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. 2007 May 1;6(1):113–143. doi: 10.1111/j.1582-4934.2002.tb00317.x

Molecular, immunological and clinical properties of mutated hepatitis B viruses

C Kreutz 1,✉
PMCID: PMC6740305  PMID: 12003675

Abstract

Hepatitis B virus (HBV) is at the origin of severe liver diseases like chronic active hepatitis, liver cirrhosis and hepatocellular carcinoma. There are some groups of patients with high risk of generation of HBV mutants: infected infants, immunosupressed individuals (including hemodialysis patients), patients treated with interferon and lamivudine for chronic HBV infection. These groups are the target for molecular investigations reviewed in this paper. The emergence of lamivudine‐ or other antiviral‐resistant variants, rises concern regarding long term use of these drugs. Infection or immunization with one HBV subtype confers immunity to all subtypes. However, reinfection or reactivation of latent HBV infection with HBV mutants have been reported in patients undergoing transplant and those infected with HIV. Mutations of the viral genome which are not replicative incompetent can be selected in further course of infection or under prolonged antiviral treatment and might maintain the liver disease. Four open reading frames (ORF) which are called S‐gene, C‐gene, X‐gene and P‐gene were identified within the HBV genome. Mutations may affect each of the ORFs. Mutated S‐genes were described to be responsible for HBV‐infections in successfully vaccinated persons, mutated C‐genes were found to provoke severe chronic liver diseases, mutated X‐genes could cause serious medical problemes in blood donors by escaping the conventional test systems and mutated P‐genes were considered to be the reason for chemotherapeutic drug resistance. This paper reviews molecular, immunological and clinical aspects of the HBV mutants.

Keywords: hepatitis B virus, genome, mutations, immunity, liver disease

References

  • 1. Grob P.J., Joller‐Jemelka H.I., Fortschritte in der Hepatitisdiagnostik, Schweiz. Rundschau für Medizin (Praxis), 19: 547–554, 1995. [PubMed] [Google Scholar]
  • 2. Santantonio T., Jung M.C., Miska S., Pastore G., Pape G.R., Will H., Prevalence and type of pre‐C HBV mutants in anti‐HBe positive carriers with chronic liver disease in a highly endemic area, Virology, 183: 840–844, 1991. [DOI] [PubMed] [Google Scholar]
  • 3. Chu C.M., Yeh C.T., Chiu C.T., Sheen I.S., Liaw Y.F., Precore mutant of hepatitis B virus prevails in acute and chronic infections in an area in which heptatits B is endemic, J. Clin. Microbiol., 7: 1815–1818, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Yamamoto K., Horikita M., Tsuda F., Itoh K., Akahane Y., Yotsumoto S., Okamoto H., et al., Hepatitis B virus escape mutants: “Pushing the envelope” of chronic hepatitis B virus infection, Hepatology, 3: 1995, 884–887, 1995. [DOI] [PubMed] [Google Scholar]
  • 5. Carman W.F., Zanetti A.R., Karayiannis P., Waters J., Manzillo G., Tanzi E., Zuckerman A.J., Thomas H.C., Vaccine‐induced escape mutant of hepatitis B virus, Lancet, 336: 325–329, 1990. [DOI] [PubMed] [Google Scholar]
  • 6. Kohno H., Inoue T., Tsuda F., Okamoto H., Akahane Y., Mutations in the envelope gene of hepatitis B virus variants co‐occurring with antibody to surface antigen in sera from patients with chronic hapatitis B, J. Gen. Virol., 77: 1825–1831, 1996. [DOI] [PubMed] [Google Scholar]
  • 7. Blum H.E., Variants of hepatitis B, C and D viruses: Molecular biology and clinical significance, Digestion, 56: 85–95, 1995. [DOI] [PubMed] [Google Scholar]
  • 8. Santantonio T., Jung M.C., Schneider R., Pastore G., Pape G.R., Will H., Selection for a pre‐C stop codon mutation in a hepatitis B virus variant with a pre‐C initiation codon mutation during interferon treatment, J. Hepatol., 3: 368–371, 1991. [DOI] [PubMed] [Google Scholar]
  • 9. Löhr H.F., Weber W., Schlaak J., Goergen B., Meyer zum Büschenfelde K.H., Gerken G., Proliferative response of CD4+ T cells and hepatitis B virus clearance in chronic hepatitis with or without hepatitis B e‐minus hepatitis B virus mutants, Hepatology, 1: 61–68, 1995. [DOI] [PubMed] [Google Scholar]
  • 10. Laskus T., Rakela J., Persing D.H., Nucleotide sequence analysis of precore and proximal core regions in patients with chronic hepatitis B treated with interfernon, Dig. Dis. Sci., 1: 1–7, 1995. [DOI] [PubMed] [Google Scholar]
  • 11. Bartholomew M.M., Jansen R.W., Jeffers L.J., Reddy K.R., Johnson L.C., Bunzendahl H., Condreay L.D., Tzakis A.G., Schiff E.R., Brown N.A., Hepatitis‐B‐virus resistance to lamivudine given for recurrent infection after orthotopic liver tranplantation, Lancet, 349: 20–22, 1997. [DOI] [PubMed] [Google Scholar]
  • 12. Lee Y.I., Hur G.M., Suh D.J., Kim S.H., Novel pre‐C/C gene mutants of hepatitis B virus in chronic active hepatitis: naturally occurring escape mutants, J. Gen. Virol., 77: 1129–1138, 1996. [DOI] [PubMed] [Google Scholar]
  • 13. Günther S., Baginski S., Kissel H., Reinke P., Krüger D.H., Will H., Meisel H., Accumulation and persistence of hepatitits B virus core gene deletion mutants in renal transplant patients are associated with end‐stage liver disease, Hepatology, 4: 751–758, 1996. [DOI] [PubMed] [Google Scholar]
  • 14. Guptan R.C., Thakur V., Sarin S.K., Banerjee K., Khandekar P., Frequency and clinical profile of precore and surface hepatitis B mutants in Asian‐Indian patients with chronic liver disease, A. J. G., 7: 1312–1317, 1996. [PubMed] [Google Scholar]
  • 15. Günther S., Li B.C., Miska S., Krüger D.H., Meisel H., Will H., A novel method for efficient amplification of whole hepatitis B virus genomes permits rapid functional analysis and reveals deletion mutants in immunosuppressed patients, J. Virol., 9: 5437–5444, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Hosono S., Tai P.C., Wang W., Ambrose M., Hwang D.G.Y., Yuan T.T., Peng B.H., Yang C.S., Lee C.S., Shih C., Core antigen mutations of human hepatitis B virus in hepatomas accumulate in MHC class II‐restricted T cell epitopes, Virology, 212: 151–162, 1995. [DOI] [PubMed] [Google Scholar]
  • 17. Wang X.W., Forrester K., Yeh H., Feitelson M.A., Gu J.R., Harris C.C., Hepatitis B virus X protein inhibits p53 sequence‐specific DNA binding, transcriptional activity, and association with transcription factor ERCC3, Proc. Natl. Acad. Sci. USA, 91: 2230–2234, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Takada S., Koike K., Trans‐activation function of a 3 ' truncated X gene‐cell fusion product from integrated hepatitis B virus DNA in chronic hepatitis tissues, Proc. Natl. Acad. Sci. USA, 15: 5628–5632, 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Galibert F., Mandart E., Fitoussi F., Tiollais P., Charnay P., Nucleotide sequence of the hepatitis B virus genome (subtyp ayw) cloned in e. coli, Nature, 281: 646–650, 1979. [DOI] [PubMed] [Google Scholar]
  • 20. Tiollais P., Pourcel C., Dejean A., The hepatitis B virus, Nature, 317: 489–495, 1985. [DOI] [PubMed] [Google Scholar]
  • 21. Norder H., Couroucé A.M., Magnius L.O., Molecular basis of hepatitis B virus serotype variations within the four major subtypes, J. Gen. Virol., 73: 3141–3145, 1992. [DOI] [PubMed] [Google Scholar]
  • 22. Ohnuma H., Machida A., Okamoto H., Tsuda F., Sakamoto M., Tanaka T., Miyakawa Y., Mayumi M., Allelic subtypic determinants of hepatitis B surface antigen (i and t) that are distinct from d/y or w/r, J. Virol., 2: 927–932, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Kidd‐Ljunggren K., Variability in hepatitis B virus DNA: Phylogenetic, epidemiological and clinical implications, Scand. J. Infect. Dis., 2: 111–116, 1996. [DOI] [PubMed] [Google Scholar]
  • 24. Courouce‐Pauty A.M., Plancon A., Soulier J.P., Distribution of HBsAg subtypes in the world, Vox Sang, 4: 197–211, 1983. [DOI] [PubMed] [Google Scholar]
  • 25. Fiordalisi G., Ghiotto F., Castelnuovo F., Primi D., Cariani E., Analysis of the hepatitis B virus genome and immune response in HBsAG, anti‐HBs positive chronic hepatitis, J. Hepatol., 4: 487–493, 1994. [DOI] [PubMed] [Google Scholar]
  • 26. Brown S.E., Howard C.R., Zuckerman A.J., Steward M.W., Affinity of antibody responses in man to hepatitis B vaccine determined with synthetic peptides, Lancet, 2: 184–187, 1984. [DOI] [PubMed] [Google Scholar]
  • 27. Ghany M.G., Ayola B., Villamil F.G., Gish R.G., Rojter S., Vierling J.M., Lok A.S., Hepatitis B virus S mutants in liver transplant recipients who were reinfected despite hepatitis B immune globulin prophylaxis, Hepatology, 1: 213–222, 1998. [DOI] [PubMed] [Google Scholar]
  • 28. Ngui S.L., O' Connell S., Eglin R.P., Heptonstall J., Teo C.G., Low detection rate and maternal provenance of hepatitis B virus S gene mutants in cases of failed postnatal immunoprophylaxis in England and Wales, J. Infec. Dis., 5: 1360–1365, 1997. [DOI] [PubMed] [Google Scholar]
  • 29. Hsu H.Y., Chang M.H., Ni Y.H., Lin H.H., Wang S.M., Chen D.S., Surface gene mutants of hepatitis B virus in infants who develop acute or chronic infections despite immunoprophylaxis, Hepatology, 3: 786–791, 1997. [DOI] [PubMed] [Google Scholar]
  • 30. Oon C.J., Chen W.N., Goo K.S., Goh K.T., Intrafamilial evidence of horizontal transmission of hepatitis B virus surface antigen mutant G145R, J. Infection., 3: 260–264, 2000. [DOI] [PubMed] [Google Scholar]
  • 31. Mele A., Tancredi F., Romano L., Giuseppone A., Colucci M., Sangiuolo A., Lecce R., Adamo B., Tosti M.E., Taliani G., Zanetti A.R., Effectiveness of hepatitis B vaccination in babies born to hepatitis B surface antigen‐positive mothers in Italy, J. Infect. Dis., 7: 905–908, 2001. [DOI] [PubMed] [Google Scholar]
  • 32. Zhong S., Chan J.Y., Yeo W., Tam J.S., Johnson P.J., Hepatitis B envelope protein mutants in human hepatocellular carcinoma tissues, J. Viral Hep., 3: 195–202, 1999. [DOI] [PubMed] [Google Scholar]
  • 33. He J.W., Lu Q., Zhu Q.R., Duan S.C., Wen Y.M., Mutations in the ‘a’ determinant of hepatitis B surface antigen among Chinese infants receiving active postexposure hepatitis B immunization, Vaccine, 2–3: 170–173, 1998. [DOI] [PubMed] [Google Scholar]
  • 34. Kato J., Hasegawa K., Torii N., Yamauchi K., Hayashi N., A molecular analysis of viral persistence in surface antigen‐negative chronic hepatitis B, Hepatology, 23: 391–395, 1996. [DOI] [PubMed] [Google Scholar]
  • 35. Oon C.J., Chen W.N., Current aspects of hepatitis B surface antigen mutants in Singapore, J. Viral Hepatitis, 5: (Suppl. 2), 17–23, 1998. [DOI] [PubMed] [Google Scholar]
  • 36. Schories M., Peters T., Rasenack J., Isolation, characterization and biological significance of hepatitis B virus mutants from serum of a patient with immunologically negative HBV infection, J. Hepatol., 5: 799–811, 2000. [DOI] [PubMed] [Google Scholar]
  • 37. Chirara M.M., Chetsanga C.J., Variant of hepatitis B virus isolated in Zimbabwe, J. Med. Virol., 42: 73–78, 1994. [DOI] [PubMed] [Google Scholar]
  • 38. Oon C.J., Lim G.K., Ye Z., Goh K.T., Tan K.L., Yo S.L., Hopes E., Harrison T.J., Zuckerman A.J., Molecular epidemiology of hepatitis B virus vaccine variants in Singapore, Vaccine, 8: 699–702, 1995. [DOI] [PubMed] [Google Scholar]
  • 39. Shields P.L., Owsianka A., Carman W.F., Boxall E., Hubscher S.G., Shaw J., O'Donnell K., Elias E., Mutimer D.J., Selection of hepatitis B surface “escape” mutants during passive immune prophylaxis following liver transplantation: potential impact of genetic changes on polymerase protein function, Gut, 2: 306–309, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Brind A., Jiang J., Samuel D., Gigou M., Feray C., Brechot C., Kremsdorf D., Evidence for selection of hepatitis B mutants after liver transplantation through peripheral blood mononuclear cell infection, J. Hepatol., 2: 228–235, 1997. [DOI] [PubMed] [Google Scholar]
  • 41. Protzer‐Knolle U., Naumann U., Bartenschlager R., Berg T., Hopf U., Meyer zum Büschenfelde K.H., Neuhaus P., Gerken G., Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high‐dose hepatitis B immune globulin after liver transplantation, Hepatology, 1: 254–263, 1998. [DOI] [PubMed] [Google Scholar]
  • 42. Seddigh‐Tonekaboni S., Lim W.L., Young B., Hou J.L., Waters J., Luo K.X., Thomas H.C., Karayiannis P., Hepatitis B surface antigen variants in vaccinees, blood donors and an interferon‐treated patient, J.Viral.Hepat., 2: 154–158, 2001. [DOI] [PubMed] [Google Scholar]
  • 43. Oon C.J., Chen W.N., Lim N., Koh S., Lim G.K., Leong A.L., Tan G.S., Hepatitis B virus variants with lamivudine‐related mutations in the DNA polymerase and the ‘a’ epitope of the surface antigen are sensitive to ganciclovir, Antiviral Researche, 3: 113–118, 1999. [DOI] [PubMed] [Google Scholar]
  • 44. Sterneck M., Kalinina T., Günther S., Fischer L., Santantonio T., Greten H., Will H., Functional analysis of HBV genomes from patients with fulminant hepatitis, Hepatology, 5: 1390–1397, 1998. [DOI] [PubMed] [Google Scholar]
  • 45. Moraes M.T.B., Gomes S.A., Niel C., Sequence analysis of pre‐S/S gene of hepatitis B virus strains of genotypes A, D, and F isolated in Brazil, Arch. Virol. 141: 1767–1773, 1996. [DOI] [PubMed] [Google Scholar]
  • 46. Ho M.S., Lu C.F., Kuo J., Mau Y.C., Chao W.H., A family cluster of an immune escape variant of hepatitis B virus infecting a mother and her two fully immunized children, Clin. Diagn. Lab. Immunol., 2: 760–762, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Yamamoto K., Horikita M., Tsuda F., Itoh K., Akahane Y., Yotsumoto S., Okamoto H., Miyakawa Y., Mayumi M., Naturally occurring escape mutants of heptatitis B virus with various mutations in the S gene in carriers seropostive for antibody to hepatitis B surface antigen, J. Virol., 4: 2671–2676, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Yoshida E.M., Ramji A., Erb S.R., Davis J.E., Steinbrecher U.P., Sherlock C.H., Scudamore C.H., Chung S.W., Williams M., Gutfreund K.S., De novo acute hepatitis B infection in a previously vaccinated liver transplant recipient due to a strain of HBV with a Met 133 Thr mutation in the “a” determinant, Liver, 5: 411–114, 2000. [DOI] [PubMed] [Google Scholar]
  • 49. Karthigesu V., Allison L., D'Mello F., Fortuin M., Whittle H., Howard C.R., Breakthrough infections among children immunized against hepatitis B due to a novel variant (Abstract), La Jolla, CA: 1992. Meeting on Molecular Biology of Hepatitis B Viruses.
  • 50. Rodriguez‐Frias F., Buti M., Jardi R., Vargas V., Quer J., Cotrina M., Martell M., Esteban R., Guardia J., Genetic alternations in the S gene of hepatitis B virus in patients with acute hepatitis B, chronic hepatitis B and hepatitis B liver cirrhosis before and after liver transplantation, Liver, 3: 177–182, 1999. [DOI] [PubMed] [Google Scholar]
  • 51. Carman W.F., Wallace L., Carulla J., McPhee R., Decker R., Natural occurance of arginine at aa 145 of HBsAg undetected by current assays causing fulminant hepatitis [Abstract 773] International Symposium on Viral Hepatitis and Liver Disease, 289, 1993.
  • 52. Solomon L.R., Suhar T., Decker R., Okasinski G., Mimms L., Novel insertional S gene mutant in a fulminant hepatitis patient [Abstact 79] Molecular biology of hepatitis B viruses, Washington D.C : Georgetown University Press, 1993. [Google Scholar]
  • 53. Chong‐Jin O., Wei Ning C., Shiuan K., Gek Keow L., Identification of hepatitis B surface antigen variants with alterations outside the “a” determinant in immunized Singapore infants, J. Infect. Dis., 1: 259–263, 1999. [DOI] [PubMed] [Google Scholar]
  • 54. Blum H.E., Hepatitis B virus: Significance of naturally occurring mutants, Intervirology, 35: 40–50, 1993. [DOI] [PubMed] [Google Scholar]
  • 55. Ngui S.L., Andrews N.J., Underhill G.S., Heptonstall J., Teo C.G., Failed postnatal immunoprophylaxis for hepatitis B: characteristics of maternal hepatitis B virus as risk factors, Clin. Infect. Dis., 1: 100–106, 1998. [DOI] [PubMed] [Google Scholar]
  • 56. Lelie P.N., Ip H.M.H., Reesnik H.W., Wong V.C.W., Kuhns M.C., Prevention of the hepatitis B virus carrier state in infants of mothers with high and low serum levels of HBV‐DNA In:Hollinger F.B., Lemon S.M., Margolis H.S., eds., Viral hepatitis and liver disease, Baltimore : Williams & Wilkins, 1991, pp. 753–756. [Google Scholar]
  • 57. Carman W.F., Trautwein C., van Deursen F.J., Colman K., Dornan E., McIntyre G., Waters J., et al, Hepatitis B virus envelope variation after transplantation with and without hepatitis B immune globulin prophylaxis, Hepatology, 24: 489–493, 1996. [DOI] [PubMed] [Google Scholar]
  • 58. Tai P., Banik D., Lin G., Pai S., Pai K., Lin M.H., Yuoh G., et al, Novel and frequent mutations of hepatitis B virus coincide with a major histocompatibility complex class‐I restricted T‐cell epitope of the surface antigen, J. Virol., 71: 4852–4856, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59. Yap I., Chan S.H., A new pre‐S containing recombinant hepatitis B vaccine and its effect on non‐responders: A preliminary observation, Ann. Acad. Med. Singapore, 1: 120–122, 1996. [PubMed] [Google Scholar]
  • 60. Yap I., Guan R., Chan S.H., Study on the comparative immunogenicity of a recombinant DNA hepatitis B vaccine containing pre‐S components of the HBV coat protein with non pre‐S containing vaccines, J. Gastroenterol. Hepatol., 1: 51–55, 1995. [DOI] [PubMed] [Google Scholar]
  • 61. Fernholz D., Galle P.R., Stemler M., Brunetto M., Bonino F., Will H., Infectious hepatitis B virus variant defective in pre‐S2 protein expression in a chronic carrier, Virology, 194: 137–148, 1993. [DOI] [PubMed] [Google Scholar]
  • 62. Trautwein C., Schrem H., Tillmann H.L., Kubicka S., Walker D., Böker K.H.W., Maschek H.J., Pichlmayr R., Manns M.P., Hepatitis B virus mutations in the pre‐S genome before and after liver transplantation, Hepatology, 3: 482–488, 1996. [DOI] [PubMed] [Google Scholar]
  • 63. Melegari M., Scaglioni P.P., Wands J.R., The small envelope protein is required for secretion of a naturally occurring hepatitis B virus mutant with pre‐S1 deleted, J. Virol., 7: 5449–5454, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Budkowska A., Bedossa P., Groh F., Louise A., Pillot J., Fibronectin of human liver sinusoids binds hepatitis B virus: Identification by an anti‐idiotypic antibody bearing the internal image of the pre‐S2 domain, J. Virol., 2: 840–848, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65. Le Seyec J., Chouteau P., Cannie I., Guguen‐Guillouzo C., Gripon P., Role of the pre‐S2 domain of the large envelope protein in hepatitis B virus assembly and infectivity, J. Virol., 7: 5573–5578, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66. Bruss V., A short linear sequence in the pre‐S domain of the large hepatitis B virus envelope protein required for virion formation, J. Virol., 12: 9350–9357, 1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67. Gerner P.R., Friedt M., Oettinger R., Lausch E., Wirth S., The hepatitis B virus seroconversion to anti‐Hbe is frequently associated with HBV genotype changes and selection of preS2‐defective particles in chronically infected children, Virology, 1: 163–172, 1998. [DOI] [PubMed] [Google Scholar]
  • 68. Hawkins A.E., Gilson R.J.C., Bickerton E.A., Tedder R.S., Weller I.V.D., Conservation of precore and core sequences of hepatitis B virus in chronic viral carriers, J. Med. Virol., 43: 5–12, 1994. [DOI] [PubMed] [Google Scholar]
  • 69. Schödel F., Peterson D., Zheng J., Jones J.E., Hughes J.L., Milich D.R., Structure of hepatitis B virus core and e‐antigen, J. Biol. Chem., 2: 1332–1337, 1993. [PubMed] [Google Scholar]
  • 70. Takahashi K., Kishimoto S., Ohori K., Yoshizawa H., Machida A., Ohnuma H., Tsuda F., Munekata E., Miyakawa Y., Mayumi M., Molecular heterogeneity of e antigen polypeptides in sera from carriers of hepatitis B virus, J. Immunol., 9: 3156–3160, 1991. [PubMed] [Google Scholar]
  • 71. 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., 9: 3389–3396, 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72. Tavis J.E., Perri S., Ganem D., Hepadnavirus reverse transcription initiates within the stem‐loop of the RNA packaging signal and employs a novel strand transfer, J. Virol., 6: 3536–3543, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73. Okamoto H., Tsuda F., Sakugawa H., Sastrosoewignjo R.I., Imai M., Miyakawa Y., Mayumi M., Typing hepatitis B virus by homology in nucleotide sequence: Comparison of surface antigen subtypes, J. Gen. Virol., 69: 2575–2583, 1988. [DOI] [PubMed] [Google Scholar]
  • 74. Norder H., Couroucé A.M., Magnius L.O., Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes, Virology, 198: 489–503, 1994. [DOI] [PubMed] [Google Scholar]
  • 75. Stuyver L., de Gendt S., van Geyt C., Zoulim F., Fried M., Schinazi R.F., Rossau R., A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness, J. Gen. Virol., 1: 67–74, 2000. [DOI] [PubMed] [Google Scholar]
  • 76. Stuyver L., de Gendt S., van Geyt C., Zoulim F., Fried M., Schinazi R.F., Rossau R., Characterization of a new hepatitis B virus: complete genome and phylogenetic relatedness, J. Gen. Virol., in press. [DOI] [PubMed]
  • 77. Stuyver L., van Geyt C., de Gendt S., van Reybroeck G., Zoulim F., Leroux‐Roels G., Rossau R., Line probe assay for monitoring drug resistance in hepatitis B virus‐infected patients during antiviral therapy, J. Clin. Microbiol., 2: 702–707, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78. Friedt M., Gerner P., Lausch E., Trbel H., Zabel B., Wirth S., Mutations in the basic core promotor and the precore region of hepatitis B virus and their selection in children with fulminant and chronic hepatitis B, Hepatology, 4: 1252–1258, 1999. [DOI] [PubMed] [Google Scholar]
  • 79. Niitsuma H., Ishii M., Saito Y., Miura M., Kobayashi K., Ohori H., Toyota T., Prevalence of precore‐defective mutant of hepatitits B virus in HBV carriers, J. Med. Virol., 46: 397–402, 1995. [DOI] [PubMed] [Google Scholar]
  • 80. Ulrich P.P., Bhat R.A., Kelly I., Brunetto M.R., Bonino F., Vyas G.N., A precore‐defective mutant of hepatitis B virus associated with e antigen‐negative chronic liver disease, J. Med. Virol., 32: 109–118, 1990. [DOI] [PubMed] [Google Scholar]
  • 81. Yuan T.T.T., Faruqi A., Shih J.W.K., Shih C., The mechanism of natural occurrence of two closely linked HBV precore predominant mutations, Virology, 211: 144–156, 1995. [DOI] [PubMed] [Google Scholar]
  • 82. Rodriguez‐Frias F., Buti M., Jardi R., Cotrina M., Viladomiu L., Esteban R., Guardia J., Hepatitis B virus infection: Precore mutants and its relation to viral genotypes and core mutations, Hepatology, 6: 1641–1647, 1995. [DOI] [PubMed] [Google Scholar]
  • 83. Guo Y., Hou J., Luo K., Feng X., Genetic mutations of precore region of hepatitis B virus in hepatitis B e antigen‐negative patients with fulminant hepatitis B and translation of precore variants in vitro, Zhonghua Gan Zang Bing Za Zhi, 1: 42–44, 2001. [PubMed] [Google Scholar]
  • 84. Günther S., Meisel H., Reip A., Miska S., Krüger D.H., Will H., Frequent and rapid emergence of mutated pre‐C sequences in HBV from e‐antigen positive carriers who seroconvert to anti‐HBe during interferon treatment, Virology, 187: 271–279, 1992. [DOI] [PubMed] [Google Scholar]
  • 85. Carman W.F., Jacyna M.R., Hadziyannis S., Karayiannis P., McGarvey M.J., Makris A., Thomas H.C., Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection, Lancet, 2: 588–591, 1989. [DOI] [PubMed] [Google Scholar]
  • 86. Kramvis A., Kew M.C., Bukofzer S., Hepatitis B virus precore mutants in serum and liver of Southern African Blacks with hepatocellular carcinoma, J. Hepatol., 1: 132–141, 1998. [DOI] [PubMed] [Google Scholar]
  • 87. Okamoto H., Yotsumoto S., Akahane Y., Yamanaka T., Miyazaki Y., Sugai Y., Tsuda F., Tanaka T., Miyakawa Y., Mayumi M., Hepatitis B viruses with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen, J. Virol., 3: 1298–1303, 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88. Omi S., Okamoto H., Tsuda F., Mayumi M., Defects in the precore region of hepatitis B virus DNA in a plasma pool from carriers seropositive for antibody against e antigen and with infectivity in chimpanzees, J. Gastroenterol. Hepatol., 6: 646–652, 1990. [DOI] [PubMed] [Google Scholar]
  • 89. Akahane Y., Yamanaka T., Suzuki H., Sugai Y., Tsuda F., Yotsumoto S., Omi S., Okamoto H., Miyakawa Y., Mayumi M., Chronic active hepatitis with hepatitis B virus DNA and antibody against e antigen in the serum. Disturbed synthesis and secretion of e antigen from hepatocytes due to a point mutation in the precore region, Gastoenterol., 4: 1113–1119, 1990. [DOI] [PubMed] [Google Scholar]
  • 90. Brunetto M.R., Stemler M., Bonino F., Schodel F., Oliveri F., Rizzetto M., Verme G., Will H., A new hepatitis B virus strain in patients with severe anti‐HBe positive chronic hepatitis B, J. Hepatol., 2: 258–261, 1990. [DOI] [PubMed] [Google Scholar]
  • 91. Naoumov N.V., Schneider R., Groetzinger T., Jung M.C., Miska S., Pape G.R., Will H., Precore mutant hepatitis B virus infection and liver disease, Gastroenterology, 2: 538–543, 1992. [DOI] [PubMed] [Google Scholar]
  • 92. Inoue K., Yoshiba M., Sekiyama K., Okamoto H., Mayumi M., Clinical and molecular virological differences between fulminant hepatic failures following acute and chronic infection with hepatitis B virus, J. Med. Virol., 1: 35–41, 1998. [DOI] [PubMed] [Google Scholar]
  • 93. Hasegawa K., Huang J., Rogers S.A., Blum H.E., Liang T.J., Enhanced replication of a hepatitis B virus mutant associated with an epidemic of fulminant hepatitis, J. Virol., 3: 1651–1659, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94. Kosaka Y., Takase K., Kojima M., Shimizu M., Inoue K., Yoshiba M., Tanaka S., Akahane Y., Okamoto H., Tsuda F., et al., Fulminant hepatitis B: Induction by hepatitis B virus mutants defective in the precore region and incapable of encoding e antigen, Gastroenterology, 4: 1087–1094, 1991. [DOI] [PubMed] [Google Scholar]
  • 95. Liang T.J., Hasegawa K., Rimon N., Wands J.R., Ben‐Porath E., A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis (see comments), N. Engl. J. Med., 24: 1705–1709, 1991. [DOI] [PubMed] [Google Scholar]
  • 96. Omata M., Ehata T., Yokosuka O., Hosoda K., Ohto M., Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis (see comments), N. Engl. J. Med., 24: 1699–1704, 1991. [DOI] [PubMed] [Google Scholar]
  • 97. Fujise K., Suzuki K., Naito Y., Niiya M., Ishikawa T., Takahashi H., Hoshina S., Saito A., Watanabe R., Hepatitis B virus variants in patients with acute hepatitis in whom various clinical forms develop, Kansenshogaku Zasshi, J. Japan. Association Infect. Dis., 1: 67–74, 1998. [DOI] [PubMed] [Google Scholar]
  • 98. Ito S., Nakazono K., Murasawa A., Mita Y., Hata K., Saito N., Kikuchi M., Yoshida K., Nakano M., Gejyo F., Development of fulminant hepatitis B (precore variant mutant type) after the discontinuation of low‐dose methotrexate therapy in a rheumatoid arthritis patient, Arthritis and Rheumatism, 2: 339–342, 2001. [DOI] [PubMed] [Google Scholar]
  • 99. Karasawa T., Aizawa Y., Zeniya M., Kuramoto A., Shirasawa T., Toda G., Genetic heterogeneity in the precore region of hepatitits B virus in hepatitis B e antigen‐negative chronic hepatitis B patients: spontaneous seroconversion and interferon‐induced seroconversion, J. Med. Virol., 45: 373–380, 1995. [DOI] [PubMed] [Google Scholar]
  • 100. Nakahori S., Yokosuka O., Ehata T., Chuang W. L., Imazeki F., Ito Y., Ohto M., Detection of hepatitis B virus precore stop codon mutants by selective amplification method: Frequent detection of precore mutants in hepatitis B e antigen positive healthy carriers, J. Gastroenterol. Hepatol., 4: 419–425, 1995. [DOI] [PubMed] [Google Scholar]
  • 101. Laskus T., Persing D.H., Nowicki M.J., Mosley J.W., Rakela J., Nucleotide sequence analysis of the precore region in patients with fulminant hepatitis B in the United States, Gastroenterology, 4: 1173–1178, 1993. [DOI] [PubMed] [Google Scholar]
  • 102. Naumann U., Protzer‐Knolle U., Berg T., Leder K., Lobeck H., Bechstein W.O., Gerken G., Hopf U., Neuhaus P., A pretransplant infection with precore mutants of hepatitis B virus does not influence the outcome of orthotopic liver transplantation in patients on high dose anti‐hepatitis B virus surface antigen immunoprophylaxis, Hepatology, 2: 478–484, 1997. [DOI] [PubMed] [Google Scholar]
  • 103. Dienes H.P., Gerken G., Goergen B., Heermann K., Gerlich W., Meyer zum Büschenfelde K.H., Analysis of the precore DNA sequence and detection of precore antigen in liver specimens from patients with anti‐hepatitis B e‐positive chronic hepatitis, Hepatology, 1: 1–7, 1995. [PubMed] [Google Scholar]
  • 104. Zhong S., Chan J.Y., Yeo W., Tam J.S., Johnson P.J., Frequent integration of precore/core mutants of hepatitis B virus in human hepatocellular carcinoma tissues, J. Viral Hepatitis, 2: 115–123, 2000. [DOI] [PubMed] [Google Scholar]
  • 105. Ackrill A.M., Naoumov N.V., Eddleston A.L., Williams R., Comparison of pre‐core/core hepatitis B virus region in liver tissue and serum from patients with chronic hepatitis B infection, J. Hepatol., 1‐2: 224–227, 1992. [DOI] [PubMed] [Google Scholar]
  • 106. Schlicht H.J., Wasenauer G., The quaternary structure, antigenicity, and aggregational behavior of the secretory core protein of human hepatitis B virus are determined by its signal sequence, J. Virol., 12: 6817–6825, 1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107. Wasenauer G., Köck J., Schlicht H.J., Relevance of cysteine residues for biosynthesis and antigenicity of human hepatitis B virus e protein, J. Virol., 3: 1315–1321, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 108. Clementi M., Manzin A., Paolucci S., Menzo S., Bagnarelli P., Carloni G., Bearzi I., Hepatitis B virus preC mutants in human hepatocellular carcinoma tissues, Res. Virol., 4: 297–301 1993. [DOI] [PubMed] [Google Scholar]
  • 109. Manzin A., Menzo S., Bagnarelli P., Varaldo P.E., Bearzi I., Carloni G., Galibert F., Clementi M., Sequence analysis of the hepatitis B virus pre‐C region in hepatocellular carcinoma [HCC] and nontumoral liver tissues from HCC patients, Virology, 2: 890–895, 1992. [DOI] [PubMed] [Google Scholar]
  • 110. Triki H., Ben Slimane S., Ben Mami N., Sakka T., Ben Ammar A., Dellagi K., High circulation of hepatitis B virus (HBV) precore mutants in Tunisia, North Africa, Epidemiol. Infect., 1: 169–174, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 111. Nassal M., Junker‐Niepmann M., Schaller H., Translational inactivation of RNA function: discrimination against a subset of genomic transcripts during HBV nucleocapsid assembly, Cell., 6: 1357–1363, 1990. [DOI] [PubMed] [Google Scholar]
  • 112. Birnbaum F., Nassal M., Hepatitis B virus nucleocapsid assembly: primary structure requirements in the core protein, J. Virol., 7: 3319–3330, 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113. Nassal M., The arginine‐rich domain of the hepatitis B virus core protein is required for pregenome encapsidation and productive viral positive‐strand DNA synthesis but not for virus assembly, J. Virol., 7: 4107–4116, 1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114. Missale G., Redeker A., Person J., Fowler P., Guilhot S., Schlicht H.J., Ferrari C., Chisari F.V., HLA‐A31‐ and HLA‐Aw68‐restricted cytotoxic T cell responses to a single hepatitis B virus nucleocapsid epitope during acute viral hepatitis, J. Exp. Med., 3: 751–762, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115. Bertoletti A., Chisari F.V., Penna A., Guilhot S., Galati L., Missale G., Fowler P., Schlicht H.J., Vitiello A., Chesnut R.C., et al., Definition of a minimal optimal cytotoxic T‐cell epitope within the hepatitis B virus nucleocapsid protein, J. Virol., 4: 2376–2380, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 116. Bertoletti A., Ferrari C., Fiaccadori F., Penna A., Margolskee R., Schlicht H.J., Fowler P., Guilhot S., Chisari F.V., HLA class I‐restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen, Proc. Natl. Acad. Sci. USA, 23: 10445–10449, 1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 117. Penna A., Bertoletti A., Cavalli A., Valli A., Missale G., Pilli M., Marchelli S., Giuberti T., Fowler P., Chisari F.V., Fiaccadori F., Ferrari C., Fine specificity of the human T cell response to hepatitis B virus core antigen, Arch. Virol. Suppl., 4: 23–28, 1992. [DOI] [PubMed] [Google Scholar]
  • 118. Ehata T., Omata M., Yokosuka O., Hosoda K., Ohto M., Variations in codons 84‐101 in the core nucleotide sequence correlate with hepatocellular injury in chronic hepatitis B virus infection, J. Clin. Invest., 89: 332–338, 1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 119. Salfeld J., Pfaff E., Noah M., Schaller H., Antigenic determinants and functional domains in core antigen and e antigen from hepatitis B virus, J. Virol., 2: 798–808, 1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 120. McMillian J.S., Bowden D.S., Angus P.W., McCaughan G.W., Locarnini S.A., Mutations in the hepatitis B virus precore/core gene and core promoter in patients with severe recurrent disease following liver transplantation, Hepatology, 6: 1371–1378, 1996. [DOI] [PubMed] [Google Scholar]
  • 121. Milich D.R., McLachlan A., Moriarty A., Thornton G.B., Immune response to hepatitis B virus core antigen (HBcAg): localization of T cell recognition sites within HBcAg/HBeAg, J. Immunol., 4: 1223–1231, 1987. [PubMed] [Google Scholar]
  • 122. Milich D.R., McLachlan A., Stahl S., Wingfield P., Thornton G.B., Hughes J.L., Jones J.E., Comparative immunogenicity of hepatitis B virus core and E antigens, J. Immunol., 10: 3617–3624, 1988. [PubMed] [Google Scholar]
  • 123. Carman W., Thomas H., Domingo E., Viral genetic variation: hepatitis B virus as a clinical example, Lancet, 341: 349–353, 1993. [DOI] [PubMed] [Google Scholar]
  • 124. Wakita T., Kakumu S., Shibata M., Yoshioka K., Ito Y., Shinagawa T., Ishikawa T., Takayanagi M., Morishima T., Detection of pre‐C and core region mutants of hepatitis B virus in chronic hepatitis B virus carriers, J. Clin. Invest., 6: 1793–1801, 1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 125. Maini M.K., Reignat S., Boni C., Ogg G.S., King A.S., Malacarne F., Webster G.J., Bertoletti A., T cell receptor usage of virus‐specific CD8 cells and recognition of viral mutations during acute and persistent hepatitis B virus infection, Europ. J. Immunol., 11: 3067–3078, 2000. [DOI] [PubMed] [Google Scholar]
  • 126. Ehata T., Omata M., Chuang W.L., Yokosuka O., Ito Y., Hosoda K., Ohto M., Mutations in core nucleotide sequence of hepatitis B virus correlate with fulminant and severe hepatitis, J. Clin. Invest., 3: 1206–1213, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 127. Chuang W.L., Omata M., Ehata T., Yokosuka O., Ito Y., Imazeki F., Lu S.N., Chang W.Y., Ohto M., Precore mutations and core clustering mutations in chronic hepatitis B virus infection, Gastroenterology, 1: 263–271, 1993. [DOI] [PubMed] [Google Scholar]
  • 128. Bertoletti A., Sette A., Chisari F.V., Penna A., Levrero M., de Carli M., Fiaccadori F., Ferrari C., Natural variants of cytotoxic epitopes are T‐cell receptor antagonists for antiviral cytotoxic T cells, Nature, 369: 407–410, 1994. [DOI] [PubMed] [Google Scholar]
  • 129. Günther S., Paulij W., Meisel H., Will H., Analysis of hepatitis B virus populations in an interferon‐alpha‐treated patient reveals predominant mutations in the C‐gene and changing e‐antigenicity, Virology, 1: 146–160, 1998. [DOI] [PubMed] [Google Scholar]
  • 130. Rehermann B., Pasquinelli C., Mosier S.M., Chisari F.V., Hepatitis B virus (HBV) sequence variation in cytotoxic T lymphocyte epitopes is not common in patients with chronic HBV infection, J. Clin. Invest., 96: 1527–1534, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 131. Alexopoulou A., Karayiannis P., Hadziyannis S.J., Aiba N., Thomas H.C., Emergence and selection of HBV variants in an anti‐HBe positive patient persistently infected with quasi‐species, J. Hepatol., 26: 748–753, 1997. [DOI] [PubMed] [Google Scholar]
  • 132. Stuyver L., de Gendt S., Cadranel J.F., van Geyt C., van Reybroeck G., Dorent R., Gandjbachkh I., Rosenheim M., Charlotte F., Opolon P., Huraux J.M., Lunel F., Three cases of severe subfulminant hepatitis in heart‐transplanted patients after nosocomial transmission of a mutant hepatitis B virus, Hepatology, 6: 1876–1883, 1999. [DOI] [PubMed] [Google Scholar]
  • 133. Aye T.T., Uchida T., Becker S.O., Hirashima M., Shikata T., Komine F., Moriyama M., Arakawa Y., Mima S., Mizokami M., Variations of hepatitis B virus precore/core gene sequences in acute and fulminant hepatitis B, Dig. Dis. Sci., 6: 1281–1287, 1994. [DOI] [PubMed] [Google Scholar]
  • 134. Saellberg M., Ruden U., Wahren B., Noah M., Magnius L.O., Human and murine B‐cells recognize the HBeAg/beta (or HBe2) epitope as a linear determinant, Mol. Immunol., 7: 719–726, 1991. [DOI] [PubMed] [Google Scholar]
  • 135. Yuan T.T.T., Tai P.C., Shih C., Subtype‐independent immature secretion and subtype‐dependent replication deficiency of a highly frequent, naturally occurring mutation of human hepatitis B virus core antigen, J. Virol., 73: 10122–10128, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 136. Yuan T.T., Shih C., A frequent, naturally occurring mutation (P130T) of human hepatitis B virus core antigen is compensatory for immature secretion phenotype of another frequent variant (I97L), J. Virol., 10: 4929–4932, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 137. Marinos G., Torre F., Günther S., Thomas M.G., Will H., Williams R., Naoumov N.V., Hepatitis B virus variants with core gene deletions in the evolution of chronic hepatitis B infection, Gastroenterology, 1: 183–192, 1996. [DOI] [PubMed] [Google Scholar]
  • 138. Yuan T.T., Lin M.H., Qiu S.M., Shih C., Functional characterization of naturally occurring variants of human hepatitis B virus containing the core internal deletion mutation, J. Virol., 3: 2168–2176, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 139. Fouillot N., Tiouzeau S., Rossignol J.M., Jean‐Jean O., Translation of the hepatitis B virus P gene by ribosomal scanning as an alternative to internal initiation, J. Virol., 8: 4886–4895, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 140. Scaglioni P.P., Melegari M., Wands J.R., Characterization of hepatitis B virus core mutants that inhibit viral replication, Virology, 1: 112–120, 1994. [DOI] [PubMed] [Google Scholar]
  • 141. Preikschat P., Meisel H., Will H., Günther S., Hepatitis B virus genomes from long‐term immunosuppressed virus carriers are modified by specific mutations in several regions, J. Gen. Virol., 10: 2685–2691, 1999. [DOI] [PubMed] [Google Scholar]
  • 142. Pult I., Chouard T., Wieland S., Klemenz R., Yaniv M., Blum H.E., A hepatitis B virus mutant with a new hepatocyte nuclear factor 1 binding site emerging in transplant‐transmitted fulminant hepatitis B, Hepatology, 25: 1507–1515: 1997. [DOI] [PubMed] [Google Scholar]
  • 143. Okamoto H., Wang Y., Tanaka T., Machida A., Miyakaw Y., Mayumi M., Trans‐complementation among naturally occurring deletion mutants of hepatitis B virus and integrated viral DNA for the production of viral particles with mutant genomes in hepatoma cell lines, J. Gen. Virol., 74: 407–414, 1993. [DOI] [PubMed] [Google Scholar]
  • 144. Roingeard P., Romet‐Lemonne J.L., Leturcq D., Goudeau A., Essex M., Hepatitis B virus core antigen (HBc Ag) accumulation in an HBV nonproducer clone of HepG2‐transfected cells is associated with cytopathic effect, Virology, 1: 113–120, 1990. [DOI] [PubMed] [Google Scholar]
  • 145. Chisari F.V., Filippi P., Buras J., McLachlan A., Popper H., Pinkert C.A., Palmiter R.D., Brinster R.L., Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice, Proc. Natl. Acad. Sci. USA, 19: 6909–6913, 1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 146. Lenhoff R.J., Summers J., Construction of avian hepadnavirus variants with enhanced replication and cytopathicity in pimary hepatocytes, J. Virol., 9: 5706–5713, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 147. Milich D.R., Jones J.E., Hughes J.L., Price J., Raney A.K., McLachlan A., Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero Proc. Natl. Acad. Sci. USA, 17: 6599–6603, 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 148. Tsai S.L., Chen P.J., Lai M.Y., Yang P.M., Sung J.L., Huang J.H., Hwang L.H., Chang T.H., Chen D.S., Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion, J. Clin. Invest. 1: 87–96, 1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 149. Marinos G., Torre F., Chokshi S., Hussain M., Clarke B.E., Rowlands D.J., Eddleston A.L., Naoumov N.V., Williams R., Induction of T‐helper cell response to hepatitis B core antigen in chronic hepatitis B: a major factor in activation of the host immune response to the hepatitis B virus, Hepatology, 4: 1040–1049, 1995. [DOI] [PubMed] [Google Scholar]
  • 150. Fattovich G., McIntyre G., Thursz M., Colman K., Giuliano G., Alberti A., Thomas H.C., Carman W.F., Hepatitis B virus precore/core variation and interferon therapy, Hepatology, 5: 1355–1362, 1995. [PubMed] [Google Scholar]
  • 151. Takeda K., Akahane Y., Suzuki H., Okamoto H., Tsuda F., Miyakawa Y., Mayumi M., Defects in the precore region of the HBV genome in patients with chronic hepatitis B after sustained seroconversion from HBeAg to anti‐HBe induced spontaneously or with interferon therapy, Hepatology, 6: 1284–1289, 1990. [DOI] [PubMed] [Google Scholar]
  • 152. Loriot M. A., Marcellin P., Talbodec N., Guigonis V., Gigou M., Boyer N., Bezeaud A., Erlinger S., Benhamou J.P., Low frequency of precore hepatitis B virus mutants in anti‐hepatitis B e‐positive reactivation after loss of hepatitis B e antigen in patients with chronic hepatitis B, Hepatology, 3: 627–631, 1995. [PubMed] [Google Scholar]
  • 153. Grandjacques C., Pradat P., Stuyver L., Chevallier M., Chevallier P., Pichoud C., Maisonnas M., Trepo C., Zoulim F., Rapid detection of genotypes and mutations in the pre‐core promoter and the pre‐core region of hepatitis B virus genome: correlation with viral persistence and disease severity, J. Hepatol., 3: 430–439, 2000. [DOI] [PubMed] [Google Scholar]
  • 154. Brunetto M.R., Oliveri F., Demartini A., Calvo P., Manzini P., Cerenzia M.T., Bonino F., Treatment with interferon of chronic hepatitis B associated with antibody to hepatitis B e antigen, J. Hepatol., 1: 8–11, 1991. [DOI] [PubMed] [Google Scholar]
  • 155. Maruyama T., Kuwata S., Koike K., Iino S., Yasuda K., Yotsuyanagi H., Moriya K., Maekawa H., Yamada H., Shibata Y., Milich D.R., Precore wild‐type DNA and immune complexes persist in chronic hepatitis B after seroconversion: no association between genome conversion and seroconversion, Hepatology, 1: 245–253, 1998. [DOI] [PubMed] [Google Scholar]
  • 156. 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, 1: 19–24, 1995. [PubMed] [Google Scholar]
  • 157. Brook M.G., Karayiannis P., Thomas H.C., Which patients with chronic hepatitis B virus infection will respond to alpha‐interferon therapy? A statistical analysis of predictive factors (see comments), Hepatology, 5: 761–763, 1989. [DOI] [PubMed] [Google Scholar]
  • 158. Kumar V., Jayasuryan N., Kumar R., A truncated mutant (residues 58‐140) of the hepatitis B virus X protein retains transactivation function, Proc. Natl. Acad. Sci. USA, 93: 5647–5652, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 159. Kekulé A.S., Lauer U., Weiss L., Luber B., Hofschneider P.H., Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway, Nature, 361: 742–745, 1993. [DOI] [PubMed] [Google Scholar]
  • 160. Hohne M., Schaefer S., Seifer M., Feitelson M.A., Paul D., Gerlich W.H., Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA, Embo J., 4: 1137–1145, 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 161. Kim C.M., Koike K., Saito I., Miyamura T., Jay G., HBx gene of hepatitis B virus induces liver cancer in transgenic mice, Nature, 351: 317–320, 1991. [DOI] [PubMed] [Google Scholar]
  • 162. Seifer M., Hohne M., Schaefer S., Gerlich W.H., In vitro tumorigenicity of hepatitis B virus DNA and HBx protein, J. Hepatol., 13: (Suppl. 4), 61–65, 1991. [DOI] [PubMed] [Google Scholar]
  • 163. Murakami S., Cheong J.H., Kaneko S., Human hepatitis virus X gene encodes a regulatory domain that repesses transactivation of X protein, J. Biol. Chem., 21: 15118–15123, 1994. [PubMed] [Google Scholar]
  • 164. Faktor O., Shaul Y., The identification of hepatitis B virus X gene responsive elements reveals functional similarity of X and HTLV‐I tax, Oncogene, 5: 867–872, 1990. [PubMed] [Google Scholar]
  • 165. Seto E., Mitchell P.J., Yen T.S., Transactivation by the hepatitis B virus X protein depends on AP‐2 and other transcription factors, Nature, 344: 72–74, 1990. [DOI] [PubMed] [Google Scholar]
  • 166. Wu J.Y., Zhou Z.Y., Judd A., Cartwright C.A., Robinson W.S., The hepatitis B virus‐encoded transcriptional trans‐activator hbx appears to be a novel protein serine/threonine kinase, Cell, 4: 687–695, 1990. [DOI] [PubMed] [Google Scholar]
  • 167. Natoli G., Avantaggiati M.L., Chirillo P., de Marzio E., Collepardo D., Falco M., Balsano C., Levrero M., Modulation of intracellular signal transduction pathways by the hepatitis B virus transactivator pX, J. Hepatol., 22: (Suppl. 1), 14–20, 1995. [PubMed] [Google Scholar]
  • 168. Cheong J.H., Yi M.K., Lin Y., Murakami S., Human RPB5, a subunit shared by eukaryotic nuclear RNA polymerases, binds human hepatitis B virus X protein and may play a role in X transactivation, Embo J., 1: 143–150, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 169. Haviv I., Shamay M., Doitsh G., Shaul Y., Hepatitis B virus pX targets TFIIB in transcription coactivation, Mol. Cell. Biol., 3: 1562–1569, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 170. Lin Y., Nomura T., Cheong J., Dorjsuren D., Iida K., Murakami S., Hepatitis B virus X protein is a transcriptional modulator that communicates with transcription factor IIB and the RNA polymerase II subunit 5, J. Biol. Chem., 11: 7132–7139, 1997. [DOI] [PubMed] [Google Scholar]
  • 171. Oadri I., Maguire H.F., Siddiqui A., Hepatitis B virus transactivator protein x interacts with the TATA‐binding protein, Pro. Natl. Acad. Sci. USA, 4: 1003–1007, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 172. Maquire 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, 252: 842–844, 1991. [DOI] [PubMed] [Google Scholar]
  • 173. Unger T., Shaul Y., The X protein of the hepatitis B virus acts as a transcription factor when targeted to its responsive element, Embo J., 6: 1889–189, 1905. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 174. Becker S.A., Lee T.H., Butel J.S., Slagle B.L., Hepatitis B virus X protein interferes with cellular DNA repair, J. Virol., 1: 266–272, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 175. Feitelson M., Lega L., Guo J., Resti M., Rossi M.E., Azzari C., Blumberg B.S., Vierucci A., Pathogenesis of posttransfusion viral hepatitis in children with b‐thalassemia, Hepatology, 3: 558–568, 1994. [DOI] [PubMed] [Google Scholar]
  • 176. Honda A., Yokosuka O., Suzuki K., Saisho H., Detection of mutations in hepatitis B virus enhancer 2/core promoter and X protein regions in patients with fatal hepatitis B virus infection, J. Med. Virol., 2: 167–176, 2000. [DOI] [PubMed] [Google Scholar]
  • 177. Li J., Buckwold V.E., Hon M.W., Ou J.H., Mechanism of suppression of hepatitis B virus precore RNA transcription by a frequent double mutation, J. Virol., 73: 1239–1244, 1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 178. Uchida T., Gotoh K., Shikata T., Complete nucleotide sequences and the characteristics of two hepatitis B virus mutants causing serologically negative acute or chronic hepatitis B, J. Med. Virol., 45: 247–252, 1995. [DOI] [PubMed] [Google Scholar]
  • 179. 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., 4: 281–285, 1994. [DOI] [PubMed] [Google Scholar]
  • 180. Hsia C.C., Nakashima Y., Tabor E., Deletion mutants of the hepatitis B virus X gene in human hepatocellular carcinoma, Biochem. Biophys. Res. Commun., 3: 726–729, 1997. [DOI] [PubMed] [Google Scholar]
  • 181. Rho H.M., Kim K., Hyun S.W., Kim Y.S., The nucleotide sequence and reading frames of a mutant hepatitis B virus subtype adr, Nucleic. Acids. Res., 5: 2124, 1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 182. Kim S.H., Hong S.P., Kim S.K., Lee W.S., Rho H.M., Replication of a mutant hepatitis B virus with a fused X‐C reading frame in hepatoma cells, J. Gen. Virol., 73: 2421–2424, 1992. [DOI] [PubMed] [Google Scholar]
  • 183. Repp R., Keller C., Borkhardt A., Csecke A., Schaefer S., Gerlich W.H., Lampert F., Detection of a hepatitis B virus variant with a truncated X gene and enhancer II, Arch. Virol., 125: 299–304, 1992. [DOI] [PubMed] [Google Scholar]
  • 184. Dejean A., Sonigo P., Wain‐Hobson S., Tiollais P., Specific hepatitis B virus integration in hepatocellular carcinoma DNA through a viral 11‐base‐pair direct repeat, Proc. Natl. Acad. Sci. USA, 17: 5350–5354, 1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 185. Shaul Y., Ziemer M., Garcia P.D., Crawford R., Hsu H., Valenzuela P., Rutter W.J., Cloning and analysis of integrated hepatitis virus sequences from a human hepatoma cell line, J. Virol., 3: 776–787, 1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 186. Feitelson M.A., Duan L.X., Guo J., Horiike N., McIntyre G., Blumberg B.S., Thomas H.C., Carman W., Precore and X region mutants in hepatitis B virus infections among renal dialysis patients, J. Viral Hepat., 1: 19–31, 1995. [DOI] [PubMed] [Google Scholar]
  • 187. Laskus T., Rakela J., Tong M.J., Nowicki M.J., Mosley J.W., Persing D.H., Naturally occurring hepatitis B virus mutants with deletion in the core promoter region, J. Hepatol., 6: 837–841, 1994. [DOI] [PubMed] [Google Scholar]
  • 188. Feitelson M.A., Duan L.X., Guo J., Blumberg B.S., X region deletion mutants associated with surface antigen‐positive hepatitis B virus infections, Gastroenterology, 6: 1810–1819, 1995. [DOI] [PubMed] [Google Scholar]
  • 189. Blum H.E., Zhang Z.S., Galun E., von Weizsaecker F., Garner B., Liang T.J., Wands J.R., Hepatitis B virus X protein is not central to the viral life cycle in vitro, J. Virol., 2: 1223–1227, 1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 190. Moriyama K., Reduced antigen production by hepatitis B virus harbouring nucleotide deletions in the overlapping X gene and precore‐core promoter, J. Gen. Virol., 6: 1479–1486, 1997. [DOI] [PubMed] [Google Scholar]
  • 191. Honigwachs J., Faktor O., Dikstein R., Shaul Y., Laub O., Liver‐specific expression of hepatitis B virus is determined by the combined action of the core gene promoter and the enhancer, J. Virol., 2: 919–924, 1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 192. Lopez‐Cabrera M., Letovsky J., Hu K.Q., Siddiqui A., Multiple liver‐specific factors bind to the hepatitis B virus core/pregenomic promoter: transactivation and repression by CCAAT/enhancer binding protein, Proc. Natl. Acad. Sci. USA, 13: 5069–5073, 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 193. Lopez‐Cabrera M., Letovsky J., Hu K.Q., Siddiqui A., Transcriptional factor C/EBP binds to and transactivates the enhancer element II of the hepatitits B virus, Virology, 2: 825–829, 1991. [DOI] [PubMed] [Google Scholar]
  • 194. Yee J.K., A liver‐specific enhancer in the core promoter region of human hepatitis B virus, Science, 246: 4930, 658–661, 1989. [DOI] [PubMed] [Google Scholar]
  • 195. Yuh C.H., Chang Y.L., Ting L.P., Transcriptional regulation of precore and pregenomic RNAs of hepatitits B virus, J. Virol., 7: 4073–4084, 1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 196. Yuh C.H., Ting L.P., The genome of hepatitis B virus contains a second enhancer: cooperation of two elements within this enhancer is required for its function, J. Virol., 9: 4281–4287, 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 197. 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., 47: 1995, 204–208. [DOI] [PubMed] [Google Scholar]
  • 198. Ogata N., Miller R.H., Ishak K.G., Purcell R.H., The complete nucleotide sequence of a pre‐core mutant of hepatitis B virus implicated in fulminant hepatitis and its biological characterization in chimpanzees, Virology, 1: 263–276, 1993. [DOI] [PubMed] [Google Scholar]
  • 199. Honda A., Yokosuka O., Ehata T., Tagawa M., Imazeki F., Saisho H., Detection of mutations in the enhancer 2/core promoter region of hepatitis B virus in patients with chronic hepatitis B virus infection: comparison with mutations in precore and core regions in relation to clinical status, J. Med. Virol., 57: 337–344, 1999. [PubMed] [Google Scholar]
  • 200. Lindh M., Hannoun C., Dhillon A.P., Norkrans G., Horal P., Core promoter mutations and genotypes in relation to viral replication and liver damage in East Asian hepatitis B virus carriers, J. Infect. Dis., 4: 775–782, 1999. [DOI] [PubMed] [Google Scholar]
  • 201. Baumert T., Rogers S., Hasegawa K., Liang T., Two core promoter mutations identified in a hepatitis B virus strain associated with fulminant hepatitis result in enhanced viral replication, J. Clin. Invest., 98: 2268–2276, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 202. Kao J.H., Wu N.H., Chen P.J., Lai M.Y., Chen D.S., Hepatitis B genotypes and the response to interferon therapy, J. Hepatol., 6: 998–1002, 2000. [DOI] [PubMed] [Google Scholar]
  • 203. Buckwold V., Xu Z., Chen M., Yen S.B., Ou J.H., Effects of naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication, J. Virol., 70: 5845–5851, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 204. Moriyama K., Okamoto H., Tsuda F., Mayumi M., Reduced precore transcription and enhanced core‐pregenome transcription of hepatitis B virus DNA after replacement of the precore‐core promoter with sequences associated with e antigenseronegative persistent infections, Virology, 226: 269–280, 1996. [DOI] [PubMed] [Google Scholar]
  • 205. Buckwold V.E., Xu Z., Yen T.S, Ou J.H., Effects of a frequent double‐nucleotide basal core promoter mutation and its putative single‐nucleotide precursor mutations on hepatitis B virus gene expression and replication, J. Gen. Virol., 78: 2055–2065, 1997. [DOI] [PubMed] [Google Scholar]
  • 206. Günther 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., 70: 8318–8331, 1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 207. Günther S., Piwon N., Will H., Wild‐type levels of pregenomic RNA and replication but reducet pre‐C RNA and e‐antigen synthesis of hepatitis B virus with C(1653) T, A(1762) T and G(1764) A mutations in the core promoter, J. Gen. Virol., 79: 375–380, 1998. [DOI] [PubMed] [Google Scholar]
  • 208. Okamoto H., Tsuda F., Akahane Y., Sugai Y., Yoshiba M., Moriyama K., Tanaka T., 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., 68: 8102–8110, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 209. Kurosaki M., Enomoto N., Asahina Y., Sakuma I., Ikeda T., Tozuka S., Izumi N., et al., Mutations in the core promoter region of hepatitis B virus in patients with chronic hepatitis B, J. Med. Virol., 49: 115–123, 1996. [DOI] [PubMed] [Google Scholar]
  • 210. Orito E., Mizokami M., Sakugawa H., Michitaka K., Ishikawa K., Ichida T., Okanoue T., Yotsuyanagi H., Iino S., A case‐control study for clinical and molecular biological differences between hepatitis B viruses of genotypes B and C. Japan HBV Genotype Research Group, Hepatology, 1: 218–223, 2001. [DOI] [PubMed] [Google Scholar]
  • 211. Chan H.L.Y., Hussain M., Lok A.S.F., Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion, Hepatology, 3: 976–984, 1999. [DOI] [PubMed] [Google Scholar]
  • 212. Lanford R.E, Notvall L., Beames B., Nucleotide priming and reverse transcriptase activity of hepatitis B virus polymerase expressed in insect cells, J. Virol., 7: 4431–4439, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 213. Condreay L.D., Wu T.T., Aldrich C.E., Delaney M.A., Summers J., Seeger C., Mason W.S., Replication of DHBV genomes with mutations at the sites of initiation of minus‐ and plus‐strand DNA synthesis, Virology, 1: 208–216, 1992. [DOI] [PubMed] [Google Scholar]
  • 214. Nagaya T., Nakamura T., Tokino T., Tsurimoto T., Imai M., Mayumi T., Kamino K., Yamamura K., Matsubara K., The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinoma, Genes. Dev., 1: 773–782, 1987. [DOI] [PubMed] [Google Scholar]
  • 215. Hino O., Ohtake K., Rogler C.E., Features of two hepatitis B virus (HBV) DNA integrations suggest mechanisms of HBV integration, J. Virol., 6: 2638–2643, 1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 216. Wang H.P., Rogler C.E., Topoisomerase I‐mediated integration of hepadnavirus DNA in vitro, J. Virol., 5: 2381–2392, 1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 217. 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., 7: 4185–4192, 1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 218. Chang L.J., Hirsch R.C., Ganem D., Varmus H.E., Effects of insertional and point mutations on the functions of the duck hepatitis B virus polymerase, J. Virol., 11: 5553–5558, 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 219. Radziwill G., Tucker W., Schaller H., Mutational analysis of the hepatitis B virus P gene product: domain structure and RNase H activity, J. Virol., 2: 613–620, 1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 220. Saldanha J.A., Qiu H., Thomas H.C., Monjardino J., Mapping of 5' ends of virion‐derived HBV DNA, Virology, 1: 358–361, 1992. [DOI] [PubMed] [Google Scholar]
  • 221. Gerlich W.H., Robinson W.S., Hepatitis B virus contains protein attached to the 5' terminus of its complete DNA strand, Cell, 3: 801–809, 1980. [DOI] [PubMed] [Google Scholar]
  • 222. Zoulim F., Seeger C., Reverse transcription in hepatitis B viruses is primed by a tyrosine residus of the polymerase, J. Virol., 1: 6–13, 1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 223. Wang G.H., Seeger C., Novel mechanism for reverse transcription in hepatitis B viruses, J. Virol., 11: 6507–6512, 1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 224. Blum H.E., Galun E., Liang T.J., von Weizsaecker F., Wands J. R., Naturally occurring missense mutation in the polymerase gene terminating hepatitis B virus replication, J. Virol., 4: 1836–1842, 1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 225. Poch O., Sauvaget I., Delarue M., Tordo N., Identification of four conserved motifs among the RNA‐dependent polymerase encoding elements, Embo J., 8: 3867–3874, 1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 226. Tipples G.A., Ma M.M., Fischer K.P., Bain V.G., Kneteman N.M., Tyrrell D.L.J., Mutation in HBV RNA‐dependent DNA polymerase confers resistance to lamivudine in vivo, Hepatology, 3: 714–717, 1996. [DOI] [PubMed] [Google Scholar]
  • 227. Liaw Y.F., Chein R.N., Yeh C.T., Tsai S.L., Chu C.M., Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy, Hepatology, 2: 567–572, 1999. [DOI] [PubMed] [Google Scholar]
  • 228. Melegari M., Scaglioni P.P., Wands J.R., Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective, Hepatology, 2: 628–633, 1998. [DOI] [PubMed] [Google Scholar]
  • 229. Ladner S.K., Miller T.J., King R.W., The M539V polymerase variant of human hepatitis B virus demonstrates resistance to 2'‐deoxy‐ 3'‐ thiacytidine and a reduced ability to sythesize viral DNA, Antimicrob. Agents Chemother., 42: 2128–2131, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 230. Fu, L. , Cheng, Y.C. , Role of additional mutations outside the YMDD motif of hepatitis B virus polymerase in L(‐) SddC (3TC) resistence Biochem. Pharmacol., 10: 1567–1572, 1998. [DOI] [PubMed] [Google Scholar]
  • 231. Allen M.I., Deslauriers M., Andrews C.W., et al., Identification and characterisation of mutations in hepatitis B virus resistant to lamivudine, Hepatology, 27: 1670–1677, 1998. [DOI] [PubMed] [Google Scholar]
  • 232. Mutimer D., Pillay D., Cook P., Ratcliffe D., O'Donnel K., Dowling D., Shaw J., Elias E., Cane P.A., Selection of multiresistant hepatitis B virus during sequential nucleoside‐analogue therapy. J. Infect. Dis., 181: 713–716, 2000. [DOI] [PubMed] [Google Scholar]
  • 233. de Man R.A., Bartholomeusz A.I., Niesters H.G., Zondervan P.E., Locarnini S.A., The sequential occurrence of viral mutations in a liver transplant receipient re‐infected with hepatitis B: hepatitis B immune globulin escape, famiciclovir non‐response, followed by lamivudine resistance resulting in graft loss, J. Hepatol., 4: 669–675, 1998. [DOI] [PubMed] [Google Scholar]
  • 234. Cane P.A., Mutimer D., Ratcliffe D., Cook P., Beards G., Elias E., Pillay D., Analysis of hepatitis B virus quasispecies changes during emergence and reversion of lamivudine resistance in liver transplantation, Antivir. Ther., 1: 7–14, 1999. [PubMed] [Google Scholar]
  • 235. Pillay D., Bartholomeusz A., Cane P., et al., Mutations in the hepatitis B DNA polymerase associated with antiviral resistance, Int. Antiviral News, 6: 167–169, 1998. [Google Scholar]
  • 236. Bartholomeusz A., Schinazi R.F., Locarnini S., Significance of mutations in the hepatitis B virus polymerase selected by nucleoside analogues and implications for controlling chronic disease, Viral. Hepat. Rev., (in press).
  • 237. Aye T.T., Bartholomeusz A., Shaw T., Bowden S., Breschkin A., McMillan J., Angus P., Locarnini S., Hepatitis B virus polymerase mutations during antiviral therapy in a patient following liver transplantation, J. Hepatol., 26: 1148–1153, 1997. [DOI] [PubMed] [Google Scholar]
  • 238. Chayama K., Suzuki Y., Kobayashi M., Tsubota A., Hashimoto M., Miyano Y., Koike H., Kobayashi M., Koida I., Arase Y., Saitoh S., Murashima N., Ikeda K., Kumada H., Emergence and takeover of YMDD motif mutant hepatitis B virus during long‐term lamivudine therapy and retakeover by wild type after cessation of therapy, Hepatology, 6: 1711–1716, 1998. [DOI] [PubMed] [Google Scholar]
  • 239. Seta T., Yokosuka O., Imazeki F., Tagawa M., Saisho H., Emergence of YMDD motif mutants of hepatitis B virus during lamivudine treatment of immunocompetent type B hepatitis patients, J. Med. Virol., 1: 8–16, 2000. [DOI] [PubMed] [Google Scholar]
  • 240. Ling R., Mutimer D., Ahmed M., Boxall E.H., Elias E., Dusheiko G.M., Harrison T.J., Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine, Hepatology, 3: 711–713, 1996. [DOI] [PubMed] [Google Scholar]
  • 241. Peters M.G., Singer F., Howard T., Jacobsmeyer S., Xiong X., Gibbs C.S., Lamy P., Murray A., Fulminant hepatic failure resulting from lamivudine‐resistant hepatitis B virus in a renal transplant recipient: durable response after orthotopic liver transplantation on adefovir dipivoxil and hepatitis B immune globulin, Transplantation, 12: 1912–1914, 1999. [DOI] [PubMed] [Google Scholar]
  • 242. Chen Y., Robinson W.S., Marion P.L., Naturally occurring point mutation in the C terminus of the polymerase gene prevents duck hepatitis B virus RNA packaging, J. Virol., 2: 1282–1287, 1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 243. Rehermann B., Fowler P., Sidney J., Person J., Redeker A., Brown M., Moss B., Sette A., Chisari F.V., The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis, J. Exp. Med., 181: 1047–1058, 1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 244. Grellier L., Mutimer D., Ahmed M., Brown D., Burroughs A.K., Rolles K., McMaster P., Beranek P., Kennedy F., Kibbler H., McPhillips P., Elias E., Dusheiko G., Lamivudine prophylaxis against reinfection in liver transplantation for hepatitis B cirrhosis, Lancet, 348: 1212–1215, 1996. [DOI] [PubMed] [Google Scholar]
  • 245. Centers for Disease Control, Recommendations of the Immunisation Practices Advisory Committee , Recommendations for protection against viral hepatitis, MMWR, 34: 329–335, 1985. [Google Scholar]
  • 246. International Group , Immunisation against hepatitis B, Lancet, 1: 875–876, 1998. [Google Scholar]
  • 247. World Health Organization , Informal consultation on quadrivalent diptheria‐tetanus‐pertussis‐hepatitis B vaccine: final report, Geneva : WHO, 1992. [Google Scholar]
  • 248. European consensus group on hepatitis B immunity , Are booster immunisations needed for lifelong hepatitis B immunity Lancet, 355: 561–565, 2000. [PubMed] [Google Scholar]
  • 249. Lee P.I., Lee C.Y., Huang L.M., Chang M.H., Longterm efficacy of recombinant hepatitis B vaccine and risk of infection in infants born to mothers with hepatitis B e antigen, Pediatrics, 126: 716–721, 1995. [DOI] [PubMed] [Google Scholar]
  • 250. Beasley R.P., Hwang L.Y., Overview on the epidemiology of hepatocellular carcinoma In; Hollinger F.B., Lemon S.M., Margolis H., eds., Viral hepatitis and liver disease, Baltimore ; Williams & Wilkins, 1991, pp. 532–535. [Google Scholar]
  • 251. Zuckerman A.J., Harrison T.J., Oon C.J., Mutations in the S region of hepatitis B virus, Lancet, 343: 737–738, 1994. [DOI] [PubMed] [Google Scholar]
  • 252. Coleman P.F., Chen Y.C.J., Mushahwar I.K., Immunoassay detection of hepatitis B surface antigen mutants, J. Med. Virol., 1: 19–24, 1999. [DOI] [PubMed] [Google Scholar]
  • 253. Chen W.N., Oon C.J., Koh S., Horizontal transmission of a hepatitis B virus surface antigen mutant, J. Clin. Microbiol., 2: 938–939. 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 254. Ijaz S., Torre F., Tedder R.S., Williams R., Naoumov N.V., Novel immunoassay for the detection of hepatitis B surface ‘escape’ mutants and its application in liver transplant recipients, J. Med. Virol., 3: 210–216, 2001. [DOI] [PubMed] [Google Scholar]
  • 255. Mushahwar I.K., Brawner T., Radioimmunoassays In: Spector S., Lancz G., Eds., Clinical virology manual. 2nd Ed New York : Elsevier, 1992, pp. 129–151. [Google Scholar]
  • 256. Li J.S., Tong S.P. Vitvitski L., Zoulim F., Trépo C., Rapid detection and further characterization of infection with hepatitis B virus variants containing a stop codon in the distal pre‐C region, J. Gen. Virol., 71: 1993–1998, 1990. [DOI] [PubMed] [Google Scholar]
  • 257. Gramegna M., Lampertico P., Lobbiani A., Colucci G., Detection of the hepatitis B virus major pre‐core mutation by the amplification refractorymutation system technique, Res. Virol., 144: 307–309. 1993. [DOI] [PubMed] [Google Scholar]
  • 258. Lindh M., Furuta Y., Ljunggren K.K., Norkrans G., Horal P., Detection of hepatitis B virus precore TAG mutant by an amplification‐created restriction site method, J. Infect. Dis., 171: 194–197, 1995. [DOI] [PubMed] [Google Scholar]
  • 259. Whalley S.A., Brown D., Teo C.G., Dusheiko G.M., Saunders N.A., Monitoring the emergence of hepatitis B virus polymerase gene variants during lamivudine therapy using the LightCycler, J. Clin. Microbiol., 4: 1456–1459, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]

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