBV genotyping and precore/core mutations were analyzed by direct sequencing. All patients were confirmed to have genotype C infections. Mutations in the C region were distributed in a non-random manner. In particular, mutations in the MHC class II restricted region were found to be significantly related to HCC. Six (preC-W28*, C-P5H/L/T, C-E83D, C-I97F/L, C-L100I and C-Q182K/*) and seven types (preC-W28*, preC-G29D, C-D32N/H, C-E43K, C-P50A/H/Y, C-A131G/N/P and C-S181H/P) of mutations in the preC/C region were found to be related to HCC and to affect the HBeAg serostatus, respectively. In conclusion, our data indicated that HBV variants in the C region, particularly in the MHC class II restricted region, may contribute to the progress of HCC in chronic patients infected with genotype C. In addition, we found several distinct preC/C mutations in the Korean chronic cohort, which affect the clinical status of HCC and HBeAg serostatus of patients infected with genotype C.
Collapse
Affiliation(s)
- Dong-Won Kim
- Department of Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - Seoung-Ae Lee
- Department of Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - Eung-Soo Hwang
- Department of Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - Yoon-Hoh Kook
- Department of Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| | - Bum-Joon Kim
- Department of Microbiology and Immunology, Liver Research Institute and Cancer Research Institute, College of Medicine, Seoul National University, Seoul, Korea
| |
Collapse
|
|
21
|
Blackadar CB. Systematic review of hepatocellular carcinoma mortality rates among hepatitis B virus-infected renal transplant recipients, with supplemental analyses of liver failure and all-cause mortality. Int J Infect Dis 2012; 17:e24-36. [PMID: 23036372 DOI: 10.1016/j.ijid.2012.08.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2012] [Revised: 08/15/2012] [Accepted: 08/19/2012] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVES The purpose of this review was to compare the mortality rates for hepatocellular carcinoma (HCC) among hepatitis B surface antigen (HBsAg)-seropositive renal transplant (RT) patients versus HBsAg-seropositive persons of the general population. METHODS A comprehensive search was performed to identify cohort studies of HBsAg-seropositive RT patients with at least 4 years of follow-up. Data were analyzed as outlined below. HCC was a rare event in regions of low and intermediate seroprevalence of HBsAg. Subsequently, studies from low and intermediate seroprevalence areas were analyzed separately from those of high seroprevalence areas. RESULTS Thirty-one retrospective studies that followed 1277 seropositive RT patients were identified for inclusion. The studies were pooled and compared to four different general population studies that included 12558 seropositive persons using Poisson methods. The mortality rate of HCC was increased in low and intermediate seroprevalence areas (RR 7.67, 95% confidence interval (CI) 3.93-15.0; RR 9.92, 95% CI 5.38-18.3). In high seroprevalence areas, the mortality rate of HCC was increased compared to one population study, but not another (RR 2.76, 95% CI 1.64-4.63; RR 1.02, 95% CI 0.61-1.69). CONCLUSIONS Mortality due to HCC was increased in low and intermediate seroprevalence areas, but the evidence was inconclusive for high seroprevalence areas.
Collapse
|
|
22
|
Mason WS. Hepadnaviruses and Hepatocellular Carcinoma. CANCER ASSOCIATED VIRUSES 2012:531-569. [DOI: 10.1007/978-1-4614-0016-5_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
23
|
Ryu HJ, Kim DY, Park JY, Chang HY, Lee MH, Han KH, Chon CY, Ahn SH. Clinical features and prognosis of hepatocellular carcinoma with respect to pre-S deletion and basal core promoter mutations of hepatitis B virus Genotype C2. J Med Virol 2011; 83:2088-95. [DOI: 10.1002/jmv.22238] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
|
|
24
|
Lee MH, Kim DY, Kim JK, Chang HY, Kang SH, Ryu HJ, Ju HL, Kim SU, Lee JM, Park JY, Han KH, Chon CY, Ahn SH. Combination of preS deletions and A1762T/G1764A mutations in HBV subgenotype C2 increases the risk of developing HCC. Intervirology 2011; 55:296-302. [PMID: 21865669 DOI: 10.1159/000329941] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2010] [Accepted: 05/25/2011] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The interactions among hepatitis B virus (HBV) mutations in developing hepatocellular carcinoma (HCC) remain unclear and thus we investigated the risk of HCC related with single or multiple HBV mutations in Korean patients infected with HBV subgenotype C2. METHODS From January 2003 to December 2008, HBV isolates from 135 patients with HCC were compared with those from 135 patients without HCC, matching for age, gender, and HBeAg status. The prevalence of preS deletions and G1896A and A1762T/G1764A mutations was evaluated. RESULTS The frequency of preS deletions significantly differed between the non-HCC and HCC groups, with 6 (4.4%) versus 25 (18.5%) patients, respectively (p < 0.001). Additionally, the frequency of A1762T/G1764A mutations was higher in the HCC than the non-HCC group [82 (60.7%) versus 30 (22.2%), p < 0.001]. For combined mutations, the odds ratio (OR) was highest in patients with both preS deletions and the A1762T/G1764A mutation, with 1 (0.7%) versus 11 (8.1%) patients (p = 0.005; OR 11.887). CONCLUSIONS HCC was associated with preS deletions and A1762T/G1764A mutations, and the combination of both mutations had a stronger association with HCC in Korean patients infected with HBV subgenotype C2.
Collapse
Affiliation(s)
- Myoung Ha Lee
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
25
|
Kalia H, Fabrizi F, Martin P. Hepatitis B virus and renal transplantation. Transplant Rev (Orlando) 2011; 25:102-9. [PMID: 21530218 DOI: 10.1016/j.trre.2011.02.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Hepatitis B virus (HBV) infection remains an important cause of liver disease in the renal transplant (RT) population, potentially diminishing survival. Consequences of HBV infection after RT include progression to decompensated cirrhosis and an increased risk of hepatocellular carcinoma. Although precautions initially recommended by the Centers for Diseases Control and Prevention 30 years ago have substantially reduced HBV transmission within hemodialysis units, acute HBV outbreaks continue to be reported in patients with chronic kidney disease on maintenance hemodialysis. In addition, immigration from areas of high HBV prevalence implies that HBV-infected organs with chronic kidney disease will continue to enter the RT pool. Fortunately, the advent of oral therapy for HBV infection now reduces the risk of HBV progression post-RT.
Collapse
Affiliation(s)
- Harmit Kalia
- Division of Hepatology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
| | | | | |
Collapse
|
|
26
|
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.
Collapse
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:
| |
Collapse
|
|
27
|
Zhu Y, Jin Y, Guo X, Bai X, Chen T, Wang J, Qian G, Groopman JD, Gu J, Li J, Tu H. Comparison study on the complete sequence of hepatitis B virus identifies new mutations in core gene associated with hepatocellular carcinoma. Cancer Epidemiol Biomarkers Prev 2010; 19:2623-2630. [PMID: 20699378 DOI: 10.1158/1055-9965.epi-10-0469] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Mutations in the hepatitis B virus (HBV) genome may influence the activity of liver disease. The aim of this study was to identify new viral variations associated with hepatocellular carcinoma (HCC). METHODS We carried out a comparison study on the complete sequence of HBV isolated from 20 HCC and 35 non-HCC patients in Qidong, China, an area with a high incidence of HCC. We compared the HBV sequences in a consecutive series of plasma samples from four HCC cases before and after the occurrence of HCC. In addition, we selected four mutations in the HBV core (C) gene to verify their relationships to HCC in an independent set of 103 HCC cases and 103 sex- and age-matched non-HCC controls. RESULTS The pre-S deletion and 12 point mutations, namely, the pre-S2 start codon mutation, T53C in the pre-S2 gene, T766A in the S gene, G1613A, C1653T, A1762T, G1764A in the X gene, and G1899A, C2002T, A2159G, A2189C, and G2203W (A or T) in the pre-C/C gene, showed close associations with HCC. In the validation study, A2159G, A2189C, and G2203W showed consistent associations with HCC by univariate analysis. Multivariate analysis showed that A2189C and G2203W were independent risk factors for HCC. The odds ratios (95% confidence interval) were 3.99 (1.61-9.92) and 9.70 (1.17-80.58), respectively, for A2189C and G2203W. CONCLUSIONS These results implicate A2189C and G2203W as new predictive markers for HCC. IMPACT The complete genome analysis of HBV provided pilot data for the identification of novel mutations that could serve as markers for HCC.
Collapse
Affiliation(s)
- Yu Zhu
- Shanghai Medical College, Fudan University, Shanghai, China
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
28
|
Abstract
Although the prevalence of chronic hepatitis B virus (HBV) infection has declined in renal transplant recipients (RTRs), it remains a relevant clinical problem with high morbidity and mortality in long-term follow up. A thorough evaluation, including liver biopsy as well as assessment of HBV replication in serum (i.e. hepatitis B e antigen and/or HBV DNA) is required before transplantation. Interferon should not be used in this setting because of low efficacy and precipitation on acute allograft rejection. The advent of effective antiviral therapies offers the opportunity to prevent the progression of liver disease after renal transplantation. However, as far as we are aware, no studies have compared prophylactic and preemptive strategies. To date, the majority of RTRs with HBV-related liver disease have had a high virological and biochemical response to lamivudine use. However, lamivudine resistance is frequent with a prolonged course of therapy. Considering long-term treatment, antiviral agents with a high genetic barrier to resistance and lack of nephrotoxicity are suggested. The optimal strategy in RTRs with HBV infection remains to be established in the near future.
Collapse
|
|
29
|
Audsley J, Littlejohn M, Yuen L, Sasadeusz J, Ayres A, Desmond C, Spelman T, Lau G, Matthews GV, Avihingsanon A, Seaberg E, Philp F, Saulynas M, Ruxrungtham K, Dore GJ, Locarnini SA, Thio CL, Lewin SR, Revill PA. HBV mutations in untreated HIV-HBV co-infection using genomic length sequencing. Virology 2010; 405:539-47. [PMID: 20655563 DOI: 10.1016/j.virol.2010.06.038] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2010] [Revised: 04/07/2010] [Accepted: 06/22/2010] [Indexed: 11/30/2022]
Abstract
HIV infection has a significant impact on the natural progression of hepatitis B virus (HBV) related liver disease. In HIV-HBV co-infected patients, little is known about mutations in the HBV genome, which can influence severity of liver disease. The aim of this study was to characterize and to determine the frequency of known clinically significant mutations in the HBV genomes from HIV-HBV co-infected patients and from HBV mono-infected patients. To accomplish this, genomic length HBV sequencing was performed in highly-active anti-retroviral therapy (HAART)-naïve HIV-HBV co-infected patients (n=74) and in anti-HBV therapy-naïve HBV mono-infected patients (n=55). The frequency of HBV mutations differed between the co-infected and mono-infected patients when comparing patients with the same genotype. BCP mutations A1762T and G1764A were significantly more frequent in HBV genotype C mono-infection and the -1G frameshift was significantly more frequent in co-infection and was only observed in HBV genotype A co-infection. PreS2 deletions were observed more frequently in the setting of co-infection. Further work is needed to determine if these mutational patterns influence the differences in liver disease progression in HIV-HBV co-infected and HBV mono-infected patients.
Collapse
Affiliation(s)
- Jennifer Audsley
- Department of Medicine, Monash University, Melbourne, Victoria, Australia.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
30
|
Kim JH, Jung YK, Joo MK, Kim JH, Yim HJ, Park JJ, Kim JS, Bak YT, Yeon JE, Byun KS. Hepatitis B viral surface mutations in patients with adefovir resistant chronic hepatitis B with A181T/V polymerase mutations. J Korean Med Sci 2010; 25:257-264. [PMID: 20119580 PMCID: PMC2811294 DOI: 10.3346/jkms.2010.25.2.257] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2008] [Accepted: 03/25/2009] [Indexed: 12/24/2022] Open
Abstract
The hepatitis B virus (HBV) polymerase gene has overlapping reading frames with surface genes, which allows to alter the amino acid codon of the surface genes. In adefovir (ADV) treated chronic hepatitis B patients carrying rtA181T/rtA181V mutations, overlap with surface gene mutations such as sW172stop/sL173F has been reported. However, the clinical consequences of such surface mutations have not been determined. The aim of this study was to determine the surface gene sequence in ADV-resistant patients carrying the A181T/V mutation and to describe the clinical significance. Of the 22 patients included in this study, 13 were ADV-resistant with rtA181T/V mutations (polymerase mutation group, Group P) and nine were antiviral treatment-naïve (control group, Group C). The Pre-S1 gene mutation, V60A, was detected in 11 patients (Group P=8, Group C=3). A start codon mutation in the Pre-S2 gene was found in five patients (Group P=3, Group C=2). An S gene mutation, sA184V, was found in nine patients, all of whom were in group P. Although sW172stop and sL173F mutations were detected, reduced HBsAg titer was not observed. Further study of these mutations and their clinical implications are needed.
Collapse
Affiliation(s)
- Jeong Han Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Young Kul Jung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Moon Kyung Joo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Ji Hoon Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Hyung Joon Yim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Jong-Jae Park
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Jae Seon Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Young-Tae Bak
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Jong Eun Yeon
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Kwan Soo Byun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| |
Collapse
|
|
31
|
Sung FY, Jung CM, Wu CF, Lin CL, Liu CJ, Liaw YF, Tsai KS, Yu MW. Hepatitis B virus core variants modify natural course of viral infection and hepatocellular carcinoma progression. Gastroenterology 2009; 137:1687-97. [PMID: 19664630 DOI: 10.1053/j.gastro.2009.07.063] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2009] [Revised: 06/11/2009] [Accepted: 07/23/2009] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS We assessed the influence of genetic variants in the hepatitis B virus (HBV) core, which is a principal immunologic target, on the progression to hepatocellular carcinoma (HCC) in a cohort of 4841 male HBV carriers followed up for 16 years. METHODS First, baseline sera from 116 HCC cases and 154 controls nested within the cohort were used for sequencing of the HBV core gene to screen for variants with effects on HCC progression. By applying a high-throughput assay for detecting viral single nucleotide substitutions, we then used a longitudinal study (n = 1143) to examine whether 2 identified variants that lie in the region within or flanking epitopes affected the natural course of hepatitis B through investigating their relationships with time trends for viral load and clinical features. RESULTS In the nested case-control study, there were 6 core variants associated with decreased risk of HCC after accounting for viral genotype; 5 lie in the region within or flanking epitopes (P < .04). Each variant correlated with a 0.7- to 1-log decrease in viral load and hepatitis B virus e antigen negativity at baseline. The longitudinal study further showed that the appearance of 2 such variants (T1938C and T2045A) was preceded by long-term diminished viral load and decreased rate of liver abnormalities and was significantly less frequent in individuals with a prolonged immune clearance phase that associated with spectrum of liver disease than those in inactive carrier or reactivation phase. CONCLUSIONS HBV core variants affecting the kinetics of host-virus interplay may influence longitudinal viral load and HCC progression.
Collapse
Affiliation(s)
- Feng-Yu Sung
- Graduate Institute of Epidemiology, College of Public Health, National Taiwan University, Taipei, Taiwan
| | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Tangkijvanich P, Komolmit P, Mahachai V, Sa-nguanmoo P, Theamboonlers A, Poovorawan Y. Low pretreatment serum HBsAg level and viral mutations as predictors of response to PEG-interferon alpha-2b therapy in chronic hepatitis B. J Clin Virol 2009; 46:117-123. [PMID: 19651540 DOI: 10.1016/j.jcv.2009.07.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2008] [Revised: 04/08/2009] [Accepted: 07/07/2009] [Indexed: 02/08/2023]
Abstract
BACKGROUND Viral genomic mutations have become increasingly recognized as being associated with the outcome of chronic HBV infection. However, the role of viral mutations as a predictor of response to pegylated-interferon (PEG-IFN) therapy has so far remained unclear. STUDY DESIGN Viral mutations in the enhancer II/basal core promoter (BCP)/precore and the pre-S regions were characterized by direct sequencing in pretreatment serum samples of 50 patients with chronic hepatitis B (33 HBeAg-positive and 17 HBeAg-negative), who were treated for 48 weeks with PEG-IFN alpha-2b. RESULTS Sustained virological response at 48 weeks post treatment, defined as HBeAg seroconversion and HBV DNA<2000IU/mL for HBeAg-positive patients, and HBV DNA<200IU/mL for HBeAg-negative patients, was achieved in 12 (36.4%) and 6 (35.3%) of HBeAg-positive and HBeAg-negative patients, respectively. Response to PEG-IFN therapy correlated to low pretreatment HBsAg level but did not correlate with HBV genotype, pretreatment alanine transaminase and HBV DNA levels. In HBeAg-positive hepatitis, PEG-IFN response correlated with the appearance of double BCP mutations (A1762T/G1764A) at baseline (P=0.041). In the HBeAg-negative group, response to PEG-IFN therapy was associated with the presence of pre-S mutation/deletions (P=0.028). Multivariate analysis identified low pretreatment HBsAg level as an independent factor associated with SVR in both groups. CONCLUSIONS Pretreatment quantitative HBsAg determination is useful for predicting response to PEG-IFN therapy. The presence of double BCP and pre-S mutation/deletions at entry may be associated with a high rate of antiviral response in HBeAg-positive and HBeAg-negative hepatitis, respectively.
Collapse
Affiliation(s)
- Pisit Tangkijvanich
- Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | | | | | | | | | | |
Collapse
|
|
33
|
Shen FC, Su IJ, Wu HC, Hsieh YH, Yao WJ, Young KC, Chang TC, Hsieh HC, Tsai HN, Huang W. A pre-S gene chip to detect pre-S deletions in hepatitis B virus large surface antigen as a predictive marker for hepatoma risk in chronic hepatitis B virus carriers. J Biomed Sci 2009; 16:84. [PMID: 19751529 PMCID: PMC2755474 DOI: 10.1186/1423-0127-16-84] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2009] [Accepted: 09/15/2009] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Chronic hepatitis B virus (HBV) infection is an important cause of hepatocellular carcinoma (HCC) worldwide. The pre-S1 and -S2 mutant large HBV surface antigen (LHBS), in which the pre-S1 and -S2 regions of the LHBS gene are partially deleted, are highly associated with HBV-related HCC. METHODS The pre-S region of the LHBS gene in two hundred and one HBV-positive serum samples was PCR-amplified and sequenced. A pre-S oligonucleotide gene chip was developed to efficiently detect pre-S deletions in chronic HBV carriers. Twenty serum samples from chronic HBV carriers were analyzed using the chip. RESULTS The pre-S deletion rates were relatively low (7%) in the sera of patients with acute HBV infection. They gradually increased in periods of persistent HBV infection: pre-S mutation rates were 37% in chronic HBV carriers, and as high as 60% in HCC patients. The Pre-S Gene Chip offers a highly sensitive and specific method for pre-S deletion detection and is less expensive and more efficient (turnaround time 3 days) than DNA sequencing analysis. CONCLUSION The pre-S1/2 mutants may emerge during the long-term persistence of the HBV genome in carriers and facilitate HCC development. Combined detection of pre-S mutations, other markers of HBV replication, and viral titers, offers a reliable predictive method for HCC risks in chronic HBV carriers.
Collapse
Affiliation(s)
- Fan-Ching Shen
- Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan, Republic of China
| | - Ih-Jen Su
- Division of Infectious Diseases, National Health Research Institutes, Tainan, Taiwan, Republic of China
| | - Han-Chieh Wu
- Division of Infectious Diseases, National Health Research Institutes, Tainan, Taiwan, Republic of China
| | - Yi-Hsuan Hsieh
- Institute of Basic Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China
| | - Wei-Jen Yao
- Department of Radiology, National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China
| | - Kung-Chia Young
- Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan, Republic of China
| | - Tsung-Chuan Chang
- Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan, Republic of China
| | - Hui-Chuan Hsieh
- Institute of Basic Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China
| | - Han-Ni Tsai
- Institute of Basic Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China
| | - Wenya Huang
- Department of Medical Laboratory Science and Biotechnology, National Cheng Kung University, Tainan, Taiwan, Republic of China
- Institute of Basic Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China
- Center for Signal Transduction and Gene Regulation, National Cheng Kung University, Tainan, Taiwan, Republic of China
- Laboratory of Molecular Diagnostics, Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan, Republic of China
| |
Collapse
|
|
34
|
Iser DM, Lewin SR. The pathogenesis of liver disease in the setting of HIV–hepatitis B virus coinfection. Antivir Ther 2009. [DOI: 10.1177/135965350901400207] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
There are many potential reasons for increased liver-related mortality in HIV–hepatitis B virus (HBV) coinfection compared with either infection alone. HIV infects multiple cells in the liver and might potentially alter the life cycle of HBV, although evidence to date is limited. Unique mutations in HBV have been defined in HIV–HBV-coinfected individuals and might directly alter pathogenesis. In addition, an impaired HBV- specific T-cell immune response is likely to be important. The roles of microbial translocation, immune activation and increased hepatic stellate cell activation will be important areas for future study.
Collapse
Affiliation(s)
- David M Iser
- Department of Medicine, The University of Melbourne, St Vincent's Hospital, Melbourne, Victoria, Australia
- Infectious Diseases Unit, The Alfred Hospital, Melbourne, Victoria, Australia
| | - Sharon R Lewin
- Infectious Diseases Unit, The Alfred Hospital, Melbourne, Victoria, Australia
- Department of Medicine, Monash University, Melbourne, Victoria, Australia
| |
Collapse
|
|
35
|
Chen CH, Changchien CS, Lee CM, Hung CH, Hu TH, Wang JH, Wang JC, Lu SN. Combined mutations in pre-s/surface and core promoter/precore regions of hepatitis B virus increase the risk of hepatocellular carcinoma: a case-control study. J Infect Dis 2008; 198:1634-42. [PMID: 18939932 DOI: 10.1086/592990] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND We sought to investigate the role of sequence variations in pre-S/surface and basal core promoter (BCP)/precore regions of the hepatitis B virus (HBV) in hepatocellular carcinoma (HCC). METHODS The direct sequencing in pre-S/surface and BCP/precore regions of HBV was determined for 80 patients with HCC and 160 control patients with HBV infection. RESULTS Compared with control patients, patients with HCC had higher frequencies of pre-S deletions and amino acid substitutions at codon 4, 7, and 81 in pre-S1 genes; at the start codon in pre-S2 genes; and at codon 68 in surface genes. Patients also had a lower frequency of amino acid substitution at codon 2 in pre-S2 genes, compared with control patients. In BCP/precore regions, patients with HCC had higher frequencies of C or G1753, A1762/T1764, T1846, and A1899. Multivariate analysis showed that pre-S deletions, I68T surface gene, T1762/A1764, and A1899 were independent factors associated with the development of HCC. The HBV strain with a complex mutation pattern rather than a single mutation was associated with HCC, and the HCC risks increased for patients having these factors in combination. CONCLUSIONS Pre-S deletions, I68T in surface gene, T1762/A1764, and A1899 were independent risk factors for HCC. Combination of these viral mutations appeared to increase the risk of HCC.
Collapse
Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan
| | | | | | | | | | | | | | | |
Collapse
|
|
36
|
Shen T, Yan XM, Zou YL, Gao JM, Dong H. Virologic characteristics of hepatitis B virus in patients infected via maternal-fetal transmission. World J Gastroenterol 2008; 14:5674-5682. [PMID: 18837083 PMCID: PMC2748201 DOI: 10.3748/wjg.14.5674] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2008] [Revised: 08/22/2008] [Accepted: 08/29/2008] [Indexed: 02/06/2023] Open
Abstract
AIM To determine whether HBV with the same characteristics causes dissimilar mutations in different hosts. METHODS Full-length HBV genome was amplified and linked with pMD T18 vector. Positive clones were selected by double-restriction endonuclease digestion (EcoRI and HindIII) and PCR. Twenty seven clones were randomly selected from an asymptomatic mother [at two time points: 602 (1 d) and 6022 (6 mo)] and her son [602 (S)], and the phylogenetic and mutational analysis was performed using BioEditor, Clustal X and MEGA software. Potential immune epitopes were determined by the Stabilized Matrix Method (SMM), SMM-Align Method and Emini Surface Accessibility Prediction. RESULTS All of the 27 sequences were genotype C, the divergence between the mother and son was 0%-0.8%. Compared with another 50 complete sequences of genotype C, the mother and her son each had 13 specific nucleotides that differed from the other genotype C isolates. AA 1-11 deletion in preS1 was the dominant mutation in the mother (14/18). The 1762T/1764A double mutation existed in all clones of the mother, 3 of them were also coupled with G1896A mutation, but none were found in the son. 17 bp deletion starting at nucleotide 2330 was the major mutation (5/9) in the son, which caused seven potential HLA class I epitopes and one B cell epitope deletion, and produced a presumptive new start codon, downstream from the original one of the P gene. CONCLUSION The HBV strain in the son came from his mother, and discrepant mutation occurred in the mother and her son during infection.
Collapse
|
|
37
|
Co-replication analyses of naturally occurring defective hepatitis B virus variants with wild-type. Virology 2008; 372:247-59. [DOI: 10.1016/j.virol.2007.10.039] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2007] [Revised: 06/29/2007] [Accepted: 10/31/2007] [Indexed: 11/18/2022]
|
|
38
|
Chen CH, Hung CH, Lee CM, Hu TH, Wang JH, Wang JC, Lu SN, Changchien CS. Pre-S deletion and complex mutations of hepatitis B virus related to advanced liver disease in HBeAg-negative patients. Gastroenterology 2007; 133:1466-74. [PMID: 17915220 DOI: 10.1053/j.gastro.2007.09.002] [Citation(s) in RCA: 190] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2006] [Accepted: 08/09/2007] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS This longitudinal study investigated the interactions and roles of hepatitis B virus (HBV) genotypes, pre-S deletions, and core promoter and precore mutations on the progression of liver disease in hepatitis B e antigen (HBeAg)-negative patients. METHODS A total of 141 HBeAg-negative patients without liver cirrhosis or hepatocellular carcinoma at study entry were recruited for this study, including 45 inactive HBV carriers and 96 patients with HBeAg-negative chronic hepatitis B. The HBV genotypes and the sequences of pre-S, core promoter, and precore regions were determined. RESULTS Compared with patients without developing liver cirrhosis, patients with the development of liver cirrhosis had higher rates of genotype C; pre-S deletions; C or G1753, T1762/A1764, T1766, and/or A1768 mutants; and G1799 variant. Cox regression analysis showed that older age, higher total bilirubin and HBV DNA levels, pre-S deletions, and T1766 and/or A1768 mutants were significantly associated with the development of liver cirrhosis. HBV with a complex mutation pattern (pre-S deletion, T1762/A1764, and T1766 and/or A1768 mutants) rather than a single mutation was associated with the development of liver cirrhosis, and the patterns of mutation combinations differed between HBV genotype B and C. Moreover, pre-S deletion was a significant risk factor for hepatocellular carcinoma. CONCLUSIONS This study indicated that pre-S deletion and combined mutations of HBV are useful molecular markers for predicting the clinical outcomes of HBeAg-negative patients.
Collapse
Affiliation(s)
- Chien-Hung Chen
- Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan
| | | | | | | | | | | | | | | |
Collapse
|
|
39
|
Ito K, Tanaka Y, Kato M, Fujiwara K, Sugauchi F, Sakamoto T, Shinkai N, Orito E, Mizokami M. Comparison of complete sequences of hepatitis B virus genotype C between inactive carriers and hepatocellular carcinoma patients before and after seroconversion. J Gastroenterol 2007; 42:837-844. [PMID: 17940837 DOI: 10.1007/s00535-007-2100-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2007] [Accepted: 07/31/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND Most patients who acquire chronic hepatitis B virus (HBV) infection by perinatal transmission become inactive carriers (IC) after hepatitis B e (HBe) antigen seroconversion, whereas some patients have persistent abnormal serum transaminase levels and develop hepatocellular carcinoma (HCC) in the anti-HBe-positive phase. The aim of this study was to investigate the HCC-related mutations of HBV. METHODS Complete sequences of HBV were examined among eight IC and eight HCC patients infected with HBV genotype C before and after seroconversion. RESULTS The frequency of the T1653 mutation tended to be higher among HCC patients after seroconversion (16.7% vs. 62.5%; P = 0.086). The prevalence of a basal core promoter double mutation (T1762/A1764) was high among both IC and HCC patients after seroconversion (83.3% vs. 87.5%; P = 0.825). Among the HCC patients, a pre-S deletion mutant was detected in 62.5% patients before seroconversion, and in 37.5% patients after seroconversion. The core deletion mutant was also detected in 50% of HCC patients only before seroconversion. Deletion mutants of the pre-S or core region before seroconversion were significantly associated with HCC patients (0% vs. 62.5%; P = 0.007, 0% vs. 50%; P = 0.021, respectively). CONCLUSIONS Our data showed a significant association of pre-S and core deletion mutants before seroconversion with HCC development. The T1653 mutation after seroconversion was frequently found in HCC patients infected with HBV genotype C. These results suggest that mutations may be predictive factor for development of HCC.
Collapse
Affiliation(s)
- Kiyoaki Ito
- Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho, Nagoya 467-8601, Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
40
|
Gao ZY, Li T, Wang J, Du JM, Li YJ, Li J, Lu FM, Zhuang H. Mutations in preS genes of genotype C hepatitis B virus in patients with chronic hepatitis B and hepatocellular carcinoma. J Gastroenterol 2007; 42:761-8. [PMID: 17876546 DOI: 10.1007/s00535-007-2085-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2006] [Accepted: 06/06/2007] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hepatitis B virus (HBV) preS mutations are frequently isolated from patients with severe forms of liver disease. Meanwhile, genotype C has been shown to cause more serious liver disease than genotype B. This study assesses the frequency of preS mutation in Chinese patients with genotype C chronic HBV infection and its relation to liver damage. METHODS Seventy-nine persistently infected patients (25 asymptomatic carriers, 28 with chronic hepatitis, and 26 with hepatocellular carcinoma) with genotype C HBV were analyzed. Levels of HBV DNA, hepatitis B e antigen (HBeAg), alanine aminotransferase, and aspartate transaminase and mutations in the preS region were determined. RESULTS The correlations of preS deletion with disease progression were distinct: preS deletion mutations were more commonly found in the hepatocellular carcinoma (HCC) group than in the chronic hepatitis B (CHB) or asymptomatic carrier (ASC) groups, with the frequencies of 38.46% (10/26) in the HCC, 7.14% (2/28) in the CHB, and 4.00% (1/25) in the ASC (P = 0.001) groups. The HBeAg-positive rate and HBV DNA levels were comparable between patients with the preS mutation and those without. CONCLUSIONS PreS deletion mutations of genotype C HBV might play a role in HBV-related hepatocarcinogenesis.
Collapse
Affiliation(s)
- Zhi Yong Gao
- Department of Microbiology, Peking University Health Science Center, 38 Xueyuan Road, 100083, Beijing, China
| | | | | | | | | | | | | | | |
Collapse
|
|
41
|
Revill PA, Littlejohn M, Ayres A, Yuen L, Colledge D, Bartholomeusz A, Sasaduesz J, Lewin SR, Dore GJ, Matthews GV, Thio CL, Locarnini SA. Identification of a novel hepatitis B virus precore/core deletion mutant in HIV/hepatitis B virus co-infected individuals. AIDS 2007; 21:1701-10. [PMID: 17690567 DOI: 10.1097/qad.0b013e32826fb305] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Although HAART has resulted in improved health outcomes for most HIV-infected individuals, liver failure has emerged as a major cause of morbidity and mortality in people co-infected with hepatitis B virus (HBV). In HBV mono-infected individuals, core deletion mutants are associated with more aggressive liver disease. As HIV accelerates HBV liver disease progression, we hypothesized that HIV-HBV co-infected individuals have increased frequency of core mutations including deletions. To test this hypothesis, we have analysed genome-length sequences of HBV DNA from patients both prior to and during antiviral therapy. SETTING Prospective HIV/HBV co-infected cohort study. METHODS Genomic length HBV DNA was amplified by PCR from the serum samples of ten HIV/HBV co-infected individuals and five HBV mono-infected individuals prior to the commencement of lamivudine therapy and again after nine to 74 months of treatment. The complete genomes were sequenced and in order to further analyse some mutations, their frequency was determined in additional HIV/HBV co-infected and HBV mono-infected individuals. RESULTS A novel -1G mutation was identified in the HBV precore and overlapping core genes that truncated the deduced precore/core proteins. The mutant genome was the dominant species in some HIV/HBV co-infected individuals and was more prevalent in HIV/HBV co-infected individuals than HBV mono-infected individuals. The mutation was also associated with high HBV DNA concentrations in HIV/HBV co-infected individuals. Additional mutations were identified in the core/precore and polymerase genes and regulatory regions. CONCLUSION Mutations in the HBV core and precore genes may be contributing to disease pathogenesis in HIV/HBV co-infected individuals.
Collapse
Affiliation(s)
- Peter A Revill
- Victorian Infectious Diseases Reference Laboratory, 10 Wreckyn Street, North Melbourne, Victoria 3051, Australia.
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Lin CL, Liu CH, Chen W, Huang WL, Chen PJ, Lai MY, Chen DS, Kao JH. Association of pre-S deletion mutant of hepatitis B virus with risk of hepatocellular carcinoma. J Gastroenterol Hepatol 2007; 22:1098-1103. [PMID: 17608857 DOI: 10.1111/j.1440-1746.2006.04515.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND Pre-S deletion mutant of hepatitis B virus (HBV) affects the expression of middle and small surface proteins, resulting in intracellular accumulation of large surface protein. The correlation between pre-S deletion mutant and risk of hepatocellular carcinoma (HCC) in hepatitis B virus carriers remains unclear. METHODS Using molecular assays, pre-S deletion mutant of HBV were determined in 266 patients with chronic HBV genotype B or C infection. They included 202 asymptomatic carriers and 64 HCC patients. RESULTS The overall prevalence of pre-S deletion mutant was 16.5%. Hepatocellular carcinoma (odds ratio [OR], 3.23; 95% confidence interval [CI], 1.23-8.48, P = 0.02) and genotype C (OR, 3.19; 95%CI, 1.54-6.62, P = 0.002) were independently associated with the presence of pre-S deletion mutant. The prevalence of pre-S deletion mutant was comparable between HCC patients with genotype B and C infection. Nevertheless, in asymptomatic carriers, patients with genotype C infection were significantly associated with the presence of pre-S deletion mutant compared to those with genotype B infection (20.8% vs 7.2%, P = 0.007). Compared with age- and genotype B-matched asymptomatic carriers, young HCC patients (<50 years of age) had a significantly higher frequency of pre-S deletion (3.4% vs 20%, P = 0.04). CONCLUSIONS Pre-S deletion mutant is more frequent in HBV carriers with genotype C infection, and those with pre-S deletion mutant may be associated with the development of HCC, irrespective of HBV genotype.
Collapse
Affiliation(s)
- Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Choi MS, Kim DY, Lee DH, Lee JH, Koh KC, Paik SW, Rhee JC, Yoo BC. Clinical significance of pre-S mutations in patients with genotype C hepatitis B virus infection. J Viral Hepat 2007; 14:161-8. [PMID: 17305881 DOI: 10.1111/j.1365-2893.2006.00784.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
We investigated the overall and site-specific prevalence of pre-S mutations and its clinical significance in patients with genotype C hepatitis B virus (HBV) infection. Three hundred subjects were included: 50 asymptomatic carriers (AC), 87 chronic hepatitis (CH), 91 liver cirrhosis (LC) and 72 hepatocellular carcinoma (HCC). Pre-S mutations were determined by nucleotide sequence analysis. Possible correlations between pre-S mutations and clinical/virological parameters were examined. Pre-S mutations were detected in 82 cases (27.3%); it was more frequently found in HCC (43.1%) and LC (35.2%) group than in the CH (20.7%) and AC (2.0%) group. Pre-S2 deletion was the most commonly found mutation (10.7%), followed by pre-S2 start codon mutation (9.7%), pre-S1-S2 deletion (3.0%) and both pre-S2 deletion and start codon mutation (2.7%). Pre-S2 deletion and pre-S2 start codon mutation were more frequently detected in advanced diseases (LC and HCC). Pre-S mutations were associated with older age and higher rates of positive HBV DNA (>/=0.5 pg/mL). Advanced disease and positive HBV DNA were shown to be independent predictors of pre-S mutations by logistic regression analysis. These findings suggest that pre-S mutations, especially pre-S2 deletions and pre-S2 start codon mutations, are common in patients with genotype C HBV infection and are associated with advanced liver disease and active viral replication.
Collapse
Affiliation(s)
- M S Choi
- Department of Medicine and Digestive Disease Research Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
44
|
López JL, Mathet VL, Oubiña JR, Campos RH. Intrahost evolution of HBe antigen-negative hepatitis B virus genomes ascribed to the F genotype: a longitudinal 3 year retrospective study. J Gen Virol 2007; 88:86-91. [PMID: 17170440 DOI: 10.1099/vir.0.82331-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The intrahost hepatitis B virus (HBV) genomic evolution process of an HBe antigen (HBeAg)-negative chronic HBV patient (designated RI) was studied. Two nearly full-length direct sequences obtained in 1995 (RI95) and 1998 (RI98) showed: (a) a mutation rate of 2.7x10(-3) nucleotides per site per year; (b) nucleotide changes mainly located at single coding regions (P=0.002); (c) mixed populations; and (d) a predominance of non-synonymous substitutions (P=0.0036). Population heterogeneity was assessed by cloning and sequencing of a fragment spanning nearly half the genome. Two-thirds of the analysed clones exhibited long nucleotide deletions. Pairwise genetic diversity revealed that diversity was higher for RI95 than for RI98 cloned sequences. In conclusion, a highly heterogeneous genomic population circulated within patient RI, which might support the persistence of HBV. Finally, the structure of the deletant genomes suggests that they might serve as intermediates for integration to the host-cell genome.
Collapse
Affiliation(s)
- José Luis López
- Cátedra de Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, Piso 4, 1113 Buenos Aires, Argentina
| | - Verónica Lidia Mathet
- Laboratorio de Hepatitis Virales, Departamento de Microbiología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Piso 11, 1121 Buenos Aires, Argentina
| | - José Raúl Oubiña
- Laboratorio de Hepatitis Virales, Departamento de Microbiología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, Piso 11, 1121 Buenos Aires, Argentina
| | - Rodolfo Héctor Campos
- Cátedra de Virología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, Piso 4, 1113 Buenos Aires, Argentina
| |
Collapse
|
|
45
|
Abstract
Infection with hepatitis B virus (HBV) leads to a wide spectrum of clinical presentations ranging from an asymptomatic carrier state to self-limited acute or fulminant hepatitis to chronic hepatitis with progression to cirrhosis and hepatocellular carcinoma. Infection with HBV is one of the most common viral diseases affecting man. Both viral factors as well as the host immune response have been implicated in the pathogenesis and clinical outcome of HBV infection. In this review, we will discuss the impact of virus-host interactions for the pathogenesis of HBV infection and liver disease. These interactions include the relevance of naturally occurring viral variants for clinical disease, the role of virus-induced apoptosis for HBV-induced liver cell injury and the impact of antiviral immune responses for outcome of infection.
Collapse
Affiliation(s)
- Thomas F Baumert
- Department of Medicine I, Schlosspark Klinik, Teaching Hospital of the Charite, Humboldt University, Heubnerweg 2, D-14059 Berlin, Germany
| | | | | |
Collapse
|
|
46
|
Braun S, Zajakina A, Aleksejeva J, Sharipo A, Bruvere R, Ose V, Pumpens P, Garoff H, Meisel H, Kozlovska T. Proteasomal degradation of core protein variants from chronic hepatitis B patients. J Med Virol 2007; 79:1312-21. [PMID: 17607782 DOI: 10.1002/jmv.20939] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The accumulation of complex hepatitis B virus (HBV) variants with internal in-frame deletions in the C gene in immunosuppressed renal transplant recipients is associated with a severe course of the infection leading to end-stage liver disease (ESLD). A set of six HBV C genes with internal in-frame deletions corresponding to the pattern of HBV population in immunosuppressed patients has been expressed in two different eukaryotic cell lines. Synthesis and proteasomal degradation of HBV core (HBc) protein variants were compared with those of the wild-type HBc. In all cases, the steady-state level of internally deleted HBc proteins, predominantly with longer deletions, were considerably lower and turnover was significantly higher in comparison with those of the wild-type HBc, since all deletion variants were degraded rapidly via the proteasome pathway. Involvement and consequences of the proteasomal degradation machinery in the HBc protein turnover during HBV infection with complex HBV variants in the immunosuppressed patients are discussed.
Collapse
Affiliation(s)
- Sabine Braun
- Universitätsmedizin Berlin, Charité, Institut für Virologie, Campus Mitte, Charitéplatz 1, Berlin, Germany
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
47
|
Paik YH, Brenner DA. Immunosuppression, hepatitis B virus variants: Synergistic role in hepatic fibrogenesis. Gastroenterology 2006; 131:957-60. [PMID: 16952565 DOI: 10.1053/j.gastro.2006.07.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
|
|
48
|
Märschenz S, Endres AS, Brinckmann A, Heise T, Kristiansen G, Nürnberg P, Krüger DH, Günther S, Meisel H. Functional analysis of complex hepatitis B virus variants associated with development of liver cirrhosis. Gastroenterology 2006; 131:765-80. [PMID: 16952546 DOI: 10.1053/j.gastro.2006.07.008] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2005] [Accepted: 06/08/2006] [Indexed: 12/31/2022]
Abstract
BACKGROUND & AIMS Development of cirrhosis in renal transplant recipients with chronic hepatitis B is associated with the accumulation of complex hepatitis B virus (HBV) variants carrying deletions in the C gene and/or preS region and deletions/insertions in the core promoter. Here, we characterized for the first time the phenotype of these complex HBV variants. METHODS Representative full-length genomes of the HBV variants that were isolated and cloned from serum and liver of an immunosuppressed renal transplant recipient before and during end-stage liver disease were transfected into the human hepatoma cell line HuH7 and functionally analyzed. RESULTS The variant genomes showed considerably reduced levels of precore and surface messenger RNA (mRNA) and of the major spliced pregenomic RNA, an increased level of pregenomic RNA, and a partial or complete defect in hepatitis B e antigen, core, and surface protein expression/secretion. Very low amounts of variant core protein with internal deletion were detectable. Reduced hepatitis B surface antigen secretion of some variants correlated with aberrant localization of surface proteins in endoplasmic reticulum. Despite the defects in viral protein expression, enhanced replication and enrichment in competition to wild-type HBV were observed. Enhanced reverse transcription and possibly increased levels of pregenomic RNA seem to be responsible for this effect. CONCLUSIONS Development of cirrhosis is associated with accumulation of complex variants, which exhibit a drastically altered phenotype combining enhanced replication with defects in protein expression. This phenotype appears to be based on the major mutations in the core promoter and C gene but is considerably influenced by additional mutations throughout the genome.
Collapse
Affiliation(s)
- Stefanie Märschenz
- Institut für Virologie (Helmut-Ruska-Haus), Charité-Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany
| | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Calabrese LH, Zein NN, Vassilopoulos D. Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies. Ann Rheum Dis 2006; 65:983-9. [PMID: 16627542 PMCID: PMC1798254 DOI: 10.1136/ard.2005.043257] [Citation(s) in RCA: 171] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/05/2006] [Indexed: 12/23/2022]
Abstract
Understanding of the natural history and basic biology of hepatitis B virus (HBV) has increased greatly in recent years. In view of this, the following are reviewed here: (a) recent advances in HBV biology pertinent to the rheumatic disease population; (b) the risks of HBV reactivation in patients with rheumatic disease undergoing immunosuppression; and (c) potential strategies to manage these risks.
Collapse
Affiliation(s)
- L H Calabrese
- Department of Rheumatic and Immunological Disease, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195, USA.
| | | | | |
Collapse
|
|
50
|
Chen BF, Liu CJ, Jow GM, Chen PJ, Kao JH, Chen DS. High prevalence and mapping of pre-S deletion in hepatitis B virus carriers with progressive liver diseases. Gastroenterology 2006; 130:1153-68. [PMID: 16618410 DOI: 10.1053/j.gastro.2006.01.011] [Citation(s) in RCA: 232] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2005] [Accepted: 12/21/2005] [Indexed: 12/17/2022]
Abstract
BACKGROUND & AIMS The interactions among pre-S deletion, precore (PC) mutation, and basal core promoter (BCP) mutation in various stages of chronic hepatitis B virus (HBV) infection remain unclear and were thus investigated in this study. METHODS The sequences of the pre-S region and the BCP (A1762T, G1764A) and PC (G1896A) mutations were determined in 46 HBV chronic carriers (CC) and 106 age-matched carriers with different stages of liver diseases, including 38 chronic hepatitis (CH), 18 cirrhosis (LC), and 50 hepatocellular carcinoma (HCC). RESULTS A higher prevalence of pre-S deletion and BCP and PC mutations was found in carriers with progressive liver diseases compared with the CC group. By logistic regression analysis, patients with pre-S deletion and BCP mutation were significantly associated with the development of progressive liver diseases than those without. Combination of mutations rather than single mutation was associated with the development of progressive liver diseases, especially in combination with pre-S deletion. Sequencing analysis showed that the deleted regions were more often in the 3' terminus of pre-S1 and the 5' terminus of pre-S2. Further mapping of these pre-S deletion sequences found that all the deletion regions encompassed T- and B-cell epitopes, and most of them lost 1 or more functional sites. CONCLUSIONS Our data indicate that patients with progressive liver diseases have a higher frequency of pre-S deletion.
Collapse
Affiliation(s)
- Bing-Fang Chen
- School of Medicine, Fu Jen Catholic University, Taipei, Taiwan
| | | | | | | | | | | |
Collapse
|