Biopolym. Cell. 1999; 15(2):109-121.
Reviews
The hepatitis B virus: general description, physical structure, genetic organization, gene transcripts arid genomic regulatory elements
1Adjamian F.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680

Abstract

The HBV genome is a circular partially double-stranded DNA molecule. It contains four overlapping open reading frames (ORFs) genes. The S (preS1, preS2) region(s) encodes the major (small), middle and large proteins (HBsAg). The C and pre-C regions encode HBcAg and HBeAg. The X region encodes a polypeptide expressed during HBV infection. The P region codes for a protein with several, functions in replication. Four classes of HBV mRNAs have been identified, in the HBV genome the pre-S1 promoter expresses the large protein. The pre-S2/S promoters produce both major and middle proteins. The X promoter produces 0.7 and 0.9 kb transcripts. The C and pre-C promoters produce the Core, pol(HBcAg), and the HBeAg proteins. Enhancer I and II are key regulatory elements in the transcriptional regulation of HBV. The activity of enhancer II is highly the liwr specific. Enhancer II activates the transcriptional activity of both the pre-S1 and preS2/S promoters. Two HBV enhancers strongly affect the activity of all three major HBV promoters. A box-α in the II-A and box-β in II-B elements of HBV genome, are necessary for the enhancer II function. Either box-α or box-β can regulate the activity of the Core promoter, a, b, f proteins and c, d proteins bind to box-α and box-β, respectively, and mediate the enhancer function.

References

[1] Pourcel C, Louise A, Gervais M, Chenciner N, Dubois MF, Tiollais P. Transcription of the hepatitis B surface antigen gene in mouse cells transformed with cloned viral DNA. J Virol. 1982;42(1):100-5.
[2] Gough NM. Core and E antigen synthesis in rodent cells transformed with hepatitis B virus DNA is associated with greater than genome length viral messenger RNAs. J Mol Biol. 1983;165(4):683-99.
[3] Chakraborty PR, Ruiz-Opazo N, Shouval D, Shafritz DA. Identification of integrated hepatitis B virus DNA and expression of viral RNA in an HBsAg-producing human hepatocellular carcinoma cell line. Nature. 1980;286(5772):531-3.
[4] Cattaneo R, Will H, Hernandez N, Schaller H. Signals regulating hepatitis B surface antigen transcription. Nature. 1983;305(5932):336-8.
[5] Siddiqui A, Jameel S, Mapoles J. Transcriptional control elements of hepatitis B surface antigen gene. Proc Natl Acad Sci USA. 1986;83(3):566-70.
[6] Galibert F, Chen TN, Mandart E. Nucleotide sequence of a cloned woodchuck hepatitis virus genome: comparison with the hepatitis B virus sequence. J Virol. 1982;41(1):51-65.
[7] Summers J, Mason WS. Replication of the genome of a hepatitis B--like virus by reverse transcription of an RNA intermediate. Cell. 1982;29(2):403-15.
[8] Seeger C, Ganem D, Varmus HE. Biochemical and genetic evidence for the hepatitis B virus replication strategy. Science. 1986;232(4749):477-84.
[9] Bayer ME, Blumberg BS, Werner B. Particles associated with Australia antigen in the sera of patients with leukaemia, Down's Syndrome and hepatitis. Nature. 1968;218(5146):1057-9.
[10] Summers J, Smolec JM, Snyder R. A virus similar to human hepatitis B virus associated with hepatitis and hepatoma in woodchucks. Proc Natl Acad Sci USA. 1978;75(9):4533-7.
[11] Marion PL, Oshiro LS, Regnery DC, Scullard GH, Robinson WS. A virus in Beechey ground squirrels that is related to hepatitis B virus of humans. Proc Natl Acad Sci USA. 1980;77(5):2941-5.
[12] Feitelson MA, Millman I, Blumberg BS. Tree squirrel hepatitis B virus: antigenic and structural characterization. Proc Natl Acad Sci USA. 1986;83(9):2994-7.
[13] Mason WS, Seal G, Summers J. Virus of Pekin ducks with structural and biological relatedness to human hepatitis B virus J Virol. 1980;36(3):829-36.
[14] Sprengel R, Kaleta EF, Will H. Isolation and characterization of a hepatitis B virus endemic in herons. J Virol. 1988;62(10):3832-9.
[15] Skelly J, Copeland JA, Howard CR, Zuckerman AJ. Hepatitis B surface antigen produced by a human hepatoma cell line. Nature. 1979;282(5739):617-8.
[16] Szmuness W. Hepatocellular carcinoma and the hepatitis B virus: evidence for a causal association. Prog Med Virol. 1978;24:40-69.
[17] Tiollais P, Pourcel C, Dejean A. The hepatitis B virus. Nature. 1985;317(6037):489-95.
[18] Aspinall S, Alexander J, Bos P. Comparative expression of hepatitis B virus antigens in several cell model systems. J Gen Virol. 1986;67 (Pt 11):2315-23.
[19] Johnson PF, Landschulz WH, Graves BJ, McKnight SL. Identification of a rat liver nuclear protein that binds to the enhancer core element of three animal viruses. Genes Dev. 1987;1(2):133-46.
[20] Beasley RP, Hwang LY, Lin CC, Chien CS. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet. 1981;2(8256):1129-33.
[21] Moroy T, Marchio A, Etiemble J, Trepo C, Tiollais P, Buendia MA. Rearrangement and enhanced expression of c-myc in hepatocellular carcinoma of hepatitis virus infected woodchucks. Nature. 1986;324(6094):276-9.
[22] Fourel G, Trepo C, Bougueleret L, Henglein B, Ponzetto A, Tiollais P, Buendia MA. Frequent activation of N-myc genes by hepadnavirus insertion in woodchuck liver tumours. Nature. 1990;347(6290):294-8.
[23] Dejean A, Brechot C, Tiollais P, Wain-Hobson S. Characterization of integrated hepatitis B viral DNA cloned from a human hepatoma and the hepatoma-derived cell line PLC/PRF/5. Proc Natl Acad Sci U S A. 1983;80(9):2505-9.
[24] Fowler MJ, Thomas HC, Monjardino J. Cloning and analysis of integrated hepatitis B virus DNA of the adr subtype derived from a human primary liver cell carcinoma. J Gen Virol. 1986;67 ( Pt 4):771-5.
[25] Koshy R, Koch S, von Loringhoven AF, Kahmann R, Murray K, Hofschneider PH. Integration of hepatitis B virus DNA: evidence for integration in the single-stranded gap. Cell. 1983;34(1):215-23.
[26] Mizusawa H, Taira M, Yaginuma K, Kobayashi M, Yoshida E, Koike K. Inversely repeating integrated hepatitis B virus DNA and cellular flanking sequences in the human hepatoma-derived cell line huSP. Proc Natl Acad Sci USA. 1985;82(1):208-12.
[27] Rogler CE, Sherman M, Su CY, Shafritz DA, Summers J, Shows TB, Henderson A, Kew M. Deletion in chromosome 11p associated with a hepatitis B integration site in hepatocellular carcinoma. Science. 1985;230(4723):319-22.
[28] Shaul Y, Ziemer M, Garcia PD, Crawford R, Hsu H, Valenzuela P, Rutter WJ. Cloning and analysis of integrated hepatitis virus sequences from a human hepatoma cell line. J Virol. 1984;51(3):776-87.
[29] Yaginuma K, Kobayashi M, Yoshida E, Koike K. Hepatitis B virus integration in hepatocellular carcinoma DNA: duplication of cellular flanking sequences at the integration site. Proc Natl Acad Sci U S A. 1985;82(13):4458-62.
[30] Ziemer M, Garcia P, Shaul Y, Rutter WJ. Sequence of hepatitis B virus DNA incorporated into the genome of a human hepatoma cell line. J Virol. 1985;53(3):885-92.
[31] Ou J, Rutter WJ. Hybrid hepatitis B virus-host transcripts in a human hepatoma cell. Proc Natl Acad Sci U S A. 1985;82(1):83-7.
[32] Su H., Yee J-K. Regulation of hepatitis B virus gene expression by its two enhancers. Proc Nat. Acad. Sci. USA. 1992. 89:2708—2712.
[33] Brechot C, Hadchouel M, Scotto J, Fonck M, Potet F, Vyas GN, Tiollais P. State of hepatitis B virus DNA in hepatocytes of patients with hepatitis B surface antigen-positive and -negative liver diseases. Proc Natl Acad Sci U S A. 1981;78(6):3906-10.
[34] Brechot C, Pourcel C, Louise A, Rain B, Tiollais P. Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature. 1980;286(5772):533-5.
[35] Chen DS, Hoyer BH, Nelson I, Purcell RH, Gerin JL. Detection and properties of hepatitis B viral DNA in liver tissues from patients with hepatocellular carcinoma. Hepatologj. 1982; 2:42—46,
[36] Edman JC, Gray P, Valenzuela P, Rall LB, Rutter WJ. Integration of hepatitis B virus sequences and their expression in a human hepatoma cell. Nature. 1980;286(5772):535-8.
[37] Shafritz DA, Shouval D, Sherman HI, Hadziyannis SJ, Kew MC. Integration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma. Studies in percutaneous liver biopsies and post-mortem tissue specimens. N Engl J Med. 1981;305(18):1067-73.
[38] Rossner MT. Review: hepatitis B virus X-gene product: a promiscuous transcriptional activator. J Med Virol. 1992;36(2):101-17.
[39] Araki K, Miyazaki J, Hino O, Tomita N, Chisaka O, Matsubara K, Yamamura K. Expression and replication of hepatitis B virus genome in transgenic mice. Proc Natl Acad Sci U S A. 1989;86(1):207-11.
[40] Hollinger FB. Hepatitis B virus. Lippincott: Raven publ., 1996:2739—2807.
[41] Cattaneo R, Will H, Schaller H. Hepatitis B virus transcription in the infected liver. EMBO J. 1984;3(9):2191-6.
[42] Elfassi E, Romet-Lemonne JL, Essex M, Frances-McLane M, Haseltine WA. Evidence of extrachromosomal forms of hepatitis B viral DNA in a bone marrow culture obtained from a patient recently infected with hepatitis B virus. Proc Natl Acad Sci U S A. 1984;81(11):3526-8.
[43] Farza H, Hadchouel M, Scotto J, Tiollais P, Babinet C, Pourcel C. Replication and gene expression of hepatitis B virus in a transgenic mouse that contains the complete viral genome. J Virol. 1988;62(11):4144-52.
[44] Heermann KH, Goldmann U, Schwartz W, Seyffarth T, Baumgarten H, Gerlich WH. Large surface proteins of hepatitis B virus containing the pre-s sequence. J Virol. 1984;52(2):396-402.
[45] Machida A, Kishimoto S, Ohnuma H, Miyamoto H, Baba K, Oda K, Nakamura T, Miyakawa Y, Mayumi M. A hepatitis B surface antigen polypeptide (P31) with the receptor for polymerized human as well as chimpanzee albumins. Gastroenterology. 1983;85(2):268-74.
[46] Tiollais P, Charnay P, Vyas GN. Biology of hepatitis B virus. Science. 1981;213(4506):406-11.
[47] Galibert F, Mandart E, Fitoussi F, Tiollais P, Charnay P. Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E. coli. Nature. 1979;281(5733):646-50.
[48] Pasek M, Goto T, Gilbert W, Zink B, Schaller H, MacKay P, Leadbetter G, Murray K. Hepatitis B virus genes and their expression in E. coli. Nature. 1979;282(5739):575-9.
[49] Bosch K. Kuhn C., Schaller H. Hepatitis B virus replication. Retroviruses, viroids, and RNA recombination, RNA genetics. Eds E Domingo, JJ Holland, P Ahiquist. Cleveland: CRC press, 1988. Vol. 2: 43—58.
[50] Pfaff E, Klinkert MQ, Theilmann L, Schaller H. Characterization of large surface proteins of hepatitis B virus by antibodies to preS-S encoded amino acids. Virology. 1986;148(1):15-22.
[51] Ganem D. Assembly of hepadnaviral virions and subviral particles. Curr Top Microbiol Immunol. 1991;168:61-83.
[52] Stibbe W, Gerlich WH. Structural relationships between minor and major proteins of hepatitis B surface antigen. J Virol. 1983;46(2):626-8.
[53] Ganem D. Hepadnaviridae and their replication. Lippincott: Raven publ., 1996:2703—2737.
[54] Ganem D, Varmus HE. The molecular biology of the hepatitis B viruses. Annu Rev Biochem. 1987;56:651-93.
[55] Chisari FV, Klopchin K, Moriyama T, Pasquinelli C, Dunsford HA, Sell S, Pinkert CA, Brinster RL, Palmiter RD. Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell. 1989;59(6):1145-56.
[56] Chisari FV, Filippi P, Buras J, McLachlan A, Popper H, Pinkert CA, Palmiter RD, Brinster RL. Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice. Proc Natl Acad Sci U S A. 1987;84(19):6909-13.
[57] Cheng KC, Smith GL, Moss B. Hepatitis B virus large surface protein is not secreted but is immunogenic when selectively expressed by recombinant vaccinia virus. J Virol. 1986;60(2):337-44.
[58] Molnar-Kimber KL, Jarocki-Witek V, Dheer SK, Vernon SK, Conley AJ, Davis AR, Hung PP. Distinctive properties of the hepatitis B virus envelope proteins. J Virol. 1988;62(2):407-16.
[59] Ou JH, Rutter WJ. Regulation of secretion of the hepatitis B virus major surface antigen by the preS-1 protein. J Virol. 1987;61(3):782-6.
[60] Ramakrishnan M, Tugizov S, Pereira L, Lee AS. Conformation-defective herpes simplex virus 1 glycoprotein B activates the promoter of the grp94 gene that codes for the 94-kD stress protein in the endoplasmic reticulum. DNA Cell Biol. 1995;14(5):373-84.
[61] Bruss V, Ganem D. The role of envelope proteins in hepatitis B virus assembly. Proc Natl Acad Sci U S A. 1991;88(3):1059-63.
[62] Yen TSB. Regulation of hepatitis B virus gene expression. Semin. Virology. 1993. 4:33—42.
[63] Xu Z, Jensen G, Yen TS. Activation of hepatitis B virus S promoter by the viral large surface protein via induction of stress in the endoplasmic reticulum. J Virol. 1997;71(10):7387-92.
[64] Chang CM, Jeng KS, Hu CP, Lo SJ, Su TS, Ting LP, Chou CK, Han SH, Pfaff E, Salfeld J, et al. Production of hepatitis B virus in vitro by transient expression of cloned HBV DNA in a hepatoma cell line. EMBO J. 1987;6(3):675-80.
[65] Sells MA, Chen ML, Acs G. Production of hepatitis B virus particles in Hep G2 cells transfected with cloned hepatitis B virus DNA. Proc Natl Acad Sci U S A. 1987;84(4):1005-9.
[66] Tsurimoto T, Fujiyama A, Matsubara K. Stable expression and replication of hepatitis B virus genome in an integrated state in a human hepatoma cell line transfected with the cloned viral DNA. Proc Natl Acad Sci U S A. 1987;84(2):444-8.
[67] Yaginuma K, Shirakata Y, Kobayashi M, Koike K. Hepatitis B virus (HBV) particles are produced in a cell culture system by transient expression of transfected HBV DNA. Proc Natl Acad Sci U S A. 1987;84(9):2678-82.
[68] Matsui T, Takano M, Miyamoto K, Itoh Y, Yoshizawa H, Koike M, Mochizuki T, Tanaka E, Okamoto H, Imai M, et al. Nude mice bearing human primary hepatocellular carcinoma that produces hepatitis B surface, core, and e antigens, as well as deoxyribonucleic acid polymerase. Gastroenterology. 1986;90(1):135-42.
[69] Gough NM, Murray K. Expression of the hepatitis B virus surface, core and E antigen genes by stable rat and mouse cell lines. J Mol Biol. 1982;162(1):43-67.
[70] Will H, Cattaneo R, Pfaff E, Kuhn C, Roggendorf M, Schaller H. Expression of hepatitis B antigens with a simian virus 40 vector. J Virol. 1984;50(2):335-42.
[71] Sureau C, Romet-Lemonne JL, Mullins JI, Essex M. Production of hepatitis B virus by a differentiated human hepatoma cell line after transfection with cloned circular HBV DNA. Cell. 1986;47(1):37-47.
[72] Gripon P1, Diot C, Theze N, Fourel I, Loreal O, Brechot C, Guguen-Guillouzo C. Hepatitis B virus infection of adult human hepatocytes cultured in the presence of dimethyl sulfoxide. J Virol. 1988;62(11):4136-43.
[73] Ochiya T, Tsurimoto T, Ueda K, Okubo K, Shiozawa M, Matsubara K. An in vitro system for infection with hepatitis B virus that uses primary human fetal hepatocytes. Proc Natl Acad Sci U S A. 1989;86(6):1875-9.
[74] Chisari FV, Pinkert CA, Milich DR, Filippi P, McLachlan A, Palmiter RD, Brinster RL. A transgenic mouse model of the chronic hepatitis B surface antigen carrier state. Science. 1985;230(4730):1157-60.
[75] Babinet C, Farza H, Morello D, Hadchouel M, Pourcel C. Specific expression of hepatitis B surface antigen (HBsAg) in transgenic mice. Science. 1985;230(4730):1160-3.
[76] Standring DN, Rutter WJ, Varmus HE, Ganem D.
[77] Le Bouvier G. L The heterogeneity of Australia antigen. J. Infect. Diseases. 1971. 123—P. 671—675. Transcription of the hepatitis B surface antigen gene in cultured murine cells initiates within the presurface region. J Virol. 1984;50(2):563-71.
[78] Bancroft WH, Mundon FK, Russell PK. Detection of additional antigenic determinants of hepatitis B antigen. J Immunol. 1972;109(4):842-8.
[79] Fujiyama A, Miyanohara A, Nozaki C, Yoneyama T, Ohtomo N, Matsubara K. Cloning and structural analyses of hepatitis B virus DNAs, subtype adr. Nucleic Acids Res. 1983;11(13):4601-10.
[80] Okamoto H, Tsuda F, Sakugawa H, Sastrosoewignjo RI, Imai M, Miyakawa Y, Mayumi M. Typing hepatitis B virus by homology in nucleotide sequence: comparison of surface antigen subtypes. J Gen Virol. 1988;69 ( Pt 10):2575-83.
[81] Charnay P, Mandart E, Hampe A, Fitoussi F, Tiollais P, Galibert F. Localization on the viral genome and nucleotide sequence of the gene coding for the two major polypeptides of the hepatitis B surface antigen (HBs Ag). Nucleic Acids Res. 1979;7(2):335-46.
[82] Stibbe W, Gerlich WH. Structural relationships between minor and major proteins of hepatitis B surface antigen. J Virol. 1983;46(2):626-8.
[83] De-Medina T, Faktor O, Shaul Y. The S promoter of hepatitis B virus is regulated by positive and negative elements. Mol Cell Biol. 1988;8(6):2449-55.
[84] Courtois G, Baumhueter S, Crabtree GR. Purified hepatocyte nuclear factor 1 interacts with a family of hepatocyte-specific promoters. Proc Natl Acad Sci U S A. 1988;85(21):7937-41.
[85] Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA. Hepatitis B virus DNA contains a glucocorticoid-responsive element. Proc Natl Acad Sci U S A. 1986;83(6):1627-31.
[86] Tur-Kaspa R, Shaul Y, Moore DD, Burk RD, Okret S, Poellinger L, Shafritz DA. The glucocorticoid receptor recognizes a specific nucleotide sequence in hepatitis B virus DNA causing increased activity of the HBV enhancer. Virology. 1988;167(2):630-3.
[87] Farza H, Salmon AM, Hadchouel M, Moreau JL, Babinet C, Tiollais P, Pourcel C. Hepatitis B surface antigen gene expression is regulated by sex steroids and glucocorticoids in transgenic mice. Proc Natl Acad Sci U S A. 1987;84(5):1187-91.
[88] Uy A, Bruss V, Gerlich WH, K?chel HG, Thomssen R. Precore sequence of hepatitis B virus inducing e antigen and membrane association of the viral core protein. Virology. 1986;155(1):89-96.
[89] Levrero M, Jean-Jean O, Balsano C, Will H, Perricaudet M. Hepatitis B virus (HBV) X gene expression in human cells and anti-HBx antibodies detection in chronic HBV infection. Virology. 1990;174(1):299-304.
[90] Twu JS, Schloemer RH. Transcriptional trans-activating function of hepatitis B virus. J Virol. 1987;61(11):3448-53.
[91] Spandau DF, Lee CH. trans-activation of viral enhancers by the hepatitis B virus X protein. J Virol. 1988;62(2):427-34.
[92] Twu JS, Robinson WS. Hepatitis B virus X gene can transactivate heterologous viral sequences. Proc Natl Acad Sci U S A. 1989;86(6):2046-50.
[93] Gunther S, Piwon N, Iwanska A, Schilling R, Meisel H, Will H. Type, prevalence, and significance of core promoter/enhancer II mutations in hepatitis B viruses from immunosuppressed patients with severe liver disease. J Virol. 1996;70(12):8318-31.
[94] Bartenschlager R, Schaller H. The amino-terminal domain of the hepadnaviral P-gene encodes the terminal protein (genome-linked protein) believed to prime reverse transcription. EMBO J. 1988;7(13):4185-92.
[95] Schlicht HJ, Radziwill G, Schaller H. Synthesis and encapsidation of duck hepatitis B virus reverse transcriptase do not require formation of core-polymerase fusion proteins. Cell. 1989;56(1):85-92.
[96] Bosch V, Bartenschlager R, Radziwill G, Schaller H. The duck hepatitis B virus P-gene codes for protein strongly associated with the 5'-end of the viral DNA minus strand. Virology. 1988;166(2):475-85.
[97] Will H, Reiser W, Weimer T, Pfaff E, B?scher M, Sprengel R, Cattaneo R, Schaller H. Replication strategy of human hepatitis B virus. J Virol. 1987;61(3):904-11.
[98] Yuh CH, Ting LP. The genome of hepatitis B virus contains a second enhancer: cooperation of two elements within this enhancer is required for its function. J Virol. 1990;64(9):4281-7.
[99] Valenzticla P, Qurioga M, Zaldiver I, Cray P, Rutter WJ. The nucleotide sequence of the hepatitis B viral genome and identification of the major viral genes. Animal Virus Genetics: ICN/UCLA Symp. on Mol. and Cell. Biol. Eds B. N. Fields, R Jaenlsch, CF Fox. San Diego: Acad, press, 1980:57—70.
[100] Malpiece Y, Michel ML, Carloni G, Revel M, Tiollais P, Weissenbach J. The gene S promoter of hepatitis B virus confers constitutive gene expression. Nucleic Acids Res. 1983;11(13):4645-54.
[101] Rall LB, Standring DN, Laub O, Rutter WJ. Transcription of hepatitis B virus by RNA polymerase II. Mol Cell Biol. 1983;3(10):1766-73.
[102] Persing DH, Varmus HE, Ganem D. Inhibition of secretion of hepatitis B surface antigen by a related presurface polypeptide. Science. 1986;234(4782):1388-91.
[103] Standring DN, Ou JH, Rutter WJ. Assembly of viral particles in Xenopus oocytes: pre-surface-antigens regulate secretion of the hepatitis B viral surface envelope particle. Proc Natl Acad Sci U S A. 1986;83(24):9338-42.
[104] Chang HK, Ting LP. The surface gene promoter of the human hepatitis B virus displays a preference for differentiated hepatocytes. Virology. 1989;170(1):176-83.
[105] Chang HK, Wang BY, Yuh CH, Wei CL, Ting LP. A liver-specific nuclear factor interacts with the promoter region of the large surface protein gene of human hepatitis B virus. Mol Cell Biol. 1989;9(11):5189-97.
[106] Raney AK, Milich DR, McLachlan A. Characterization of hepatitis B virus major surface antigen gene transcriptional regulatory elements in differentiated hepatoma cell lines. J Virol. 1989;63(9):3919-25.
[107] Treinin M, Laub O. Identification of a promoter element located upstream from the hepatitis B virus X gene. Mol Cell Biol. 1987;7(1):545-8.
[108] Enders GH, Ganem D, Varmus H. Mapping the major transcripts of ground squirrel hepatitis virus: the presumptive template for reverse transcriptase is terminally redundant. Cell. 1985;42(1):297-308.
[109] Mandart E, Kay A, Galibert F. Nucleotide sequence of a cloned duck hepatitis B virus genome: comparison with woodchuck and human hepatitis B virus sequences. J Virol. 1984;49(3):782-92.
[110] Yuh CH, Ting LP. Differentiated liver cell specificity of the second enhancer of hepatitis B virus. J Virol. 1993;67(1):142-9.
[111] Kobayashi M, Koike K. Complete nucleotide sequence of hepatitis B virus DNA of subtype adr and its conserved gene organization. Gene. 1984;30(1-3):227-32.
[112] Laub O, Rall LB, Truett M, Shaul Y, Standring DN, Valenzuela P, Rutter WJ. Synthesis of hepatitis B surface antigen in mammalian cells: expression of the entire gene and the coding region. J Virol. 1983;48(1):271-80.
[113] Kaneko S, Miller RH. X-region-specific transcript in mammalian hepatitis B virus-infected liver. J Virol. 1988;62(11):3979-84.
[114] Yen T. S. B. Viral Hepatitis. New York: Williams and Wilkins, 1991.
[115] Fouillot N1, Tlouzeau S, Rossignol JM, Jean-Jean O. Translation of the hepatitis B virus P gene by ribosomal scanning as an alternative to internal initiation. J Virol. 1993;67(8):4886-95.
[116] Weimer T, Salfeld J, Will H. Expression of the hepatitis B virus core gene in vitro and in vivo. J Virol. 1987;61(10):3109-13.
[117] Lopez-Cabrera M1, Letovsky J, Hu KQ, Siddiqui A. Multiple liver-specific factors bind to the hepatitis B virus core/pregenomic promoter: trans-activation and repression by CCAAT/enhancer binding protein. Proc Natl Acad Sci U S A. 1990;87(13):5069-73.
[118] Yaginuma K, Koike K. Identification of a promoter region for 3.6-kilobase mRNA of hepatitis B virus and specific cellular binding protein. J Virol. 1989;63(7):2914-20.
[119] Yuh CH, Chang YL, Ting LP. Transcriptional regulation of precore and pregenomic RNAs of hepatitis B virus. J Virol. 1992;66(7):4073-84.
[120] Chen IH, Huang CJ, Ting LP. Overlapping initiator and TATA box functions in the basal core promoter of hepatitis B virus. J Virol. 1995;69(6):3647-57.
[121] Guo W, Chen M, Yen TS, Ou JH. Hepatocyte-specific expression of the hepatitis B virus core promoter depends on both positive and negative regulation. Mol Cell Biol. 1993;13(1):443-8.
[122] Wang Y, Chen P, Wu X, Sun AL, Wang H, Zhu YA, Li ZP. A new enhancer element, ENII, identified in the X gene of hepatitis B virus. J Virol. 1990;64(8):3977-81.
[123] Yuh CH, Ting LP. C/EBP-like proteins binding to the functional box-alpha and box-beta of the second enhancer of hepatitis B virus. Mol Cell Biol. 1991;11(10):5044-52.
[124] Zhou DX, Yen TS. Differential regulation of the hepatitis B virus surface gene promoters by a second viral enhancer. J Biol Chem. 1990;265(34):20731-4.
[125] Johnson JL, Raney AK, McLachlan A. Characterization of a functional hepatocyte nuclear factor 3 binding site in the hepatitis B virus nucleocapsid promoter. Virology. 1995;208(1):147-58.
[126] Zhang P, Raney AK, McLachlan A. Characterization of functional Sp1 transcription factor binding sites in the hepatitis B virus nucleocapsid promoter. J Virol. 1993;67(3):1472-81.
[127] Raney AK, Easton AJ, Milich DR, McLachlan A. Promoter-specific transactivation of hepatitis B virus transcription by a glutamine- and proline-rich domain of hepatocyte nuclear factor 1. J Virol. 1991;65(11):5774-81.
[128] Hasegawa K, Huang J, Rogers SA, Blum HE, Liang TJ. Enhanced replication of a hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. J Virol. 1994;68(3):1651-9.
[129] Horikita M, Itoh S, Yamamoto K, Shibayama T, Tsuda F, Okamoto H. Differences in the entire nucleotide sequence between hepatitis B virus genomes from carriers positive for antibody to hepatitis B e antigen with and without active disease. J Med Virol. 1994;44(1):96-103.
[130] Kaneko M, Uchida T, Moriyama M, Arakawa Y, Shikata T, Gotoh K, Mima S. Probable implication of mutations of the X open reading frame in the onset of fulminant hepatitis B. J Med Virol. 1995;47(3):204-8.
[131] Sato S, Suzuki K, Akahane Y, Akamatsu K, Akiyama K, Yunomura K, Tsuda F, Tanaka T, Okamoto H, Miyakawa Y, Mayumi M. Hepatitis B virus strains with mutations in the core promoter in patients with fulminant hepatitis. Ann Intern Med. 1995;122(4):241-8.
[132] Moriyama K, Takada T, Tsutsumi Y, Fukada K, Ishibashi H, Niho Y, Maeda Y. Mutations in the transcriptional regulatory region of the precore and core/pregenome of a hepatitis B virus with defective HBeAg production. Fukuoka Igaku Zasshi. 1994;85(11):314-22.
[133] Okamoto H, Tsuda F, Akahane Y, Sugai Y, Yoshiba M, Moriyama K, Tanaka T, Miyakawa Y, Mayumi M. Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen. J Virol. 1994;68(12):8102-10
[134] Takahashi K, Aoyama K, Ohno N, Iwata K, Akahane Y, Baba K, Yoshizawa H, Mishiro S. The precore/core promoter mutant (T1762A1764) of hepatitis B virus: clinical significance and an easy method for detection. J Gen Virol. 1995;76 ( Pt 12):3159-64.
[135] Fukuda R, Nguyen XT, Ishimura N, Ishihara S, Chowdhury A, Kohge N, Akagi S, Watanabe M, Fukumoto S. X gene and precore region mutations in the hepatitis B virus genome in persons positive for antibody to hepatitis B e antigen: comparison between asymptomatic "healthy" carriers and patients with severe chronic active hepatitis. J Infect Dis. 1995;172(5):1191-7.
[136] Gotoh K, Mima S, Uchida T, Shikata T, Yoshizawa K, Irie M, Mizui M. Nucleotide sequence of hepatitis B virus isolated from subjects without serum anti-hepatitis B core antibody. J Med Virol. 1995;46(3):201-6.
[137] Preisler-Adams S, Schlayer HJ, Peters T, Hettler F, Gerok W, Rasenack J. Sequence analysis of hepatitis B virus DNA in immunologically negative infection. Arch Virol. 1993;133(3-4):385-96.
[138] Uchida T, Shimojima M, Gotoh K, Shikata T, Tanaka E, Kiyosawa K. "Silent" hepatitis B virus mutants are responsible for non-A, non-B, non-C, non-D, non-E hepatitis. Microbiol Immunol. 1994;38(4):281-5.
[139] Landschulz WH, Johnson PF, Adashi EY, Graves BJ, McKnight SL. Isolation of a recombinant copy of the gene encoding C/EBP. Genes Dev. 1988;2(7):786-800.
[140] Mitchell PJ, Tjian R. Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science. 1989;245(4916):371-8.
[141] Maniatis T, Goodbourn S, Fischer JA. Regulation of inducible and tissue-specific gene expression. Science. 1987;236(4806):1237-45.
[142] Jones NC, Rigby PW, Ziff EB. Trans-acting protein factors and the regulation of eukaryotic transcription: lessons from studies on DNA tumor viruses. Genes Dev. 1988;2(3):267-81.
[143] Meyer KB, Neuberger MS. The immunoglobulin kappa locus contains a second, stronger B-cell-specific enhancer which is located downstream of the constant region. EMBO J. 1989;8(7):1959-64.
[144] Fromental C, Kanno M, Nomiyama H, Chambon P. Cooperativity and hierarchical levels of functional organization in the SV40 enhancer. Cell. 1988;54(7):943-53.
[145] Nomiyama H, Fromental C, Xiao JH, Chambon P. Cell-specific activity of the constituent elements of the simian virus 40 enhancer. Proc Natl Acad Sci U S A. 1987;84(22):7881-5.
[146] Ondek B, Shepard A, Herr W. Discrete elements within the SV40 enhancer region display different cell-specific enhancer activities. EMBO J. 1987;6(4):1017-25.
[147] Guo WT, Bell KD, Ou JH. Characterization of the hepatitis B virus EnhI enhancer and X promoter complex. J Virol. 1991;65(12):6686-92.
[148] Shaul Y, Rutter WJ, Laub O. A human hepatitis B viral enhancer element. EMBO J. 1985;4(2):427-30.
[149] Tognoni A, Cattaneo R, Serfling E, Schaffner W. A novel expression selection approach allows precise mapping of the hepatitis B virus enhancer. Nucleic Acids Res. 1985;13(20):7457-72.
[150] Shaul Y, Rutter WJ, Laub O. A human hepatitis B viral enhancer element. EMBO J. 1985;4(2):427-30.
[151] Chang HK, Chou CK, Chang C, Su TS, Hu C, Yoshida M, Ting LP. The enhancer sequence of human hepatitis B virus can enhance the activity of its surface gene promoter. Nucleic Acids Res. 1987;15(5):2261-8.
[152] Yee JK. A liver-specific enhancer in the core promoter region of human hepatitis B virus. Science. 1989;246(4930):658-61.