乙型肝炎核心启动子的研究进展
高学松, 成军, 郭江, 张黎颖, 北京地坛医院传染病研究所 北京市 100011
甄真, 河北医科大学第三医院感染科 河北省石家庄市 050051
高学松, 男, 1977-11-24生, 汉族, 医师, 2002年河北医科大学传染病学专业硕士研究生, 主要从事病毒性肝炎的发病机理与治疗的研究.
通讯作者: 成军, 100011, 北京市东城区安外大街地坛公园13号, 北京地坛医院传染病研究所. cj@genetherapy.com.cn
电话: 010-64481639 传真:010-64281540
, 百拇医药 收稿日期: 2004-12-31 接受日期: 2005-01-03
摘要
乙型肝炎病毒(HBV)核心启动子(CP)与病毒复制、转录及疾病的关系密切，近年来国内外对核心启动子的结构、功能进行了广泛的研究，但目前研究的热点集中在核心启动子变异后的生物学活性改变以及与治疗的关系等方面，本文就其研究进展作一综述.
关键词:乙型肝炎病毒;核心启动子
高学松,成军, 甄真,郭江,张黎颖. 乙型肝炎核心启动子的研究进展.世界华人消化杂志 2005;13(8):933-9361 成军. 慢性病毒性肝炎发病机制的分子生物学研究. 世界华人消化杂志 2002;10:125-128
, 百拇医药 2 骆抗先. 乙型肝炎基础和临床. 第2版. 北京:人民卫生出版社, 2001:25-34
3 Yuh CH, Chang YL, Ting LP. Transcriptional regulation of precoreand pregenomic RNAs of hepatitis B virus.
J Virol 1992;66:4073-4084
4 Kramvis A, Kew MC. The core promoter of hepatitis B virus. JViral Hepat 1999;6:415-427
5 杨艳杰, 成军,陈东风,刘妍, 杨倩,王建军.乙型肝炎病毒核心启动子的结构及调节研究.
世界华人消化杂志 2003;11:1006-1008
, 百拇医药
6 Lopez-Cabrera M, Letovsky J, Hu KQ, Siddiqui A. Transcriptionalfactor C/EBP binds to and transactivates the
enhancer element II of the hepatitisB virus. Virology 1991;183:825-829
7 Raney AK, Johnson JL, Palmer CN, McLachlan A. Members of thenuclear receptor superfamily regulate transcription
from the hepatitis B virusnucleocapsid promoter. J Virol 1997;71:1058-1071
, 百拇医药
8 Yu X, Mertz JE. Differential regulation of the pre-C and pregenomicpromoter of human hepatitis B virus by members
of the nuclear receptor superfamily.J Virol 1997;71:9366-9374
9 Guo W, Chen M, Yen TS, Ou JH. Hepatocyte-specific expression of thehepatitis B virus core promoter depends on
both positive and negativeregulation. Mol Cell Biol 1993;13:443-448
, 百拇医药 10 Gilbert S, Galarneau L, Lamontagne A, Roy S, Belanger L. Thehepatitis B virus core promoter is strongly activated by
the liver nuclear receptorfetoprotein transcription factor or by ectopically expressed steroidogenicfactor 1.
J Virol 2000;74:5032-5039
11 Lin WJ, Li J, Lee YF, Yeh SD, Altuwaijri S, Ou JH, Chang C.Suppression of hepatitis b virus core promoter by the
, 百拇医药
nuclear orphan receptor TR4. JBiol Chem 2003;278:9353-9360
12 Okamoto H, Tsuda F, Akahane Y, Sugai Y, Yoshiba M, Moriyama K,Tanaka T, Miyakawa Y, Mayumi M. Hepatitis B
virus with mutations in thecore promoter for an e antigen-negative phenotype in carriers withantibody to e antigen.
J Virol 1994;68:8102-8110
13 Buckwold VE, Xu Z, Chen M, Yen TS, Ou JH. Effects of a naturallyoccurring mutation in the hepatitis B virus basal
, 百拇医药
core promoter on precore geneexpression and viral replication. J Virol 1996;70:5845-5851
14 Parekh S, Zoulim F, Ahn SH, Tsai A, Li J, Kawai S, Khan N, Trepo C,Wands J, Tong S. Genome replication, virion
secretion, and e antigenexpression of naturally occurring hepatitis B virus core promotermutants.
J Virol 2003;77:6601-6612
15 Ogata N, Miller RH, Ishak KG, Purcell RH. The complete nucleotidesequence of a pre-core mutant of hepatitis B
, http://www.100md.com
virus implicated in fulminanthepatitis and its biological characterization in chimpanzees. Virology 1993;194:263-276
16 Hasegawa K, Huang J, Rogers SA, Blum HE, Liang TJ. Enhancedreplication of a hepatitis B virus mutant associated
with an epidemic of fulminanthepatitis. J Virol 1994;68:1651-1659
17 Alexopoulou A, Karayiannis P, Hadziyannis SJ, Hou J, Pickering J,Luo K, Thomas HC. Whole genome analysis of
, 百拇医药
hepatitis B virus from fourcases of fulminant hepatitis:genetic variability and its potential role indisease pathogenicity.
J Viral Hepat 1996;3:173-181
18 Gerner P, Lausch E, Friedt M, Tratzmuller R, Spangenberg C, WirthS. Hepatitis B virus core promoter mutations
in children with multipleanti-HBe/HBeAg reactivations result in enhanced promoter activity. JMed Virol
, 百拇医药
1999;59:415-423
19 Scaglioni PP, Melegari M, Wands JR. Biologic properties ofhepatitis B viral genomes with mutations in the precore
promoter and precore openreading frame. Virology 1997;233:374-381
20 Gunther S, Piwon N, Will H. Wild-type levels of pregenomic RNA andreplication but reduced pre-C RNA and e-antigen
synthesis of hepatitis B viruswith C(1653)→T,A(1762)→Tand G(1764)→A mutations in the core promoter.
, 百拇医药
J Gen Virol 1998;79:375-380
21 Li J, Buckwold VE, Hon MW, Ou JH. Mechanism of suppression of hepatitis B virus precore RNA transcription by a
frequent double mutation. J Virol 1999;73:1239-1244
22 Chu CJ, Keeffe EB, Han SH, Perrillo RP, Min AD, Soldevila-Pico C, Carey W, Brown RS Jr, Luketic VA, Terrault N,Lok AS; U. S. HBV Epidemiology Study Group. Prevalence of HBV precore/core promoter variants in the United States.
, 百拇医药
Hepatology 2003;38:619-628
23 Hussain M, Chu CJ, Sablon E, Lok AS. Rapid and sensitive assays for determination of hepatitis B virus(HBV)genotypes
and detection of HBV precore and core promoter variants. J Clin Microbiol 2003;41:3699-3705
24 Kuang SY, Jackson PE, Wang JB, Lu PX, Munoz A, Qian GS, Kensler TW, Groopman JD. Specific mutations of hepatitis B
, http://www.100md.com virus in plasma predict liver cancer development. Proc Natl Acad Sci USA 2004;101:3575-3580
25 Huy TT, Ushijima H, Quang VX, Ngoc TT, Hayashi S, Sata T, Abe K. Characteristics of core promoter and precore stop
codon mutants of hepatitis B virus in Vietnam. J Med Virol 2004;74:228-236
26 Yuen MF, Tanaka Y, Mizokami M, Yuen JC, Wong DK, Yuan HJ, Sum SM, Chan AO, Wong BC, Lai CL. Role of hepatitis
, 百拇医药
B virus genotypes Ba and C, core promoter and precore mutations on hepatocellular carcinoma: a case control study.
Carcinogenesis 2004;25:1593-1598
27 Yuen MF, Fung SK, Tanaka Y, Kato T, Mizokami M, Yuen JC, Wong DK, Yuan HJ, Sum SM, Chan AO, Wong BC,Lai CL. Longitudinal study of hepatitis activity and viral replication before and after HBeAg seroconversion in chronic
hepatitis B patients infected with genotypes B and C. J Clin Microbiol 2004;42:5036-5040
, http://www.100md.com
28 Laskus T, Rakela J, Tong MJ, Nowicki MJ, Mosley JW, Persing DH. Naturally occurring hepatitis B virus mutants with
deletions in the core promoter region. J Hepatol 1994;20:837-841
29 Zampino R, Marrone A, Cirillo G, del Giudice EM, Utili R, Karayiannis P, Liang TJ, Ruggiero G. Sequential analysis of
hepatitis B virus core promoter and precore regions in cancer survivor patients with chronic hepatitis B before, during
, 百拇医药
and after interferon treatment. J Viral Hepat 2002;9:183-188
30 Marrone A, Zampino R, Luongo G, Utili R, Karayiannis P, Ruggiero G. Low HBeAg serum levels correlate with the
presence of the double A1762T/G1764A core promoter mutation and a positive response to interferon in patients with
chronic hepatitis B virus infection. Intervirology 2003;46:222-226
, 百拇医药 31 Zhang X, Han Y, Lu Z, Gao J, Luo Z, Zhang D. Effect of multiple mutations in the core promoter and pre-core/core
region of hepatitis B virus genome on the response to interferon in e antigen-positive chronic hepatitis B.
J Gastroenterol Hepatol 2001;16:393-398
32 Erhardt A, Reineke U, Blondin D, Gerlich WH, Adams O, Heintges T, Niederau C, Haussinger D. Mutations of the
, 百拇医药
core promoter and response to interferon treatment in chronic replicative hepatitis B. Hepatology 2000;31:716-725
33 Hannoun C, Horal P, Krogsgaard K, Lindh M; INTERPRED Study Group. Mutations in the X region and core promoter
are rare and have little impact on response to interferon therapy for chronic hepatitis B. J Med Virol 2002;66:171-178
34 Chen RY, Bowden S, Desmond PV, Dean J, Locarnini SA. Effects of interferon alpha therapy on the catalytic domains
, http://www.100md.com
of the polymerase gene and basal core promoter, precore and core regions of hepatitis B virus.
J Gastroenterol Hepatol 2003;18:630-637
35 Suzuki F. Influence of the hepatitis B e antigen/anti-HBe status on the response to lamivudine. Intervirology
2003;46:339-343
编辑 张海宁, http://www.100md.com( 高学松, 成 军, 甄 真, 郭 江, 张黎颖)
甄真, 河北医科大学第三医院感染科 河北省石家庄市 050051
高学松, 男, 1977-11-24生, 汉族, 医师, 2002年河北医科大学传染病学专业硕士研究生, 主要从事病毒性肝炎的发病机理与治疗的研究.
通讯作者: 成军, 100011, 北京市东城区安外大街地坛公园13号, 北京地坛医院传染病研究所. cj@genetherapy.com.cn
电话: 010-64481639 传真:010-64281540
, 百拇医药 收稿日期: 2004-12-31 接受日期: 2005-01-03
摘要
乙型肝炎病毒(HBV)核心启动子(CP)与病毒复制、转录及疾病的关系密切，近年来国内外对核心启动子的结构、功能进行了广泛的研究，但目前研究的热点集中在核心启动子变异后的生物学活性改变以及与治疗的关系等方面，本文就其研究进展作一综述.
关键词:乙型肝炎病毒;核心启动子
高学松,成军, 甄真,郭江,张黎颖. 乙型肝炎核心启动子的研究进展.世界华人消化杂志 2005;13(8):933-9361 成军. 慢性病毒性肝炎发病机制的分子生物学研究. 世界华人消化杂志 2002;10:125-128
, 百拇医药 2 骆抗先. 乙型肝炎基础和临床. 第2版. 北京:人民卫生出版社, 2001:25-34
3 Yuh CH, Chang YL, Ting LP. Transcriptional regulation of precoreand pregenomic RNAs of hepatitis B virus.
J Virol 1992;66:4073-4084
4 Kramvis A, Kew MC. The core promoter of hepatitis B virus. JViral Hepat 1999;6:415-427
5 杨艳杰, 成军,陈东风,刘妍, 杨倩,王建军.乙型肝炎病毒核心启动子的结构及调节研究.
世界华人消化杂志 2003;11:1006-1008
, 百拇医药
6 Lopez-Cabrera M, Letovsky J, Hu KQ, Siddiqui A. Transcriptionalfactor C/EBP binds to and transactivates the
enhancer element II of the hepatitisB virus. Virology 1991;183:825-829
7 Raney AK, Johnson JL, Palmer CN, McLachlan A. Members of thenuclear receptor superfamily regulate transcription
from the hepatitis B virusnucleocapsid promoter. J Virol 1997;71:1058-1071
, 百拇医药
8 Yu X, Mertz JE. Differential regulation of the pre-C and pregenomicpromoter of human hepatitis B virus by members
of the nuclear receptor superfamily.J Virol 1997;71:9366-9374
9 Guo W, Chen M, Yen TS, Ou JH. Hepatocyte-specific expression of thehepatitis B virus core promoter depends on
both positive and negativeregulation. Mol Cell Biol 1993;13:443-448
, 百拇医药 10 Gilbert S, Galarneau L, Lamontagne A, Roy S, Belanger L. Thehepatitis B virus core promoter is strongly activated by
the liver nuclear receptorfetoprotein transcription factor or by ectopically expressed steroidogenicfactor 1.
J Virol 2000;74:5032-5039
11 Lin WJ, Li J, Lee YF, Yeh SD, Altuwaijri S, Ou JH, Chang C.Suppression of hepatitis b virus core promoter by the
, 百拇医药
nuclear orphan receptor TR4. JBiol Chem 2003;278:9353-9360
12 Okamoto H, Tsuda F, Akahane Y, Sugai Y, Yoshiba M, Moriyama K,Tanaka T, Miyakawa Y, Mayumi M. Hepatitis B
virus with mutations in thecore promoter for an e antigen-negative phenotype in carriers withantibody to e antigen.
J Virol 1994;68:8102-8110
13 Buckwold VE, Xu Z, Chen M, Yen TS, Ou JH. Effects of a naturallyoccurring mutation in the hepatitis B virus basal
, 百拇医药
core promoter on precore geneexpression and viral replication. J Virol 1996;70:5845-5851
14 Parekh S, Zoulim F, Ahn SH, Tsai A, Li J, Kawai S, Khan N, Trepo C,Wands J, Tong S. Genome replication, virion
secretion, and e antigenexpression of naturally occurring hepatitis B virus core promotermutants.
J Virol 2003;77:6601-6612
15 Ogata N, Miller RH, Ishak KG, Purcell RH. The complete nucleotidesequence of a pre-core mutant of hepatitis B
, http://www.100md.com
virus implicated in fulminanthepatitis and its biological characterization in chimpanzees. Virology 1993;194:263-276
16 Hasegawa K, Huang J, Rogers SA, Blum HE, Liang TJ. Enhancedreplication of a hepatitis B virus mutant associated
with an epidemic of fulminanthepatitis. J Virol 1994;68:1651-1659
17 Alexopoulou A, Karayiannis P, Hadziyannis SJ, Hou J, Pickering J,Luo K, Thomas HC. Whole genome analysis of
, 百拇医药
hepatitis B virus from fourcases of fulminant hepatitis:genetic variability and its potential role indisease pathogenicity.
J Viral Hepat 1996;3:173-181
18 Gerner P, Lausch E, Friedt M, Tratzmuller R, Spangenberg C, WirthS. Hepatitis B virus core promoter mutations
in children with multipleanti-HBe/HBeAg reactivations result in enhanced promoter activity. JMed Virol
, 百拇医药
1999;59:415-423
19 Scaglioni PP, Melegari M, Wands JR. Biologic properties ofhepatitis B viral genomes with mutations in the precore
promoter and precore openreading frame. Virology 1997;233:374-381
20 Gunther S, Piwon N, Will H. Wild-type levels of pregenomic RNA andreplication but reduced pre-C RNA and e-antigen
synthesis of hepatitis B viruswith C(1653)→T,A(1762)→Tand G(1764)→A mutations in the core promoter.
, 百拇医药
J Gen Virol 1998;79:375-380
21 Li J, Buckwold VE, Hon MW, Ou JH. Mechanism of suppression of hepatitis B virus precore RNA transcription by a
frequent double mutation. J Virol 1999;73:1239-1244
22 Chu CJ, Keeffe EB, Han SH, Perrillo RP, Min AD, Soldevila-Pico C, Carey W, Brown RS Jr, Luketic VA, Terrault N,Lok AS; U. S. HBV Epidemiology Study Group. Prevalence of HBV precore/core promoter variants in the United States.
, 百拇医药
Hepatology 2003;38:619-628
23 Hussain M, Chu CJ, Sablon E, Lok AS. Rapid and sensitive assays for determination of hepatitis B virus(HBV)genotypes
and detection of HBV precore and core promoter variants. J Clin Microbiol 2003;41:3699-3705
24 Kuang SY, Jackson PE, Wang JB, Lu PX, Munoz A, Qian GS, Kensler TW, Groopman JD. Specific mutations of hepatitis B
, http://www.100md.com virus in plasma predict liver cancer development. Proc Natl Acad Sci USA 2004;101:3575-3580
25 Huy TT, Ushijima H, Quang VX, Ngoc TT, Hayashi S, Sata T, Abe K. Characteristics of core promoter and precore stop
codon mutants of hepatitis B virus in Vietnam. J Med Virol 2004;74:228-236
26 Yuen MF, Tanaka Y, Mizokami M, Yuen JC, Wong DK, Yuan HJ, Sum SM, Chan AO, Wong BC, Lai CL. Role of hepatitis
, 百拇医药
B virus genotypes Ba and C, core promoter and precore mutations on hepatocellular carcinoma: a case control study.
Carcinogenesis 2004;25:1593-1598
27 Yuen MF, Fung SK, Tanaka Y, Kato T, Mizokami M, Yuen JC, Wong DK, Yuan HJ, Sum SM, Chan AO, Wong BC,Lai CL. Longitudinal study of hepatitis activity and viral replication before and after HBeAg seroconversion in chronic
hepatitis B patients infected with genotypes B and C. J Clin Microbiol 2004;42:5036-5040
, http://www.100md.com
28 Laskus T, Rakela J, Tong MJ, Nowicki MJ, Mosley JW, Persing DH. Naturally occurring hepatitis B virus mutants with
deletions in the core promoter region. J Hepatol 1994;20:837-841
29 Zampino R, Marrone A, Cirillo G, del Giudice EM, Utili R, Karayiannis P, Liang TJ, Ruggiero G. Sequential analysis of
hepatitis B virus core promoter and precore regions in cancer survivor patients with chronic hepatitis B before, during
, 百拇医药
and after interferon treatment. J Viral Hepat 2002;9:183-188
30 Marrone A, Zampino R, Luongo G, Utili R, Karayiannis P, Ruggiero G. Low HBeAg serum levels correlate with the
presence of the double A1762T/G1764A core promoter mutation and a positive response to interferon in patients with
chronic hepatitis B virus infection. Intervirology 2003;46:222-226
, 百拇医药 31 Zhang X, Han Y, Lu Z, Gao J, Luo Z, Zhang D. Effect of multiple mutations in the core promoter and pre-core/core
region of hepatitis B virus genome on the response to interferon in e antigen-positive chronic hepatitis B.
J Gastroenterol Hepatol 2001;16:393-398
32 Erhardt A, Reineke U, Blondin D, Gerlich WH, Adams O, Heintges T, Niederau C, Haussinger D. Mutations of the
, 百拇医药
core promoter and response to interferon treatment in chronic replicative hepatitis B. Hepatology 2000;31:716-725
33 Hannoun C, Horal P, Krogsgaard K, Lindh M; INTERPRED Study Group. Mutations in the X region and core promoter
are rare and have little impact on response to interferon therapy for chronic hepatitis B. J Med Virol 2002;66:171-178
34 Chen RY, Bowden S, Desmond PV, Dean J, Locarnini SA. Effects of interferon alpha therapy on the catalytic domains
, http://www.100md.com
of the polymerase gene and basal core promoter, precore and core regions of hepatitis B virus.
J Gastroenterol Hepatol 2003;18:630-637
35 Suzuki F. Influence of the hepatitis B e antigen/anti-HBe status on the response to lamivudine. Intervirology
2003;46:339-343
编辑 张海宁, http://www.100md.com( 高学松, 成 军, 甄 真, 郭 江, 张黎颖)
