Research Article| Volume 16, ISSUE 2, P407-428, June 1996

Molecular Variants of Hepatitis B Virus

  • William F. Carman
    Address reprint requests to: William F. Carman, MBBCh, MMed, MRCPath, Institute of Virology, University of Glasgow, Church Street, Glasgow, Gil 5JR, Scotland, United Kingdom
    From the Institute of Virology, University of Glasgow, Glasgow, Scotland, United Kingdom
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      Variation in the genome of hepatitis B virus has been associated with a number of clinical parameters, but there is a paucity of functional data to show a causal relationship. For example, variants of the core and X genes have been linked with the pathogenesis of chronic hepatitis, viral replication efficiency, and serologically negative infections, among other observations. Variants of the surface antigen are linked with infection after vaccination, infection of liver grafts in patients undergoing immunotherapy, and samples that react poorly in diagnostic assays.
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        • Ackrill A.M.
        • Naoumov N.V.
        • Eddieston ALWF
        • et al.
        Specific deletions in the hepatitis B virus core open reading frame in patients with chronic active hepatitis B.
        J Med Virol. 1993; 41: 165-169
        • Akarca U.S.
        • Greene S.
        • Lok A.S.F.
        Detection of precore hepatitis B virus mutants in asymptomatic HBsAg-positive family members.
        Hepatology. 1994; 19: 1366-1370
        • Alexopoulou A.
        • Karayiannis P.
        • Hasziyannis S.J.
        • et al.
        Evidence for selection of HBV variants in a persistently infected patient with quasi-species.
        J Hepatol. 1995; 23: 104
        • Baumert T.F.
        • Rogers S.A.
        • Hasagawa K.
        • et al.
        HBV core promotor mutations cause enhanced viral replication in association with fulminant hepatitis.
        Hepatology. 1995; 22: 260A
        • Bertoletti A.
        • Ferrari C.
        • Fiaccadori F.
        • et al.
        HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized HBV core antigens.
        Proc Natl Acad Sei USA. 1991; 88: 10445-10449
        • Bertoletti A.
        • Sette A.
        • Chisari F.V.
        • et al.
        Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells.
        Nature. 1994; 369: 407-410
        • Bhat R.A.
        • Ulrich P.P.
        • Vyas G.N.
        Molecular characterisation of a new variant of hepatitis B virus in a persistently infected homosexual man.
        Hepatology. 1990; 11: 271-276
        • Boner W.
        • Schlicht H-J
        • Hanrieder K.
        • et al.
        Further characterization of two types of precore variant HBV isolates from Hong Kong.
        J Infect Dis. 1995; 171: 1461-1467
        • Booth J.C.L.
        • Goldin R.D.
        • Brown J.L.
        • et al.
        Fibrosing cholestatic hepatitis in a renal transplant recipient associated with the hepatitis B virus precore mutant.
        J Hepatol. 1995; 22: 500-503
        • Brunetto M.R.
        • Giarin M.
        • Saracco G.
        • et al.
        Hepatitis B virus unable to secrete e antigen and response to interferon in chronic hepatitis B.
        Gastroenterology. 1993; 105: 846-850
        • Brunetto M.R.
        • Oliveri F.
        • Rocca G.
        • et al.
        Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis e antigen.
        Hepatology. 1989; 10: 198-202
        • Brunetto M.R.
        • Stemmier M.
        • Schodel F.
        • et al.
        Identification of HBV variants which cannot produce precore-derived HBeAg and may be responsible for severe hepatitis.
        Ital J Gastroenterol. 1989; 21: 151-154
        • Busstra M.
        • de Man R.A.
        • Heijtink R.A.
        • et al.
        Failure of HBlg therapy after HBV related OLT is due to a reduction of HBsAg neutralisation.
        J Hepatol. 1995; 23: 103
        • Carman W.F.
        Variants of the core and X gene of HBV.
        Intervirology. 1995; 38: 75-88
      1. Carman WF, Boner WF, Fattovich G, et al: Mutation of the pre-core/core gene of hepatitis B virus during chronic infection and correlation with epitopes. J Infect Dis, in press

        • Carman W.F.
        • Fagan E.A.
        • Hadziyannis S.
        • et al.
        Association of a pre-core variant of HBV with fulminant hepatitis.
        Hepatology. 1991; 14: 219-222
        • Carman W.F.
        • Ferrao M.
        • Lok A.S.F.
        • et al.
        Pre-core sequence variation in Chinese isolates of hepatitis B virus.
        J Infect Disease. 1992; 165: 127-133
        • Carman W.F.
        • Jacyna M.R.
        • Hadziyannis S.
        • et al.
        Mutation preventing formation of e antigen in patients with chronic HBV infection.
        Lancet. 1989; 2: 588-591
        • Carman W.F.
        • Korula J.
        • Wallace L.
        • et al.
        Fulminant reactivation of hepatitis B due to envelope protein mutant of HBV that escaped detection by monoclonal HBsAg ELISA.
        Lancet. 1995; 345: 1406-1407
        • Carman W.F.
        • Thursz M.
        • Hadziyannis S.
        • et al.
        HBeAg negative chronic active hepatitis: HBV core mutations occur predominantly in known antigenic determinants.
        J Viral Hepatitis. 1995; 2: 77-84
        • Carman W.F.
        • Trautwein C.
        • Colman C.
        • et al.
        Recurrence of HBV infection after transplantation is not always due to escape mutation.
        Hepatology. 1994; 20: 138A
      2. Carman WF, Trautwein C, McIntyre G, et al: Evolution of HBsAg in transplant recipients with and without polyclonal antibody pressure. Hepatology, 1996, in press

        • Carman W.F.
        • Zanetti A.R.
        • Karayiannis P.
        • et al.
        Vaccine-induced escape mutant of hepatitis B virus.
        Lancet. 1990; 336: 325-329
        • Chisari F.V.
        • Filippi P.
        • Buras J.
        • et al.
        Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice.
        Proc Natl Acad Sei USA. 1987; 84: 6909-6913
        • Davies S.E.
        • Portmann B.C.
        • O’Grady J.G.
        • et al.
        Hepatic histological findings after transplantation for chronic hepatitis B virus infection, including a unique pattern of fibrosing cholestatic hepatitis.
        Hepatology. 1991; 13: 150-157
        • Dash S.
        • Rao K.V.S.
        • Panda S.K.
        Receptor for pre-Sl (21-47) component of hepatitis B virus on the liver cell: Role in virus cell interaction.
        J Med Virol. 1992; 37: 116-121
        • Delaplane D.
        • Yogev R.
        • Crussi F.
        • et al.
        Fatal hepatitis B in early infancy: The importance of identifying HBsAg-positive pregnant women and providing immunoprophylaxis to their newborns.
        Pediatrics. 1983; 72: 176-180
        • Fagan E.
        • Smith P.
        • Davison F.
        • et al.
        Fulminant hepatitis B in successive female sexual partners of two anti-HBe positive males.
        Lancet. 1986; 2: 538-540
        • Fang J.
        • Tung F.
        • Davis G.
        • et al.
        Fibrosing cholestatic hepatitis in a transplant recipient with hepatitis B virus precore mutant.
        Gastroenterology. 1993; 105: 901-904
        • Fattovich G.
        • McIntyre G.
        • Thursz M.
        • et al.
        Hepatitis B virus precore/core variation and interferon therapy.
        Hepatology. 1995; 22: 1355-1362
        • Feitelson M.A.
        • Duan L.X.
        • Guo J.
        • et al.
        Precore and X region mutants in hepatitis B virus infections among renal dialysis patients.
        J Viral Hepatitis. 1995; 2: 19-31
        • Fujii H.
        • Moriyama K.
        • Sakamoto N.
        • et al.
        Gly 145 to Arg substitution in HBs antigen of immune escape mutant of hepatitis B virus.
        Biochem Biophys Res Comm. 1992; 184: 1152-1157
        • Gerlich W.
        Hepatitis B virus: Structure and molecular virology.
        in: Zuckerman AJ Thomas HC Viral Hepatitis. Churchill Livingstone, Edinburgh1993: 83-113
        • Ghany M.G.
        • Avola B.
        • Villamil F.G.
        • et al.
        S gene escape mutants as a cause of HBV reinfection in patients who received HBIG post-OLT.
        Hepatology. 1995; 22: 150A
        • Hadziyannis S.
        • Bramou T.
        • Makris A.
        • et al.
        Interferon alfa-2b treatment of HBeAg negative/serum HBV DNA positive chronic active hepatitis type B.
        J Hepatol. 1990; 11: S133-S136
        • Harrison T.J.
        • Hopes E.A.
        • Oon C.J.
        • et al.
        Independent emergence of a vaccine-induced escape mutant of hepatitis-B virus.
        J Hepatol. 1991; 13: S105-S107
        • Hasegawa K.
        • Huang J.
        • Rogers S.A.
        • et al.
        Enhanced replication of a hepatitis B virus mutant associated with an epidemic of fulminant hepatitis.
        J Virol. 1994; 8: 1651-1659
        • Hatton T.
        • Zhou S.
        • Standring D.N.
        RNA-and DNA-binding activities in hepatitis B virus capsid protein: A model for their roles in viral replication.
        J Virol. 1992; 66: 5232-5241
        • Hertogs K.
        • Depla E.
        • Crabbe T.
        • et al.
        Spontaneous development of anti-hepatitis B virus (anti-idiotypic) antibodies in animals immunised with human liver endenoxin II or with the F(ab’)2 fragment of anti-human liver endonexin II immunoglobulin G: evidence for a receptor-ligand-like relationship between small hepatitis B surface antigen and endonexin II.
        J Virol. 1994; 68: 1516-1521
        • Hertogs K.
        • Leenders W.P.
        • Depla E.
        • et al.
        Endonexin II, present on human liver plasma membranes, is a specific binding protein of small hepatitis B virus (HBV) envelope protein.
        Virology. 1993; 197: 549-557
        • Hirsch R.
        • Lavine J.
        • Chang L.
        • et al.
        Polymerase gene products of hepatitis B viruses are required for genomic RNA packaging as well as for reverse transcription.
        Nature. 1990; 344: 552-555
        • Hou J.L.
        • Karayiannis P.
        • Thomas H.C.
        • et al.
        A unique insertion in the S gene of surface antigen negative HBV in Chinese carriers.
        Hepatology. 1995; 21: 273-278
        • Junker-Niepmann M.
        • Bartenschlager R.
        • Schaller H.
        A short cis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA.
        EMBO J. 1990; 9: 3389-3396
        • Karthigesu V.D.
        • Allison L.M.C.
        • Fortuin M.
        • et al.
        A novel hepatitis B virus variant in the sera of immunized children.
        J Gen Virol. 1994; 75: 443-448
        • Laskus T.
        • Nowicki M.J.
        • Persing D.H.
        • et al.
        Hepatitis B virus core promoter sequence analysis in fulminant and chronic hepatitis B.
        Hepatology. 1995; 22: 260A
        • Leenders W.P.J.
        • Glansbeek H.L.
        • de Bruin W.C.C.
        • et al.
        Binding of the major and large HBsAg to human hepatocytes and liver plasma membranes: Putative external and internal receptors for infection and secretion of hepatitis B virus.
        Hepatology. 1990; 12: 141-147
        • Li J.S.
        • Tong S.P.
        • Wen Y.M.
        • et al.
        Hepatitis B virus genotype A rarely circulates as an HBe-minus mutant: possible contribution of a single nucleotide in the precore region.
        J Virol. 1993; 67: 5402-5410
        • Liang T.J.
        • Blum H.E.
        • Wands J.R.
        Characterization and biological properties of a hepatitis B virus isolated from a patient without hepatitis B virus serologic markers.
        Hepatology. 1990; 12: 204-212
        • Liang T.J.
        • Hasegawa K.
        • Munoz S.J.
        • et al.
        Hepatitis B virus precore mutation and fulminant hepatitis in the United States. A polymerase chain reaction-based assay for the detection of specific mutation.
        J Clin Invest. 1994; 93: 550-555
        • Liang T.J.
        • Hasegawa K.
        • Rimon N.
        • et al.
        A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis.
        N Engl J Med. 1991; 324: 1705-1709
        • Laskus T.
        • Persing D.H.
        • Nowicki M.J.
        • et al.
        Nucleotide sequence analysis of the precore region in patients with fulminant hepatitis B in the United States.
        Gastroenterology. 1993; 105: 1173-1178
        • Lok A.S.F.
        • Akarca U.S.
        • Greene S.
        Predictive value of precore hepatitis B virus mutations in spontaneous and interferon-induced hepatitis B e antigen clearance.
        Hepatology. 1995; 21: 19-24
        • Lok A.S.F.
        • Akarca U.
        • Greene S.
        Mutations in the pre-core region of the hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal.
        Proc Natl Acad Sei USA. 1994; 91: 4077-4081
        • Maguire H.F.
        • Hoeffler J.P.
        • Siddiqui A.
        HBV X protein alters the DNA binding specificity of CREB and ATF-2 by protein-protein interactions.
        Science. 1991; 252: 842-844
        • Maruyama T.
        • Lino S.
        • Koike K.
        • et al.
        Serology of acute exacerbation in chronic hepatitis B virus infection.
        Gastroenterology. 1993; 105: 1141-1151
        • Mason A.
        • Wick M.
        • White H.
        • et al.
        Increased hepatocyte expression of hepatitis B virus transcription in patients with features of fibrosing cholestatic hepatitis.
        Gastroenterology. 1993; 105: 237-244
        • McMahon G.
        • Ehrlich P.H.
        • Moustafa Z.A.
        • et al.
        Genetic alterations in the gene encoding the major HBsAg: DNA and immunological analysis of recurrent HBsAg derived from monoclonal antibody-treated liver transplant patients.
        Hepatology. 1992; 15: 757-766
        • Milich D.R.
        • Jones J.E.
        • Hughes J.L.
        • et al.
        Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero?.
        Proc Natl Acad Sei USA. 1990; 87: 6599-6603
        • Nakayama J.
        • Nakanishi T.
        • Obatake T.
        • et al.
        Fulminant hepatitis caused by a hepatitis B virus core region variant strain.
        J Hepatol. 1995; 23: 199-203
        • Naoumov N.V.
        • Thomas M.G.
        • Mason A.L.
        • et al.
        Genomic variations in the hepatitis B core gene: A possible factor influencing response to interferon alfa treatment.
        Gastroenterology. 1995; 108: 505-514
        • Norder H.
        • Couroucé A-M
        • Magnius L.O.
        Molecular basis of hepatitis B virus serotype variations within the four major subtypes.
        J Gen Virol. 1992; 73: 3141-3145
        • Norder H.
        • Hammas B.
        • Löfdahl S.
        • et al.
        Comparison of the amino acid sequences of nine different serotypes of hepatitis B surface antigen and genomic classification of the corresponding hepatitis B virus strains.
        J Gen Virol. 1992; 73: 1201-1208
        • Ogata N.
        • Miller R.H.
        • Ishak K.G.
        • et al.
        The complete nucleotide sequence of a precore mutant of hepatitis B virus implicated in fulminant hepatitis and its biological characterization in chimpanzees.
        Virology. 1993; 194: 263-276
        • Okamoto H.
        • Imai M.
        • Tsuda F.
        • et al.
        Point mutation in the S gene of hepatitis B virus for a d/y or w/r subtypic change in two blood donors carrying a surface antigen of compound subtype adyr or adwr.
        J Virol. 1987; 61: 3030-3034
        • Okamoto H.
        • Omi S.
        • Wang Y.
        • et al.
        The loss of subtypic determinants in alleles, d/y or w/r, on hepatitis B surface antigen.
        Mol Immunol. 1989; 26: 197-205
        • Okamoto H.
        • Tsuda F.
        • Akahane Y.
        • et al.
        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: 8102-8110
        • Okamoto H.
        • Tsuda F.
        • Mayumi M.
        Jpn J Exp Med. 1987; 57: 217-228
        • Okamoto H.
        • Tsuda F.
        • Sakugawa H.
        • et al.
        Typing hepatitis B virus by homology in nucleotide sequence: Comparison of surface antigen subtypes.
        J Gen Virol. 1988; 69: 2575-2583
        • Okamoto H.
        • Yano K.
        • Nozaki Y.
        • et al.
        Mutations within the s gene of hepatitis-B virus transmitted from mothers to babies immunized with hepatitis-B immune globulin and vaccine.
        Paediatr Res. 1992; 32: 264-268
        • Okamoto H.
        • Yotsumoto S.
        • Akahane Y.
        • et al.
        Hepatitis B viruses with pre-core region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen.
        J Virol. 1990; 64: 1298-1303
        • Penna A.
        • Chisari F.V.
        • Bertoletti A.
        • et al.
        Cytotoxic T lymphocytes recognize an HLA-A2 restricted epitope within the hepatitis B virus nucleocapsid antigen.
        J Exp Med. 1991; 174: 1565-1570
        • Petit M-A
        • Dubanchet S.
        • Capel F.
        • et al.
        HepG2 cell binding activities of different hepatitis B virus isolates: inhibitory effect of anti-HBs and anti-preSl(21-47).
        Virology. 1991; 180: 483-491
        • Pollack J.R.
        • Ganem D.
        An RNA stem-loop structure directs hepatitis B virus genomic RNA encapsidation.
        J Virol. 1993; 67: 3254-3263
        • Rossner M.T.
        Hepatitis B virus X-gene product: A promiscuous transcriptional activator [review].
        J Med Virol. 1992; 36: 101-117
        • Roychoudhury S.
        • Faruqi A.F.
        • Shih C.
        Pregenomic RNA encapsidation analysis of eleven missense and nonsense polymerase mutants of human hepatitis B virus.
        J Virol. 1991; 65: 3617-3624
        • Santantonio T.
        • Jung M.C.
        • Schneider R.
        • et al.
        Identification of HBV pre-S mutants and their intrafamilial spreading.
        J Hepatol. 1991; 13: S69
        • Scaglione P.P.
        • Melegari M.
        • Takahashi M.
        • et al.
        Use of dominant negative mutants of the hepadna viral core protein as antiviral agents.
        Hepatology. 1995; 22: 224A
        • Schlicht H-J
        • Schaller H.
        The secretory core protein of human hepatitis B virus is expressed on the cell surface.
        J Virol. 1989; 63: 5399-5404
        • Schlicht H-J
        • Wasenauer G.
        The quaternary structure, antigenicity and aggregational behaviour of the secretory core protein of human hepatitis B virus are determined by its signal sequence.
        J Virol. 1991; 65: 6817-6825
        • Stemeck M.
        • Günther S.
        • Santantonia T.
        • et al.
        The complete nucleotide sequence of hepatitis B virus in 9 patients with fulminant hepatitis B infection.
        Hepatology. 1995; 22: 261A
        • Tong S.P.
        • Li J.S.
        • Vitvitski L.
        • et al.
        Replication capacities of natural and artificial precore stop codon mutants of hepatitis B virus: Relevance of pregenome encapsidation signal.
        Virology. 1992; 191: 237-245
        • Tong S.
        • Li J.
        • Vitvitski L.
        • et al.
        Active hepatitis B virus replication in the presence of anti-HBe is associated with viral variants containing an inactive pre-C region.
        Virology. 1990; 176: 596-603
        • Tran A.
        • Kremsdorf D.
        • Capel F.
        • et al.
        Emergence of and takeover by hepatitis B virus (HBV) with rearrangements in the pre-S/S and pre-C/C genes during chronic HBV infection.
        J Virol. 1991; 65: 3566-3574
        • Trautwein C.
        • Schrem H.
        • Tillmann H.
        • et al.
        The HBV pre-S genome before and after OLT: Implication for viral uptake and defense mechanisms.
        J Hepatol. 1995; 23: 83
        • Ulrich P.P.
        • Bhat R.A.
        • Kelly I.
        • et al.
        A precore-defective mutant of hepatitis B virus associated with e antigen-negative chronic liver disease.
        J Med Virol. 1990; 32: 109-118
        • Von Weizsäcker F.
        • Pult I.
        • Geiss K.
        • et al.
        Selective transmission of variant genomes from mother to infant in neonatal fulminant hepatitis B.
        Hepatology. 1995; 21: 8-13
        • Wakita T.
        • Kakumu S.
        • Shibata M.
        • et al.
        Detection of pre-C and core region mutants of hepatitis B virus in chronic hepatitis B virus carriers.
        J Clin Invest. 1991; 88: 1793-1801
        • Wallace L.A.
        • Echevarria J.E.
        • Echevarria J.M.
        • et al.
        Molecular characterisation of envelope antigenic variants of hepatitis B virus from Spain.
        J Infect Dis. 1994; 170: 1300-1303
        • Wang X.W.
        • Forrester K.
        • Yeh H.
        • et al.
        Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity and association with transcription factor ERCC3.
        Proc Natl Acad Sei USA. 1994; 91: 2230-2234
        • Waters J.
        • Kennedy M.
        • Voet P.
        • et al.
        Loss of the common ‘a’ determinant of hepatitis B surface antigen by a vaccine induced escape mutant.
        J Clin Invest. 1992; 90: 2543-2547
        • Williams D.
        • MacNair A.
        • Carman W.F.
        HBV core proteins with central deletions seen during chronic hepatitis do not form particles.
        Hepatology. 1995; 22: 267A
        • Wright T.L.
        • Mamish D.
        • Combs C.
        • et al.
        Hepatitis B virus and apparent fulminant non-A, non-B hepatitis.
        Lancet. 1992; 339: 952-955
        • Yamamoto K.
        • Horokita M.
        • Tsuda F.
        • et al.
        Naturally occurring escape mutants of hepatitis B virus with various mutations in the S gene in carriers seropositive for antibody to hepatitis B surface antigen.
        J Virol. 1994; 68: 2671-2676
        • Yasmin M.
        • Irish C.
        • Williams R.
        • et al.
        Enhancer, core promoter and pre-core/core sequences from 15 fulminant HBV cases.
        J Hepatol. 1995; 23: 100
        • Yee J.K.
        A liver-specific enhancer in the core promoter region of human hepatitis B virus.
        Science. 1989; 246: 658-661
        • Yuh C.H.
        • Ting L.P.
        C/EBP-like proteins binding to the functional box and box β of the second enhancer of hepatitis B virus.
        Mol Cell Biol. 1991; 11: 5044-5052
        • Xu J.
        • Brown D.
        • Harrison T.
        • et al.
        Absence of hepatitis B virus precore mutants in patients with chronic hepatitis B responding to interferon-alpha.
        J Hepatol. 1992; 15: 1002-1006