隐匿性乙型肝炎病毒发生分子机制的研究进展
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摘要
隐匿性乙型肝炎病毒感染(OBI)指用高灵敏度的核酸检测可在HBsAg阴性感染者肝组织中检测到HBV DNA。本文介绍了OBI形成的基因分子机制:s、p、x和c基因的开放阅读框突变、起始密码子和终止密码子突变;基因调控序列突变影响转录过程及转录后调控;表观遗传调控。目前OBI个体HBV复制、基因表达过程中的表观遗传调控研究尚处于起步阶段,研究前景广阔。此外,本文对欧洲、南非、东南亚以及中国献血者OBI形成的基因分子生物学机制进行了梳理和汇总。
Occult hepatitis B virus infection(OBI) means that HBV DNA can be detected in liver tissues of HBsAg negative infected people with highly sensitive nucleic acid detection. This paper introduces the gene molecular mechanism of OBI formation: open reading frame mutation, initiation codon and termination codon mutations of s, p, x and c genes; effect of mutations of gene regulatory sequences on transcriptional processes and post-transcriptional regulation;epigenetic regulation. At present, the studies on epigenetic regulation during the process of HBV replication and gene expression in OBI individuals are still in its infancy, with broad research prospect. In addition, this paper summarizes the gene molecular mechanisms of OBI formation in blood donors of Europe, South Africa, Southeast Asia and China.
Occult hepatitis B virus infection(OBI) means that HBV DNA can be detected in liver tissues of HBsAg negative infected people with highly sensitive nucleic acid detection. This paper introduces the gene molecular mechanism of OBI formation: open reading frame mutation, initiation codon and termination codon mutations of s, p, x and c genes; effect of mutations of gene regulatory sequences on transcriptional processes and post-transcriptional regulation;epigenetic regulation. At present, the studies on epigenetic regulation during the process of HBV replication and gene expression in OBI individuals are still in its infancy, with broad research prospect. In addition, this paper summarizes the gene molecular mechanisms of OBI formation in blood donors of Europe, South Africa, Southeast Asia and China.
引文
[1]Makvandi M. Update on occult hepatitis B virus infection[J].World J Gastroenterol,2016,22(39):8720-8734.
[2]陈钦艳,李生,杨进业,等.乙型肝炎病毒新基因型Ⅰ与肝脏疾病关系的研究[J].广西医学,2014,36(1):1-4.
[3]Gencay M,Vermeulen M,Neofytos D,et al. Substantial variation in the hepatitis B surface antigen(HBs Ag)in hepatitis B virus(HBV)-positive patients from South Africa:Reliable detection of HBV by the Elecsys HBsAgⅡassay[J]. J Clin Virol,2018,101:38-43.
[4]Kim MH,Kang SY,Lee WI. Occult HBV among Anti-HBc Alone:Mutation Analysis of an HBV Surface Gene and Pre-S Gene[J]. Yonsei Med J,2017,58(3):557-563.
[5]Zhang K,Liu Y,Chen R,et al. Antigenicity reduction contributes mostly to poor detectability of HBsAg by hepatitis B virus(HBV)S-gene mutants isolated from individuals with occult HBV infection[J]. J Med Virol,2018,90(2):263-270.
[6]Chen J,Liu Y,Zhao J,et al. Characterization of novel hepatitis B virus pre S/S-gene mutations in a patient with occult hepatitis B virus infection[J]. PLoS One,2016,11(5):e0155654.
[7]Lusida MI,Juniastuti,Yano Y. Current hepatitis B virus infection situation in Indonesia and its genetic diversity[J].World J Gastroenterol,2016,22(32):7264-7274.
[8]Bes M,Vargas V,Piron M,et al. T cell responses and viral variability in blood donation candidates with occult hepatitis B infection[J]. J Hepatol,2012,56(4):765-774.
[9]Rastegarv N,Makvandi M,Samarbafzadeh A,et al. Molecular Characterization of Pre-Core/Core and S Region of Hepatitis B Virus in Hemodialysis Patients With Occult Hepatitis B Infection[J]. Jundishapur J Microbiol,2015,8(10):1-5.
[10]Liao H,Liu Y,Chen J,et al. Characterization of hepatitis B virus(HBV)preS/S gene mutations in blood donors with occult HBV infection in the Baoji area of North China[J]. Transfusion,2017,57(3pt2):857-866.
[11]涂东晋,赵亮,林授,等.福州地区献血者人群隐匿性乙型肝炎病毒感染及其基因型与S区突变的研究[J].中国输血杂志,2015,28(5):523-528.
[12]王晓存,王立杰,吴军.乙型病毒性肝炎隐匿性感染与S基因氨基酸变异的研究[J].职业与健康,2015,31(7):931-934.
[13]Kim H,Lee SA,Won YS,et al. Occult infection related hepatitis B surface antigen variants showing lowered secretion capacity[J]. World J Gastroenterol,2015,21(6):1794-1803.
[14]Rendon JC,Cortes-Mancera F,Restrepo-Gutierrez JC,et al. Molecular characterization of occult hepatitis B virus infection in patients with end-stage liver disease in Colombia[J]. PLoS One,2017,12(7):e0180447.
[15]Kim H,Gong JR,Lee SA,et al. Discovery of a Novel Mutation(X8Del)Resulting in an 8-bp Deletion in the Hepatitis B Virus X Gene Associated with Occult Infection in Korean Vaccinated Individuals[J]. PLoS One,2015,10(10):e0139551.
[16]Fujise K,Tatsuzawa K,Kono M,et al. A mutation of the start codon in the X region of hepatitis B virus DNA in a patient with non-B,non-C chronic hepatitis[J]. World J Hepatol,2011,3(2):56-60.
[17]Chamni N,Louisirirotchanakul S,Oota S,et al. Genetic characterization and genotyping of hepatitis B virus(HBV)isolates from donors with an occult HBV infection[J].Vox Sang,2014,107(4):324-332.
[18]Candotti D,Lin CK,Belkhiri D,et al. Occult hepatitis B infection in blood donors from South East Asia:molecular characterisation and potential mechanisms of occurrence[J]. Gut,2012,61(12):1744-1753.
[19]Wei Y,Neuveut C,Tiollais P,et al. Molecular biology of the hepatitis B virus and role of the X gene[J]. Pathol Biol(Paris),2010,58(4):267-272.
[20]Biswas A,Panigrahi R,Chandra PK,et al. Characterization of the occult hepatitis B virus variants circulating among the blood donors from eastern India[J]. Scientific World Journal,2013,2013:212704.
[21]陈静娜,李婷婷,王镇,等.乙型肝炎病毒核心蛋白区突变与隐匿性乙型肝炎病毒感染的相关性[J].实用医学杂志,2017,33(4):533-537.
[22]刘妍,张凯,陈容娟,等.隐匿性HBV感染患者HBV S基因N-糖基化突变对HBsAg抗原性影响的分析[J].解放军医学杂志,2018,43(5):386-391.
[23]Vivekanandan P,Thomas D,Torbenson M. Hepatitis B viral DNA is methylated in liver tissues[J]. J Viral Hepat,2008,15(2):103-107.
[24]Kaur P,Paliwal A,Durantel D,et al. DNA Methylation of Hepatitis B Virus(HBV)Genome Associated with the Development of Hepatocellular Carcinoma and Occult HBV Infection[J]. J Infect Dis,2010,202(5):700-704.
[25]Vivekanandan P,Kannangai R,Ray SC,et al. Comprehensive Genetic and Epigenetic Analysis of Occult Hepatitis B from Liver Tissue Samples[J]. Clin Infect Dis,2008,46(8):1227-1236.
[26]Raimondo G,Caccamo G,Filomia R,et al. Occult HBV infection[J]. Semin Immunopathol,2013,35(1):39-52.
[27]Hoofnagle JH,Seeff LB,Bales ZB,et al. Type B hepatitis after transfusion with blood containing antibody to hepatitis B core antigen[J]. N Engl J Med,1978,298(25):1379-1383.
[28]Sosa-Jurado F,Hilda Rosas-Murrieta N,Guzman-Flores B,et al. Prevalence of Serologic Hepatitis B Markers in Blood Donors From Puebla,Mexico:The Association of Relatively High Levels of Anti-Core Antibodies With the Detection of Surface Antigen and Genomic DNA[J].Hepat Mon,2016,16(6):e36942.
[29]Kishk R,Nemr N,Elkady A,et al. Hepatitis B surface gene variants isolated from blood donors with overt and occult HBV infection in north eastern Egypt[J]. Virol J,2015,12:153.
[30]Oluyinka OO,Tong HV,Bui Tien S,et al. Occult Hepatitis B Virus Infection in Nigerian Blood Donors and Hepatitis B Virus Transmission Risks[J]. PLoS One,2015,10(7):e0131912.
[31]Liang X,Bi S,Yang W,et al. Epidemiological serosurvey of hepatitis B in China-declining HBV prevalence due to hepatitis B vaccination[J]. Vaccine,2009,27(47):6550-6557.
[32]Zhang K,Liu Y,Chen R,et al. Antigenicity reduction contributes mostly to poor detectability of HBsAg by hepatitis B virus(HBV)S-gene mutants isolated from individuals with occult HBV infection[J]. J Med Virol,2018,90(2):263-270.
[33]王东,邓雪莲,周璐,等.大连地区无偿献血者隐匿性乙型肝炎病毒感染pre-S/S区基因分析[J].中国输血杂志,2015,28(1):26-31.
[34]赵亮,周晓真,涂东晋,等.福州地区HBs Ag-/HBVDNA+献血者乙肝病毒S区MHR变异特征分析[J].中外医疗,2017(23):10-14.
[35]蒋菲菲,吕蓉,李敏,等.华东地区献血者人群隐匿性乙型肝炎病毒感染及S区变异分析[J].中国输血杂志,2017,30(7):762-766.
[36]叶贤林,李彤,孙淑君,等.核心抗体阳性合格献血者隐匿性乙肝病毒感染分子生物学特性及追踪结果的研究[J].中国输血杂志,2016,29(9):890-894.
[37]Dodd RY,Nguyen ML,Krysztof DE,et al. Blood donor testing for hepatitis B virus in the United States:is there a case for continuation of hepatitis B surface antigen detection?[J]. Transfusion,2018,58(9):2166-2170.
[2]陈钦艳,李生,杨进业,等.乙型肝炎病毒新基因型Ⅰ与肝脏疾病关系的研究[J].广西医学,2014,36(1):1-4.
[3]Gencay M,Vermeulen M,Neofytos D,et al. Substantial variation in the hepatitis B surface antigen(HBs Ag)in hepatitis B virus(HBV)-positive patients from South Africa:Reliable detection of HBV by the Elecsys HBsAgⅡassay[J]. J Clin Virol,2018,101:38-43.
[4]Kim MH,Kang SY,Lee WI. Occult HBV among Anti-HBc Alone:Mutation Analysis of an HBV Surface Gene and Pre-S Gene[J]. Yonsei Med J,2017,58(3):557-563.
[5]Zhang K,Liu Y,Chen R,et al. Antigenicity reduction contributes mostly to poor detectability of HBsAg by hepatitis B virus(HBV)S-gene mutants isolated from individuals with occult HBV infection[J]. J Med Virol,2018,90(2):263-270.
[6]Chen J,Liu Y,Zhao J,et al. Characterization of novel hepatitis B virus pre S/S-gene mutations in a patient with occult hepatitis B virus infection[J]. PLoS One,2016,11(5):e0155654.
[7]Lusida MI,Juniastuti,Yano Y. Current hepatitis B virus infection situation in Indonesia and its genetic diversity[J].World J Gastroenterol,2016,22(32):7264-7274.
[8]Bes M,Vargas V,Piron M,et al. T cell responses and viral variability in blood donation candidates with occult hepatitis B infection[J]. J Hepatol,2012,56(4):765-774.
[9]Rastegarv N,Makvandi M,Samarbafzadeh A,et al. Molecular Characterization of Pre-Core/Core and S Region of Hepatitis B Virus in Hemodialysis Patients With Occult Hepatitis B Infection[J]. Jundishapur J Microbiol,2015,8(10):1-5.
[10]Liao H,Liu Y,Chen J,et al. Characterization of hepatitis B virus(HBV)preS/S gene mutations in blood donors with occult HBV infection in the Baoji area of North China[J]. Transfusion,2017,57(3pt2):857-866.
[11]涂东晋,赵亮,林授,等.福州地区献血者人群隐匿性乙型肝炎病毒感染及其基因型与S区突变的研究[J].中国输血杂志,2015,28(5):523-528.
[12]王晓存,王立杰,吴军.乙型病毒性肝炎隐匿性感染与S基因氨基酸变异的研究[J].职业与健康,2015,31(7):931-934.
[13]Kim H,Lee SA,Won YS,et al. Occult infection related hepatitis B surface antigen variants showing lowered secretion capacity[J]. World J Gastroenterol,2015,21(6):1794-1803.
[14]Rendon JC,Cortes-Mancera F,Restrepo-Gutierrez JC,et al. Molecular characterization of occult hepatitis B virus infection in patients with end-stage liver disease in Colombia[J]. PLoS One,2017,12(7):e0180447.
[15]Kim H,Gong JR,Lee SA,et al. Discovery of a Novel Mutation(X8Del)Resulting in an 8-bp Deletion in the Hepatitis B Virus X Gene Associated with Occult Infection in Korean Vaccinated Individuals[J]. PLoS One,2015,10(10):e0139551.
[16]Fujise K,Tatsuzawa K,Kono M,et al. A mutation of the start codon in the X region of hepatitis B virus DNA in a patient with non-B,non-C chronic hepatitis[J]. World J Hepatol,2011,3(2):56-60.
[17]Chamni N,Louisirirotchanakul S,Oota S,et al. Genetic characterization and genotyping of hepatitis B virus(HBV)isolates from donors with an occult HBV infection[J].Vox Sang,2014,107(4):324-332.
[18]Candotti D,Lin CK,Belkhiri D,et al. Occult hepatitis B infection in blood donors from South East Asia:molecular characterisation and potential mechanisms of occurrence[J]. Gut,2012,61(12):1744-1753.
[19]Wei Y,Neuveut C,Tiollais P,et al. Molecular biology of the hepatitis B virus and role of the X gene[J]. Pathol Biol(Paris),2010,58(4):267-272.
[20]Biswas A,Panigrahi R,Chandra PK,et al. Characterization of the occult hepatitis B virus variants circulating among the blood donors from eastern India[J]. Scientific World Journal,2013,2013:212704.
[21]陈静娜,李婷婷,王镇,等.乙型肝炎病毒核心蛋白区突变与隐匿性乙型肝炎病毒感染的相关性[J].实用医学杂志,2017,33(4):533-537.
[22]刘妍,张凯,陈容娟,等.隐匿性HBV感染患者HBV S基因N-糖基化突变对HBsAg抗原性影响的分析[J].解放军医学杂志,2018,43(5):386-391.
[23]Vivekanandan P,Thomas D,Torbenson M. Hepatitis B viral DNA is methylated in liver tissues[J]. J Viral Hepat,2008,15(2):103-107.
[24]Kaur P,Paliwal A,Durantel D,et al. DNA Methylation of Hepatitis B Virus(HBV)Genome Associated with the Development of Hepatocellular Carcinoma and Occult HBV Infection[J]. J Infect Dis,2010,202(5):700-704.
[25]Vivekanandan P,Kannangai R,Ray SC,et al. Comprehensive Genetic and Epigenetic Analysis of Occult Hepatitis B from Liver Tissue Samples[J]. Clin Infect Dis,2008,46(8):1227-1236.
[26]Raimondo G,Caccamo G,Filomia R,et al. Occult HBV infection[J]. Semin Immunopathol,2013,35(1):39-52.
[27]Hoofnagle JH,Seeff LB,Bales ZB,et al. Type B hepatitis after transfusion with blood containing antibody to hepatitis B core antigen[J]. N Engl J Med,1978,298(25):1379-1383.
[28]Sosa-Jurado F,Hilda Rosas-Murrieta N,Guzman-Flores B,et al. Prevalence of Serologic Hepatitis B Markers in Blood Donors From Puebla,Mexico:The Association of Relatively High Levels of Anti-Core Antibodies With the Detection of Surface Antigen and Genomic DNA[J].Hepat Mon,2016,16(6):e36942.
[29]Kishk R,Nemr N,Elkady A,et al. Hepatitis B surface gene variants isolated from blood donors with overt and occult HBV infection in north eastern Egypt[J]. Virol J,2015,12:153.
[30]Oluyinka OO,Tong HV,Bui Tien S,et al. Occult Hepatitis B Virus Infection in Nigerian Blood Donors and Hepatitis B Virus Transmission Risks[J]. PLoS One,2015,10(7):e0131912.
[31]Liang X,Bi S,Yang W,et al. Epidemiological serosurvey of hepatitis B in China-declining HBV prevalence due to hepatitis B vaccination[J]. Vaccine,2009,27(47):6550-6557.
[32]Zhang K,Liu Y,Chen R,et al. Antigenicity reduction contributes mostly to poor detectability of HBsAg by hepatitis B virus(HBV)S-gene mutants isolated from individuals with occult HBV infection[J]. J Med Virol,2018,90(2):263-270.
[33]王东,邓雪莲,周璐,等.大连地区无偿献血者隐匿性乙型肝炎病毒感染pre-S/S区基因分析[J].中国输血杂志,2015,28(1):26-31.
[34]赵亮,周晓真,涂东晋,等.福州地区HBs Ag-/HBVDNA+献血者乙肝病毒S区MHR变异特征分析[J].中外医疗,2017(23):10-14.
[35]蒋菲菲,吕蓉,李敏,等.华东地区献血者人群隐匿性乙型肝炎病毒感染及S区变异分析[J].中国输血杂志,2017,30(7):762-766.
[36]叶贤林,李彤,孙淑君,等.核心抗体阳性合格献血者隐匿性乙肝病毒感染分子生物学特性及追踪结果的研究[J].中国输血杂志,2016,29(9):890-894.
[37]Dodd RY,Nguyen ML,Krysztof DE,et al. Blood donor testing for hepatitis B virus in the United States:is there a case for continuation of hepatitis B surface antigen detection?[J]. Transfusion,2018,58(9):2166-2170.