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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.
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Zhao J, Zhang X, Fang L, Pan H, Shi J. Association between IL28B Polymorphisms and Outcomes of Hepatitis B Virus Infection: A meta-analysis. BMC MEDICAL GENETICS 2020; 21:88. [PMID: 32357928 PMCID: PMC7195703 DOI: 10.1186/s12881-020-01026-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Accepted: 04/14/2020] [Indexed: 12/23/2022]
Abstract
BACKGROUND Interleukin (IL) 28B polymorphisms encoding pro-inflammatory and anti-inflammatory cytokines trigger diverse clinical outcome of hepatitis virus infection. However, there is controversy concerning the association of IL28B polymorphisms with the outcome of hepatitis B virus (HBV) infection, with several studies obtaining inconsistent results. We performed a meta-analysis to evaluate the role of 3 single nucleotide polymorphisms (SNPs) rs12979860, rs12980275 and rs8099917 in the progression of HBV infection, overall and by ethnicity. METHODS Searched PubMed, Embase and Wiley Online Library electronic databases using 'interleukin 28B', 'IL 28B', 'IL 28B polymorphism', 'hepatitis B virus', 'HBV', and performed meta- analysis for rs12979860, rs12980275 and rs8099917 in Asian and Caucasian populations under the dominant recessive and allele model. RESULTS Eighteen studies were found in total and used for this meta-analysis, including 5587 cases and 4295 controls. The IL28B polymorphism rs12979860 had no association with HBV persistence (CC vs CT + TT: OR = 0.86, 95% CI = 0.76-1.00; TT vs CT + CC: OR = 1.14, 95% CI = 0.76-1.70; T vs C: OR = 1.03, 95% CI = 0.94-1.13). Similarly, neither rs12980275 nor rs8099917 had associations with HBV persistence (rs12980275 in AA vs AG + AA: OR = 1.15, 95% CI = 0.96-1.38; rs8099917 in TT vs GT + GG: OR = 1.15, 95% CI = 0.96-1.39). There was also no significant association of IL28B polymorphisms with persistent HBV infection in Asians or Chinese. There was no evidence of an association of rs12979860 with the HBV-related hepatocellular carcinoma susceptibility (T vs C: OR = 1.53, 95% CI = 0.96-2.43). CONCLUSION IL28B polymorphisms had no association with the outcome of HBV infection overall, nor in the Asians and the Chinese. These 3 SNPs might not be relevant to the development of HBV infection.
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Affiliation(s)
- Jingyu Zhao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Regenerative Medicine Clinic, Tianjin, 300020, China
| | - Xinyue Zhang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, China
| | - Liwei Fang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Regenerative Medicine Clinic, Tianjin, 300020, China
| | - Hong Pan
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Regenerative Medicine Clinic, Tianjin, 300020, China
| | - Jun Shi
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Regenerative Medicine Clinic, Tianjin, 300020, China.
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Al-Essa M, Alyahya A, Al Mulhim A, Alyousof A, Al-Mulhim M, Essa A. Perception of and Attitude towards Hepatitis B Infection among Saudi Pregnant Females Attending Antenatal Care Unit in Al-Ahsa City, Kingdom of Saudi Arabia. Cureus 2020; 12:e6673. [PMID: 31976187 PMCID: PMC6968831 DOI: 10.7759/cureus.6673] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 01/16/2020] [Indexed: 12/23/2022] Open
Abstract
Objective This study aimed to assess the knowledge and attitudes of pregnant females in Al-Ahsa city, Kingdom of Saudi Arabia (KSA) toward hepatitis B virus infection. Methods A cross-sectional study was done at the Maternity and Children's Hospital, Al-Ahsa. A total of 422 of every third pregnant women were recruited from 6/12/2019 to 20/12/2019. Self-administered questionnaire was provided that contained three aspects: sociodemographic, perception and source of information about hepatitis B, and attitude toward hepatitis B infection. Analysis was performed using SPSS version 21 (IBM Corp., Armonk, NY). Results A total of 422 pregnant women participated in this study with a response rate of 93.7%. Among them, 44.79% had a university degree or higher education level, about 82% had information about hepatitis B virus (HBV) during their pregnancy, 0.9% knew a person with HBV, 48.1% knew that hepatitis B is caused by virus, 72% knew that hepatitis B has vaccine, 41.9% knew that hepatitis B spreads via mother, 79.6% were willing to do hepatitis B test during pregnancy, 80.1% were willing to allow for kids' vaccination against HBV, and 83.4% were willing to allow their kids for hepatitis B testing. There was a significant relationship between the level of education and the knowledge score. And there was a significant relationship between the level of education and attitudes score. Conclusion There is insufficient knowledge among pregnant women regarding hepatitis B infection, while pregnant women showed remarkably positive attitudes regarding therapy and immunization. So, we highly recommend for awareness campaigns about viral hepatitis regarding means of transmission, and possible treatment options.
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Affiliation(s)
- Meshal Al-Essa
- Medicine, College of Medicine, King Faisal University, Al-Ahsa, SAU
| | - Abdulwahab Alyahya
- Internal Medicine, College of Medicine, King Faisal University, Al-Ahsa, SAU
| | - Abdulatif Al Mulhim
- Internal Medicine, College of Medicine, King Faisal University, Al-Ahsa, SAU
| | - Abdulaziz Alyousof
- Internal Medicine, College of Medicine, King Faisal University, Al-Ahsa, SAU
| | - Mohammad Al-Mulhim
- Internal Medicine, College of Medicine, King Faisal University, Al-Ahsa, SAU
| | - Abdallah Essa
- Gastroenterology - Internal Medicine, College of Medicine, King Faisal University, Al-Ahsa, SAU
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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.
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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
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Jia J, Li H, Wang H, Chen S, Wang M, Feng H, Gao Y, Wang Y, Fang M, Gao C. Hepatitis B virus core antigen mutations predict post-operative prognosis of patients with primary hepatocellular carcinoma. J Gen Virol 2017; 98:1399-1409. [PMID: 28640739 PMCID: PMC5656792 DOI: 10.1099/jgv.0.000790] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 03/26/2017] [Indexed: 12/11/2022] Open
Abstract
The aim of this study was to explore the relationship between hepatitis B virus (HBV) core antigen (HBc) mutations and the post-operative prognosis of HBV-related hepatocellular carcinoma (HCC). In total, 98 patients suffering from HBV-related HCC and treated with surgery were enrolled, with a 48 month follow-up. The preCore/Core region of the HBV genome from tumour tissue (TT) and paired adjacent non-tumour tissue (ANTT) of these patients was sequenced, and a phylogenetic tree was reconstructed. The correlations between the viral features and evolutionary divergence of preCore/Core amino acid sequences from 67 paired TTs and ANTTs were analysed. Cox proportional hazard model analysis was applied for post-operative hazard risk evaluation. Phylogenetic analysis revealed that all of the sequences were ascribed to genotype C. The evolutionary divergence of amino acid sequences from matched TTs and ANTTs was significantly negatively correlated with serum and intrahepatic HBV DNA levels. Multivariate analysis showed that the HBc E77 mutation was associated with shorter overall survival, and HBc S87 and P156 mutations were independent risk factors for relapse. Furthermore, in contrast to with patients without the S87 mutation, no correlation was observed between serum HBV DNA and intrahepatic HBV DNA in HCC patients with the S87 mutation. Analysis of the intrahepatic sequence may advance our understanding of viral status; thus, it is useful for prognosis prediction for HBV-related HCC.
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Affiliation(s)
- Jian’an Jia
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
- Department of Laboratory Medicine, 105th Hospital of PLA, Hefei 230031, PR China
| | - Huiming Li
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Hui Wang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
- Department of Clinical Laboratory, First Affiliated Hospital of Chinese PLA’s General Hospital, Beijing 100048, PR China
| | - Shipeng Chen
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Mengmeng Wang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Huijuan Feng
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Yuzhen Gao
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Yunjiu Wang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Meng Fang
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
| | - Chunfang Gao
- Department of Laboratory Medicine, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, PR China
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Tajiri H, Takano T, Tanaka H, Ushijima K, Inui A, Miyoshi Y, Ozono K, Abukawa D, Endo T, Brooks S, Tanaka Y. Hepatocellular carcinoma in children and young patients with chronic HBV infection and the usefulness of alpha-fetoprotein assessment. Cancer Med 2016; 5:3102-3110. [PMID: 27748053 PMCID: PMC5119965 DOI: 10.1002/cam4.917] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 08/13/2016] [Accepted: 08/18/2016] [Indexed: 12/18/2022] Open
Abstract
The aims of the study were to elucidate the clinical characteristics of patients who developed hepatocellular carcinoma (HCC) related to persistent HBV infection since childhood and to investigate usefulness of assessing alpha‐fetoprotein (AFP) in this population. A nationwide multicenter survey of children with chronic HBV infection was performed. Among 548 patients, 15 patients developed HCC at the median age of 15 years (range 9–36), including 13 males and 2 females. A case–control comparison showed that HBeAg seroconversion and liver cirrhosis were associated with the occurrence of HCC. Of the 15 HCC patients, 5 were treated with interferon and none of them responded to interferon therapy as compared with 12 of the 17 responders in the control group. Of the 15 patients, 10 died and 9 of the 10 who died never visited any medical facilities until diagnosis of HCC, while the remaining 5 surviving patients never stopped their clinic visits. The usefulness of AFP assessment was shown by the findings that AFP levels were elevated in all HCC cases, that elevations in AFP levels were detected prior to the diagnosis in the surviving patients, and that sensitivity of AFP as a diagnostic test for HCC was very high among 40 patients including our 14 and an additional 26 collected from the literature. HBeAg seroconversion and liver cirrhosis are associated with the occurrence of HCC. Regular measurement of AFP might be helpful to watch for the occurrence of HCC when following children and young patients with chronic HBV infection since childhood
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Affiliation(s)
- Hitoshi Tajiri
- Department of Pediatrics, Osaka General Medical Center, Osaka, Japan
| | - Tomoko Takano
- Department of Pediatrics, Osaka General Medical Center, Osaka, Japan
| | - Hideo Tanaka
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Kosuke Ushijima
- Department of Pediatrics, Kurume University Medical Center, Kurume, Japan
| | - Ayano Inui
- Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama City Tobu Hospital, Yokohama, Japan
| | - Yoko Miyoshi
- Department of Pediatrics, Osaka University Hospital, Suita, Japan
| | - Keiichi Ozono
- Department of Pediatrics, Osaka University Hospital, Suita, Japan
| | - Daiki Abukawa
- Department of Pediatrics, Miyagi Children's Hospital, Sendai, Japan
| | - Takeshi Endo
- Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Stephen Brooks
- Department of Microbiology/Immunology, State University of New York at Buffalo, New York
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
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Qu L, Zhang H, Liu J, Liu T, Shen X, Chen T, Ni Z, Lu C. Potential Susceptibility Mutations in C Gene for Hepatitis B-Related Hepatocellular Carcinoma Identified by a Two-Stage Study in Qidong, China. Int J Mol Sci 2016; 17:1708. [PMID: 27727182 PMCID: PMC5085740 DOI: 10.3390/ijms17101708] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 09/20/2016] [Accepted: 09/26/2016] [Indexed: 12/13/2022] Open
Abstract
A two stage study was conducted to explore new potential mutations in the full genome of hepatitis B virus (HBV) on the progression of hepatocellular carcinoma (HCC) in Qidong, China. In stage 1, full genomes of HBV were compared between 30 HCC cases and 30 controls. In stage 2, an independent case-control study including 100 HCC cases and 100 controls was enrolled to verify the relationship between hot-spot mutations and HCC development. Furthermore, a longitudinal study was conducted on 11 HCC cases with serial serum samples available before HCC diagnosis. A total of 10 mutations (including pre-S2 start codon mutation and pre-S deletion in pre-S gene, G1613A, C1653T, A1762T, and G1764A mutations in X gene, A2159G, A2189Y, G2203W, and C2288R mutations in C gene) showed an increased risk of HCC. In the validation study, pre-S deletion, C1653T, A1762T/G1764A, A2159G, A2189Y, G2203W, and C2288R mutations were associated with increased HCC risk in univariate analysis. Multivariate analysis indicated that pre-S deletion, A1762T/G1764A, A2159G, and A2189Y mutations were independently related with HCC development. Moreover, a significant biological gradient of HCC risk by number of mutations in the C gene was observed. Longitudinal observation demonstrated a gradual combination of the above mutations accumulated during the progression of HCC.
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Affiliation(s)
- Lishuai Qu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, China.
| | - Haifeng Zhang
- Department of Infectious Disease, Affiliated Hospital of Nantong University, Nantong 226001, China.
| | - Jinxia Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, China.
| | - Taotao Liu
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Xizhong Shen
- Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Taoyang Chen
- Qidong Liver Cancer Institute, Qidong 226200, China.
| | - Zhengpin Ni
- Qidong Liver Cancer Institute, Qidong 226200, China.
| | - Cuihua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, China.
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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.
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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
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Loustaud-Ratti V, Jacques J, Debette-Gratien M, Carrier P. Hepatitis B and elders: An underestimated issue. Hepatol Res 2016; 46:22-8. [PMID: 25651806 DOI: 10.1111/hepr.12499] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Revised: 01/17/2015] [Accepted: 02/02/2015] [Indexed: 12/16/2022]
Abstract
As the world's population becomes older, the burden of hepatitis B virus in elderly has to be considered. The liver changes with aging and its function is eventually altered. The prevalence of hepatitis B virus is paradoxically more important in elderly in areas having vaccination programs, because of a loosening of the prevention in older patients. Some differences in hepatitis B presentation must be enhanced in elderly: lower spontaneous hepatitis B surface antigen clearance after a recent contamination, major risk of cirrhosis and hepatocarcinoma. Acute hepatitis B seems to be more often symptomatic, with a great risk of chronicity. Hepatocarcinoma linked to hepatitis B virus has a higher prevalence and a different presentation in elderly. Its treatment is the same as in younger people but is less often possible. Liver transplantation is contraindicated after 70 years old. Hepatitis B treatment panel is the same as in younger people (pegylated interferon, nucleoside or nucleotide agents). It gives identical results with no particular adverse events if the precautions for use are followed. Vaccination is less efficient, as in immunocompromised patients, and needs specific protocols.
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Affiliation(s)
- Véronique Loustaud-Ratti
- Federation of Hepatology, Gastroenterology and Hepatology Unit, CHU Limoges.,INSERM UMR 850, School of Medicine, Limoges, France
| | - Jérémie Jacques
- Federation of Hepatology, Gastroenterology and Hepatology Unit, CHU Limoges
| | | | - Paul Carrier
- Federation of Hepatology, Gastroenterology and Hepatology Unit, CHU Limoges
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10
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Suppiah J, Mohd Zain R, Bahari N, Haji Nawi S, Saat Z. G1896A Precore Mutation and Association With HBeAg Status, Genotype and Clinical Status in Patients With Chronic Hepatitis B. HEPATITIS MONTHLY 2015; 15:e31490. [PMID: 26587040 PMCID: PMC4644636 DOI: 10.5812/hepatmon.31490] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Revised: 08/17/2015] [Accepted: 08/19/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Precore stop codon (G1896A) mutation is one of the commonest mutations found in patients with chronic hepatitis B. However, over the years, this mutation was not reported much in Malaysia. OBJECTIVES We therefore investigated the presence of G1896A mutation in Malaysian population and its association with HBeAg status, clinical stage, hepatitis B virus (HBV) genotype and e-seroconversion rate. PATIENTS AND METHODS Serum samples from 93 patients confirmed as hepatitis B carriers were collected for molecular assay. The whole genome of HBV was amplified by polymerase chain reaction and directly sequenced. The precore and basal core promoter regions were analyzed for presence of mutations. RESULTS The most commonly observed mutation in the precore region was C1858T with 64.5% prevalence. The precore mutation of interest (G1896A) was identified in 25.8% of isolates. The basal core promoter mutations detected were A1762T-G1764A (26.9%), C1653T (8.6%), A1752G (10.8%) and C1766T (2.2%). No significant association was observed between G1896A mutation and HBeAg-negativity. Nonetheless, G1896A was highly prevalent among HBV genotype B. Clinical association revealed that subjects with G1896A mutations were mainly detected in asymptomatic chronic hepatitis B (58.3%) and liver cirrhosis (41.7%). One subject was diagnosed with fulminant hepatitis (4.2%) and 8.3% had hepatocellular carcinoma (HCC). CONCLUSIONS Our data suggested an intermediate prevalence of G1896A mutation among Malaysian hepatitis B carriers. The stop codon mutation has a significant association with genotype B and patients with chronic hepatitis B and liver cirrhosis.
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Affiliation(s)
- Jeyanthi Suppiah
- Virology Unit, Institute for Medical Research, Kuala Lumpur, Malaysia
- Corresponding Author: Jeyanthi Suppiah, Virology Unit, Institute for Medical Research, Jln Pahang, 50588 Kuala Lumpur, Malaysia. Tel: +60-326162674, E-mail:
| | | | | | | | - Zainah Saat
- Virology Unit, Institute for Medical Research, Kuala Lumpur, Malaysia
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11
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Xu H, Zhao M, Lou G, Zheng M, Cao Q, Chen Z. New point mutations in surface and core genes of hepatitis B virus associated with acute on chronic liver failure identified by complete genomic sequencing. PLoS One 2015; 10:e0123139. [PMID: 25849554 PMCID: PMC4388673 DOI: 10.1371/journal.pone.0123139] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 02/17/2015] [Indexed: 12/30/2022] Open
Abstract
The objective of this study was to identify new viral biomarkers associated with acute on chronic liver failure (ACLF) by complete genomic sequencing of HBV. Hepatitis B virus mutations associated with ACLF were screened by Illumina high-throughput sequencing in twelve ACLF cases and twelve age-matched mild chronic hepatitis B patients, which were validated in 438 chronic hepatitis B patients (80 asymptomatic carriers, 152 mild chronic hepatitis B patients, 102 severe chronic hepatitis B patients and 104 ACLF patients) by direct sequencing. The results of Illumina sequencing showed that the mutations at 7 sites (T216C, G285A, A1846T, G1896A, C1913A/G, A2159G, and A2189C) of 12 ACLF patients were significantly higher than those of 12 controls. In the validation cohorts, a significantly higher ratio of genotype B to C was found in patients with ACLF than in patients with non-ACLF. Multivariate analysis showed that T216C, G1896A, C1913A/G and A2159G/C were independent risk factors for ACLF. C216 in any combination, A/G1913 in any combination, and G/C2159 in any combination had high specificity for ACLF. In summary, T216C and A2159G/C mutations were novel factors independently associated with ACLF. Combined mutations in hepatitis B cases could play important roles in ACLF development.
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Affiliation(s)
- Hangdi Xu
- Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
| | - Mingfei Zhao
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Guohua Lou
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China
| | - Min Zheng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China
| | - Qingyi Cao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Institute of Infectious Diseases, First Affiliated Hospital, School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang, China
- * E-mail:
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12
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Wu JF, Ni YH, Chen HL, Hsu HY, Chang MH. The impact of hepatitis B virus precore/core gene carboxyl terminal mutations on viral biosynthesis and the host immune response. J Infect Dis 2013; 209:1374-81. [PMID: 24273041 DOI: 10.1093/infdis/jit638] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND We aimed to elucidate the impact of hepatitis B virus (HBV) precore/core gene mutations on spontaneous hepatitis B e antigen (HBeAg) seroconversion, HBV biosynthesis, and the human immune responses in chronic HBV-infected patients. METHODS We analyzed the HBV precore/core gene sequences by cloning method in 33 chronic HBV-infected patients during the inflammatory phase before spontaneous HBeAg seroconversion. The impact of the most prevalent mutant on HBeAg biosynthesis was assessed by Western blotting and native agarose gel analysis in Huh7 cells, and the human immune responses were assessed by in vitro stimulation of CD3+ CD8+ T lymphocytes of chronic HBV-infected subjects. RESULTS The P135Q and G1896A were the most prevalent mutants before HBeAg seroconversion, acting as markers of HBeAg seroconversion (hazard ratios = 2.75 and 4.50; P = .01 and <.001, respectively). The P135Q mutants displayed decreased HBeAg secretion and HBV capsid molecular weight, while showing increased 22 kD HBeAg proprotein accumulation in Huh7 cells. The P135Q mutant peptide induced less interferon-γ expression in CD3+ CD8+ T lymphocytes in HBeAg-negative subjects compared to the wild-type peptide (P = .03). CONCLUSIONS The HBV P135Q mutant emergence during the inflammatory phase was associated with HBeAg seroconversion. It was associated with altered HBV capsid assembly, HBeAg biosynthesis, and reduced human immune responses following HBeAg seroconversion.
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13
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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.
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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
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14
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Kim D, Lyoo KS, Smith D, Hur W, Hong SW, Sung PS, Yoon SK, Mehta S. Number of mutations within CTL-defined epitopes of the hepatitis B Virus (HBV) core region is associated with HBV disease progression. J Med Virol 2012; 83:2082-7. [PMID: 22012714 DOI: 10.1002/jmv.22226] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The virologic determinants of progressive liver disease associated with hepatitis B virus (HBV) remain unclear. Previous investigations have associated HBV disease with specific mutations but this association may be confounded by HBV genotype, HLA haplotype of the infected individual or both. The association between non-synonymous mutations located within putative cytotoxic T-lymphocyte directed epitopes (CDE) of the HBV core region and disease states was investigated. Subjects infected with HBV were enrolled from a clinical cohort in Seoul, Korea, and HBV core gene sequences were analyzed for mutational patterns inside and outside of CDE with respect to subject demographics and HBV-related disease states. No specific mutation or pattern of mutations were associated with progressive disease states; however, individuals with cirrhosis and hepatocellular carcinoma had greater numbers of non-synonymous mutations within CDE when compared to those with chronic HBV infection who were HBeAg positive (P = 0.007 and 0.026, respectively). In conclusion, this study demonstrates that HBV disease progression is associated with viral escape mutations that are a marker of CTL activity. These data suggest that the number of non-synonymous mutations in the HBV core region may predict HBV disease progression better than any single mutation or pattern of mutations.
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Affiliation(s)
- Daniel Kim
- University of California, La Jolla, CA, USA
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15
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Han YF, Zhao J, Ma LY, Yin JH, Chang WJ, Zhang HW, Cao GW. Factors predicting occurrence and prognosis of hepatitis-B-virus-related hepatocellular carcinoma. World J Gastroenterol 2011; 17:4258-70. [PMID: 22090781 PMCID: PMC3214700 DOI: 10.3748/wjg.v17.i38.4258] [Citation(s) in RCA: 65] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2011] [Revised: 07/12/2011] [Accepted: 07/19/2011] [Indexed: 02/06/2023] Open
Abstract
Primary liver cancer is an important cause of cancer death, and hepatocellular carcinoma (HCC) accounts for 70%-85% of total liver cancer worldwide. Chronic hepatitis B virus (HBV) infection contributes to > 75% of HCC cases. High serum viral load is the most reliable indicator of viral replication in predicting development of HCC. HBV genotype C is closely associated with HCC in cirrhotic patients aged > 50 years, whereas genotype B is associated with development of HCC in non-cirrhotic young patients and postoperative relapse of HCC. Different HBV subgenotypes have distinct patterns of mutations, which are clearly associated with increased risk of HCC. Mutations accumulate during chronic HBV infection and predict occurrence of HCC. Chronic inflammation leads to increased frequency of viral mutation via cellular cytidine deaminase induction. Mutations are negatively selected by host immunity, whereas some immuno-escaped HBV mutants are active in hepatocarcinogenesis. Inflammatory pathways contribute to the inflammation-necrosis-regeneration process, ultimately HCC. Their hallmark molecules can predict malignancy in HBV-infected subjects. Continuing inflammation is involved in hepatocarcinogenesis and closely related to recurrence and metastasis. HBV load, genotype C, viral mutations and expression of inflammatory molecules in HBV-related HCC tissues are significantly associated with poor prognosis. Imbalance between intratumoral CD8+ T cells and regulatory T cells or Th1 and Th2 cytokines in peritumoral tissues can predict prognosis of HBV-related HCC. These factors are important for developing active prevention and surveillance of HBV-infected subjects who are more likely to develop HCC, or for tailoring suitable treatment to improve survival or postpone postoperative recurrence of HCC.
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16
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Wu JF, Ni YH, Lin YT, Lee TJ, Hsu SHJ, Chen HL, Tsuei DJ, Hsu HY, Chang MH. Human interleukin-10 genotypes are associated with different precore/core gene mutation patterns in children with chronic hepatitis B virus infection. J Pediatr 2011; 158:808-13. [PMID: 21168854 DOI: 10.1016/j.jpeds.2010.11.015] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2010] [Revised: 10/08/2010] [Accepted: 11/02/2010] [Indexed: 01/27/2023]
Abstract
OBJECTIVE To elucidate the association between human interleukin-10 (IL-10) genotypes and hepatitis B virus (HBV) precore/core gene mutation in children with chronic HBV infection. STUDY DESIGN The study group comprised of 21 children with chronic HBV infection with spontaneous hepatitis B e antigen (HBeAg) seroconversion who were followed for more than 10 years. Another nine children without HBeAg seroconversion served as the control subjects. Sera at the immune tolerance and inflammatory phase (alanine aminotransferase, >80 IU/L) were subjected to HBV precore/core sequence analysis. IL-10 -1082 polymorphism was also determined. RESULTS HBV precore/core gene mutation increased significantly more in the inflammatory phase than in the tolerance phase (G1896A, 76.2% versus 4.8%; C1913A, 33.3% versus 0%; C2189A, 28.6% versus 4.8%; G2304A, 52.4% versus 14.3%) in study group (n = 21) but not the control group (n = 9). Subjects with the G/G genotype at the IL-10-1082 polymorphism site had higher C2189A mutation rate than the A allele carriers (P = .02). C2189A mutation carriers are associated with more viral load decrement from tolerance to inflammatory phase (P = .01) and earlier spontaneous HBeAg seroconversion (P = .01). CONCLUSIONS The G/G genotype at the IL-10 -1082 polymorphism is associated with higher C2189A mutations, lower HBV viral load at immune inflammatory phase, and earlier spontaneous HBeAg seroconversion than A allele carriers.
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Affiliation(s)
- Jia-Feng Wu
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
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17
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Ni YH. Natural history of hepatitis B virus infection: pediatric perspective. J Gastroenterol 2011; 46:1-8. [PMID: 20812021 DOI: 10.1007/s00535-010-0304-7] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2010] [Accepted: 07/30/2010] [Indexed: 02/07/2023]
Abstract
Hepatitis B virus (HBV) infection is an important disease globally. Chronic HBV infection may result in serious complications. Its transmission may be either perinatal or horizontal. Perinatal transmission is particularly important after the implementation of a universal vaccination program. Through either route, chronic carrier status is usually established in early childhood. The course of the disease course is determined by the host-virus interaction. The host's immune system initially tolerates the virus, and then gradually attempts to clear it. The virus, on the other hand, tries to avoid host immune system attack by a strategy involving targeted epitope mutations. By generating mutants, the virus can survive attacks from the host's immune system, enabling the infection to persist. Different individuals have different responses to HBV infection; genetic polymorphisms in cytokines, hormones, and other immune modulators may affect the final outcome of chronic HBV infection. Due to the implementation of a universal infant HBV vaccination program, HBV infection is now under control. Unfortunately, there still are some cases of vaccination failure. Very high maternal viremia, in utero infection, or escape mutants are possible reasons for vaccination failure. Immunocompromised hosts also risk vaccination failure. Blood or organ donors with occult HBV infection are possible sources for immunocompromised hosts. These victims of vaccination failure may exhibit a different disease course due to chronic HBV infection from those who acquired the infection before the universal vaccination era. The achievement of our ultimate goal of HBV elimination depends on a globally effective universal vaccination program, as well as the application of some novel successful medications to control those who are already infected.
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Affiliation(s)
- Yen-Hsuan Ni
- Department of Pediatrics, College of Medicine and Children's Hospital, National Taiwan University, 8 Chung-Shan South Road, Taipei, Taiwan.
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18
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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.
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Affiliation(s)
- Yu Zhu
- Shanghai Medical College, Fudan University, Shanghai, China
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19
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Huang HP, Hsu HY, Chen CL, Ni YH, Wang HY, Tsuei DJ, Chiang CL, Tsai YC, Chen HL, Chang MH. Pre-S2 deletions of hepatitis B virus and hepatocellular carcinoma in children. Pediatr Res 2010; 67:90-4. [PMID: 19816238 DOI: 10.1203/pdr.0b013e3181c1b0b7] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The cause of early oncogenesis in hepatitis B virus (HBV)-related childhood hepatocellular carcinoma (HCC) remains unclear. This study investigated whether pre-S deletion of HBV is related to childhood HCC. By using nested polymerase chain reaction, we compared the pre-S sequence of HBV from sera of children with HCC against control children with similar chronic HBV infection. The HBV in sera of children with HCC had a significantly higher rate of pre-S deletion than that of children with chronic HBV infection (p = 0.008). All except one of the pre-S deletions from the HCC group involved the pre-S2 region, whereas no pre-S2 deletion was found in the chronic HBV group (p = 0.003). There was a trend whereby genotype-C sera had a higher rate of pre-S2 deletion than genotype-B sera (p = 0.11). A multivariate logistic regression model revealed that pre-S deletion was an independent risk factor for HCC in children (odds ratio: 36.69, p = 0.015). In conclusion, pre-S2 deletion does not need to take decades to occur; its presence in nearly half of children with HCC, in contrast to its absence in children with chronic HBV infection, suggests a link between pre-S2 deletion and HCC development in children.
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Affiliation(s)
- Hsiang-Po Huang
- Department of Medical Research, National Taiwan University Hospital, Taipei 100, Taiwan
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20
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Liu S, Zhang H, Gu C, Yin J, He Y, Xie J, Cao G. Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis. J Natl Cancer Inst 2009; 101:1066-82. [PMID: 19574418 PMCID: PMC2720989 DOI: 10.1093/jnci/djp180] [Citation(s) in RCA: 327] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background The association between hepatitis B virus (HBV) mutations and hepatocarcinogenesis remains controversial because of conflicting data in the literature. We conducted a meta-analysis of case–control and cohort studies to examine HBV PreS, enhancer II (EnhII), basal core promoter (BCP), and precore mutations in relation to the risk of hepatocellular carcinoma (HCC). Methods We searched databases for studies of these associations that were published in English or Chinese up to August 31, 2008. HBV mutation–specific odds ratios and relative risks were pooled by use of a random-effects model and stratified by potential confounders. All statistical tests were two-sided. Results Of the 43 studies included in this meta-analysis, 40 used a case–control design. The 43 studies evaluated a total of 11 582 HBV-infected participants, of whom 2801 had HCC. Statistically significant summary odds ratios of HCC were obtained for any PreS mutation (3.77, 95% confidence interval [CI] = 2.57 to 5.52), C1653T in EnhII (2.76, 95% CI = 2.09 to 3.64), T1753V (2.35, 95% CI = 1.63 to 3.40), and A1762T/G1764A in BCP (3.79, 95% CI = 2.71 to 5.29). PreS mutations were more strongly associated with an increased risk of HCC in subjects who were infected with HBV genotype C than in those who were infected with HBV genotype B, whereas the opposite was true for A1762T/G1764A. C1653T, T1753V, and A1762T/G1764A were more strongly associated with an increased risk of HCC in hepatitis B e antigen (HBeAg)–positive subjects than in HBeAg-negative subjects. PreS mutations, C1653T, T1753V, and A1762T/G1764A accumulated during the progression of chronic HBV infection from the asymptomatic carrier state to HCC (Ptrend < .001 for each mutation). PreS mutations, C1653T, C1653T + T1753V, and A1762T/G1764A-based combinations of mutations had specificities greater than 80% for the prediction of HCC. The precore mutations G1896A and C1858T were not associated with the risk of HCC, regardless of HBeAg status and HBV genotype. Conclusions HBV PreS mutations, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC. These mutations alone and in combination may be predictive for hepatocarcinogenesis.
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Affiliation(s)
- Shijian Liu
- Department of Epidemiology, Second Military Medical University, 800 Xiang-yin Road, Shanghai, China
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21
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Liu S, Zhang H, Gu C, Yin J, He Y, Xie J, Cao G. Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis. J Natl Cancer Inst 2009. [PMID: 19574418 DOI: 10.1093/jnci/djp180.] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND The association between hepatitis B virus (HBV) mutations and hepatocarcinogenesis remains controversial because of conflicting data in the literature. We conducted a meta-analysis of case-control and cohort studies to examine HBV PreS, enhancer II (EnhII), basal core promoter (BCP), and precore mutations in relation to the risk of hepatocellular carcinoma (HCC). METHODS We searched databases for studies of these associations that were published in English or Chinese up to August 31, 2008. HBV mutation-specific odds ratios and relative risks were pooled by use of a random-effects model and stratified by potential confounders. All statistical tests were two-sided. RESULTS Of the 43 studies included in this meta-analysis, 40 used a case-control design. The 43 studies evaluated a total of 11 582 HBV-infected participants, of whom 2801 had HCC. Statistically significant summary odds ratios of HCC were obtained for any PreS mutation (3.77, 95% confidence interval [CI] = 2.57 to 5.52), C1653T in EnhII (2.76, 95% CI = 2.09 to 3.64), T1753V (2.35, 95% CI = 1.63 to 3.40), and A1762T/G1764A in BCP (3.79, 95% CI = 2.71 to 5.29). PreS mutations were more strongly associated with an increased risk of HCC in subjects who were infected with HBV genotype C than in those who were infected with HBV genotype B, whereas the opposite was true for A1762T/G1764A. C1653T, T1753V, and A1762T/G1764A were more strongly associated with an increased risk of HCC in hepatitis B e antigen (HBeAg)-positive subjects than in HBeAg-negative subjects. PreS mutations, C1653T, T1753V, and A1762T/G1764A accumulated during the progression of chronic HBV infection from the asymptomatic carrier state to HCC (P(trend) < .001 for each mutation). PreS mutations, C1653T, C1653T + T1753V, and A1762T/G1764A-based combinations of mutations had specificities greater than 80% for the prediction of HCC. The precore mutations G1896A and C1858T were not associated with the risk of HCC, regardless of HBeAg status and HBV genotype. CONCLUSIONS HBV PreS mutations, C1653T, T1753V, and A1762T/G1764A are associated with an increased risk of HCC. These mutations alone and in combination may be predictive for hepatocarcinogenesis.
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Affiliation(s)
- Shijian Liu
- Department of Epidemiology, Second Military Medical University, 800 Xiang-yin Road, Shanghai, China
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22
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Choi JW, Ahn SH, Park JY, Chang HY, Kim JK, Baatarkhuu O, Kim DY, Han KH, Chon CY. Hepatitis B e antigen-negative mutations in the precore and core promoter regions in Korean patients. J Med Virol 2009; 81:594-601. [PMID: 19235871 DOI: 10.1002/jmv.21452] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Most patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B have variants of the hepatitis B virus (HBV) that include mutations in the precore or core promoter regions of the HBV genome. The aim of this study was to investigate the patterns of precore and core promoter mutations and their relationship to HBeAg expression in Korean patients. Four hundred seventy-five Korean patients with chronic HBV infection between February 1995 and December 2003 were enrolled in this study. There were 236 HBeAg-positive and 239 HBeAg-negative patients. Blood samples were tested for HBsAg, anti-HBs, HBeAg, hepatitis B e antibody (anti-HBe), liver function tests, and serum HBV DNA. Mutations in the precore and core promoter regions were determined by direct sequencing. In the core promoter region, the C1740, C1753, T1762/A1764, and T1766 mutations were associated with HBeAg escape (all; P < 0.05). In the precore region, a higher frequency of the C1802, A1828, T1846, A1850, C1858, T1862, and A1896 mutations was found in HBeAg-negative patients (all; P < 0.05). In particular, the A1896 mutation was associated with high serum levels of ALT and HBV DNA in HBeAg-negative patients (P = 0.014 and 0.026, respectively). Mutations around the Kozak sequence (nucleotides 1809-1812) were found in 6.7% of patients and were not associated with undetectable HBeAg (P = 0.13). In Korean patients, various mutations in the precore and core promoter regions were associated with HBeAg escape and amelioration of hepatic inflammation in HBeAg- negative patients. Only the A1896 mutation contributed to HBeAg-negative chronic hepatitis B.
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Affiliation(s)
- Jong Won Choi
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea
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Chang MH. Natural history and clinical management of chronic hepatitis B virus infection in children. Hepatol Int 2008; 2:28-36. [PMID: 19669296 DOI: 10.1007/s12072-008-9050-9] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2007] [Accepted: 01/20/2008] [Indexed: 01/17/2023]
Abstract
Hepatitis B virus (HBV) infection may cause acute, fulminant, or chronic hepatitis, leading to liver cirrhosis or hepatocellular carcinoma. Despite the availability of effective vaccine, HBV infection during infancy or early childhood is common in areas of high endemicity. In these regions, mother-to-infant transmission accounts for approximately 50% of chronic infections. Although the natural history of HBV infection in adults is well characterized, little information is available in the literature regarding the natural history of HBV infection in children. Similar to infection in adults, chronic HBV infection in children can be divided into distinct phases: immune tolerant, immune clearance, and inactive carrier state. However, acute exacerbation, with reactivation of HBV replication and re-elevation of alanine aminotransferase levels after hepatitis B e antigen seroconversion, is relatively rare in children, in comparison to adults. Although several potent antiviral agents are now available for the treatment of chronic hepatitis B, experience with these agents in the pediatric setting is limited. To date, conventional interferon alpha and lamivudine are the only two antiviral agents approved to treat chronic hepatitis B in children. The rapid emergence of resistant HBV associated with long-term lamivudine therapy, as well as poor tolerability associated with conventional interferon alpha, are factors that should be considered before initiating antiviral therapy. This article reviews current knowledge regarding the natural history and treatment of chronic hepatitis B in children. Factors that affect the natural history of HBV infection in children are also reviewed.
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Affiliation(s)
- Mei-Hwei Chang
- Division of Gastroenterology and Hepatology, Department of Pediatrics, National Taiwan University Hospital, No. 7, Chung-Shan S. Road, Taipei, Taiwan,
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Sugiyama M, Tanaka Y, Kurbanov F, Nakayama N, Mochida S, Mizokami M. Influences on hepatitis B virus replication by a naturally occurring mutation in the core gene. Virology 2007; 365:285-91. [PMID: 17498766 DOI: 10.1016/j.virol.2007.04.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2006] [Revised: 01/10/2007] [Accepted: 04/07/2007] [Indexed: 01/05/2023]
Abstract
Little is known about specific naturally occurring mutations of hepatitis B virus (HBV) and underlying mechanisms of their association with fulminant hepatitis. A HBV clone isolated from a patient with fulminant hepatitis was analyzed, and the features of the particular mutations observed around furin cleavage site in core region (A2339G/G2345A) were assessed using an in vitro replication model. The clone belonged to genotype B with precore stop codon mutation (G1896A). Replication efficiency of 1.24-fold HBV genome in Huh-7 cells was increased in the presence of A2339G. Further in vitro studies using furin inhibitor indicated that the effect of the mutation was probably associated with accumulation of the full-length core protein without cleavage by furin-like protease, suggesting that a processing of the core protein might play an important role in regulation of viral replication. In conclusion, the A2339G mutation was considered as one of the viral factors involved in high replication efficiency.
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Affiliation(s)
- Masaya Sugiyama
- Department of Clinical Molecular Informative Medicine, Nagoya City University Graduate School of Medical Sciences, Kawasumi, Mizuho, Nagoya 467-8601, Japan
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Tong MJ, Blatt LM, Kao JH, Cheng JT, Corey WG. Precore/basal core promoter mutants and hepatitis B viral DNA levels as predictors for liver deaths and hepatocellular carcinoma. World J Gastroenterol 2006; 12:6620-6. [PMID: 17075974 PMCID: PMC4125666 DOI: 10.3748/wjg.v12.i41.6620] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To conduct a retrospective study in 400 chronic hepatitis B patients in order to identify hepatitis B viral factors associated with complications of liver disease or development of hepatocellular carcinoma.
METHODS: The mean follow-up time was 83.6 ± 39.6 mo. Alpha-fetoprotein test and abdominal ultrasound were used for cancer surveillance. Hepatitis B basal core promoter mutants, precore mutants, genotypes, hepatitis B viral DNA (HBV DNA) level and hepatitis B e antigen (HBeAg) were measured. Univariate analysis and logistic regression were used to assess odds ratios for viral factors related to liver deaths and hepatocellular carcinoma development.
RESULTS: During follow-up, 38 patients had liver deaths not related to hepatocellular carcinoma. On multivariate analysis, older age [odds ratio: 95.74 (12.13-891.31); P < 0.0001], male sex [odds ratio: 7.61 (2.20-47.95); P = 0.006], and higher log10 HBV DNA [odds ratio: 4.69 (1.16-20.43); P < 0.0001] were independently predictive for these liver related deaths. Also, 31 patients developed hepatocellular carcinoma. Multivariate analysis showed that older age [odds ratio: 26.51 (2.36-381.47); P = 0.007], presence of precore mutants [odds ratio: 4.23 (1.53-19.58); P = 0.02] and presence of basal core promoter mutants [odds ratio: 2.93 (1.24-7.57); P = 0.02] were independent predictors for progression to hepatocellular carcinoma.
CONCLUSION: Our results show that high levels of baseline serum HBV DNA are associated with non-hepatocellular carcinoma-related deaths of liver failure, while genetic mutations in the basal core promoter and precore regions are predictive for development of hepatocellular carcinoma.
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Affiliation(s)
- Myron J Tong
- Liver Center, Huntington Medical Research Institutes, 660 South Fair Oaks Avenue, Pasadena, California 91105, United States.
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Kang H, Lee S, Park S, Yu J, Kim Y, Jung G. Phosphorylation of hepatitis B virus Cp at Ser87 facilitates core assembly. Biochem J 2006; 398:311-7. [PMID: 16740137 PMCID: PMC1550306 DOI: 10.1042/bj20060347] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2006] [Revised: 05/31/2006] [Accepted: 06/02/2006] [Indexed: 01/20/2023]
Abstract
Protein-protein interactions can be regulated by protein modifications such as phosphorylation. Some of the phosphorylation sites (Ser155, Ser162 and Ser170) of HBV (hepatitis B virus) Cp have been discovered and these sites are implicated in the regulation of viral genome encapsidation, capsid localization and nucleocapsid maturation. In the present report, the dimeric form of HBV Cp was phosphorylated by PKA (protein kinase A), but not by protein kinase C in vitro, and the phosphorylation of dimeric Cp facilitated HBV core assembly. Matrix-assisted laser-desorption ionization-time-of-flight analysis revealed that the HBV Cp was phosphorylated at Ser87 by PKA. This was further confirmed using a mutant HBV Cp with S87G mutation. The S87G mutation inhibited the phosphorylation and, as a result, the in vitro HBV core assembly was not facilitated by PKA. In addition, when either pCMV/FLAG-Core(WT) or pCMV/FLAG-Core(S87G) was transfected into HepG2 cells, few mutant Cps (S87G) assembled into capsids compared with the wild-type (WT) Cps, although the same level of total Cps was expressed in both cases. In conclusion, PKA facilitates HBV core assembly through phosphorylation of the HBV Cp at Ser87.
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Key Words
- core protein (cp)
- core assembly
- hepatitis b virus (hbv)
- phosphorylation
- protein kinase a (pka)
- cp, core protein
- fc, flow cell
- hbv, hepatitis b virus
- maldi–tof, matrix-assisted laser-desorption ionization–time-of-flight
- orf, open reading frame
- pka, protein kinase a
- pkc, protein kinase c
- pgrna, pregenomic rna
- ru, response unit
- spr, surface plasmon resonance
- srpk1, serine/arginine protein-specific kinase 1
- tem, transmission electron microscopy
- wt, wild-type
- wt pka, pka-treated wild-type
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Affiliation(s)
- Hee Yong Kang
- *School of Biological Sciences, Seoul National University, Shillim-dong, Seoul 151-742, South Korea
| | - Seungkeun Lee
- *School of Biological Sciences, Seoul National University, Shillim-dong, Seoul 151-742, South Korea
| | - Sung Gyoo Park
- *School of Biological Sciences, Seoul National University, Shillim-dong, Seoul 151-742, South Korea
- †Institute of Microbiology, Seoul National University, Shillim-dong, Seoul 151-742, South Korea
| | - Jaehoon Yu
- ‡Department of Chemistry Education, Seoul National University, Shillim-dong, Seoul 151-742, South Korea
| | - Youngsoo Kim
- §Molecular Genomic Medicine, College of Medicine, Seoul National University, Yongon-dong, Seoul 110-799, South Korea
- ∥Cancer Research Institute, College of Medicine, Seoul National University, Yongon-dong, Seoul 110-799, South Korea
| | - Guhung Jung
- *School of Biological Sciences, Seoul National University, Shillim-dong, Seoul 151-742, South Korea
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Abstract
Due to the lack of proof reading activity of hepatitis B virus (HBV) polymerase, mutation/variation of the viral sequence is frequently found during long term follow-ups. In the majority of children with chronic HBV infection, wild type HBV is the dominant viral strain during the natural course of chronic HBV infection. During long-term follow-up, HBV precore mutants developed spontaneously in approximately 10 to 24% of children before HBeAg seroconversion and in around 50% of children after HBeAg seroconversion mutants. Occasionally, children may be infected primarily by mutant strains of HBV. Approximately 36% of children with fulminant hepatitis and 30% of children with acute hepatitis B were infected by precore mutants of HBV transmitted by their mothers or blood donors. In addition, after universal HBV vaccination, HBV surface gene variants emerge or are selected under the immune pressure generated by the host or by administration of hepatitis B immune globulin and hepatitis B vaccination. In HBV DNA positive children from four sequential surveys in Taiwan, the prevalence of hepatitis B surface gene a determinant mutants increased from 7.8% before the vaccination program, to 19.6%, 28.1% and 23.1% at 5, 10 and 15 years after the program. Nucleoside analogue may also induce mutant strains, which reduces the antiviral effects. The most common example is the YMDD mutation of the HBV polymerase gene after antiviral therapy with lamivudine. It developed in 19% of the treated children. In conclusion, children may be infected primarily by mutant strains of HBV either naturally during acute HBV infection. Those infected with wild type HBV initially may develop mutant strains gradually during the course of chronic infection under the host immune pressure. Vaccine escape mutants may develop after immunoprophylaxis. In addition, antiviral therapy with nucleoside analogues may also induce drug resistant mutant strains. Understanding the viral mutation status will help to design accurate strategies of immmunoprophylaxis and antiviral therapy against HBV infection.
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Affiliation(s)
- Mei-Hwei Chang
- Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan
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Szmaragd C, Nichols RA, Balloux F. A novel approach to characterise pathogen candidate genetic polymorphisms involved in clinical outcome. INFECTION GENETICS AND EVOLUTION 2006; 6:38-45. [PMID: 16376839 DOI: 10.1016/j.meegid.2005.01.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2004] [Revised: 01/10/2005] [Accepted: 01/10/2005] [Indexed: 01/05/2023]
Abstract
Understanding the key factors influencing the clinical outcome of an infection is crucial for early diagnosis and optimised treatment. Despite widespread recognition of the importance of the genetics composition of pathogens, most efforts so far have focused on characterising disease and susceptibility genes in humans. Here, we propose a new flexible and powerful methodological framework to detect candidate genetic polymorphisms influencing clinical outcome from pathogen genomes. The rationale is to use well-supported clades in a phylogeny as statistical predictors for clinical outcomes rather than the individual polymorphisms themselves. This greatly increases the statistical power to detect candidate polymorphisms when analysing a large number of variable sites. In a second step, the candidate polymorphisms are recovered by characterising the polymorphisms that most strongly support the clades predicting the clinical outcome. The modelling approach further allows including host factors and testing for possible interactions between factors. We illustrate the approach by an application on a dataset of hepatitis B polymerase genes. The statistical model retains age at infection as well as six candidate polymorphisms as predictors for clinical outcome (acute, chronic and fulminant). The method is straightforward to apply and computationally effective. While the approach is focused on detecting candidate polymorphisms from pathogen genomes, the method might be more broadly applied for characterising the link between genotype and phenotype while statistically controlling for environmental factors.
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Affiliation(s)
- Camille Szmaragd
- Theoretical and Molecular Population Genetics Group, Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
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Yang HZ, Zhao JA, Dai M, Li YW, Wang YZ, Guan WB, Xie HP. Traditional Chinese medicine syndromes of chronic hepatitis B with precore mutant. World J Gastroenterol 2005; 11:2004-8. [PMID: 15800995 PMCID: PMC4305726 DOI: 10.3748/wjg.v11.i13.2004] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: This study aims at exploring the distribution of TCM syndromes in CHB patients with HBV pre-core mutation (1896) and the relationship between pre-core mutation and T lymphocytes subgroup, through which to provide objective data on clinical syndrome differentiation of TCM, and further to suggest the therapeutic principle and guide clinical treatment.
METHODS: One hundred and forty CHB patients were evenly divided into two study groups, HBV pre-core mutant group and HBV pre-core wild-type group. Besides, 30 healthy blood donors were selected as a healthy control group. HBV-labeled compound, T lymphocytes subgroup, and HBV-DNA pre-core mutant were tested in the study groups. T lymphocytes subgroup were also tested in the control group. All the patients were both diagnosed by syndrome differentiation of TCM and western medicine.
RESULTS: The most common syndrome in mutant group was damp-heat combined with blood stasis, and the most common syndrome in the wild-type group was damp-heat stasis in the middle-jiao. There were more cases of medium and severe hepatitis in mutant group than that in wild-type group. The content of CD4+ lymphocytes and CD4+/CD8+ ratio were decreased gradually (healthy control group>wild-type group>mutant group). In the wild-type group, severe and medium CHB patients had considerably lower level of them than mild CHB patients. However, in the mutant group, the opposite result appeared. Meanwhile, the content of HBV-DNA in mutant group was higher than that in wild-type group.
CONCLUSION: Damp, heat, toxin and blood stasis were the basic pathogens of CHB, whether pre-core mutant or not. CHB with precore mutant may lead to more severe hepatitis. The decreased content of CD4+ lymphocytes and ratio of CD4+/CD8+ may be taken as one of the indices in confirming the deficiency syndrome of CHB patients with pre-core mutation.
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Affiliation(s)
- Hong-Zhi Yang
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, Guangdong Province, China.
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Affiliation(s)
- Eve A Roberts
- Division of Gastroenterology and Nutrition, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
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Hong Y, Liu Y, Cheng J, Yang Q, Wang JJ. Genes trans-regulated by C-terminally truncated middle surface protein of hepatitis B virus with microarray assay. Shijie Huaren Xiaohua Zazhi 2003; 11:943-946. [DOI: 10.11569/wcjd.v11.i7.943] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To study of genes trans-regulated by C-terminally truncated middle surface protein of hepatitis B virus by microarray.
METHODS The recombined expression plasmid pcDNA3.1(-)-MHBst was constructed, and HepG2 cells were transfected. Total mRNA was isolated from the HepG2 cells transfected with pcDNA3.1(-) and pcDNA3-MHBst, respectively. Microarray was employed for detecting and analyzing of both mRNA from the HepG2 cells.
RESULTS After transfecting HepG2 cells, it was found 14 genes had been up-regulated, and 23 genes down-regulated. Their encoding proteins were involved in cell signal transduction, cell proliferation and differentiation.
CONCLUSION Microarray technology is successfully used to screen the genes trans-regulated by C-terminally truncated middle surface protein of hepatitis B virus, which brings some new clues for studying the trans-regulated and immune regulation mechanism of MHBst.
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Affiliation(s)
- Yuan Hong
- Gene Therapy Research Center, Institute of Infectious Diseases, 302 Hospital of PLA, Beijing 100039, China
| | - Yan Liu
- Gene Therapy Research Center, Institute of Infectious Diseases, 302 Hospital of PLA, Beijing 100039, China
| | - Jun Cheng
- Gene Therapy Research Center, Institute of Infectious Diseases, 302 Hospital of PLA, Beijing 100039, China
| | - Qian Yang
- Gene Therapy Research Center, Institute of Infectious Diseases, 302 Hospital of PLA, Beijing 100039, China
| | - Jian-Jun Wang
- Gene Therapy Research Center, Institute of Infectious Diseases, 302 Hospital of PLA, Beijing 100039, China
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