Abstract
To elucidate the temporal relationship between liver damage and mutation(s) in hepatitis B virus core gene, serial sera from a progressive liver disease patient and an asymptomatic carrier were studied. By direct sequencing, missense mutations in the core gene were only found in serum from the progressive liver disease patient during the period with frequent exacerbation. Using methods of cloning and sequencing, missense mutations were also found in clones derived from the progressive liver disease patient at a relatively early phase, but strains with a missense mutation from earlier sera did not exist in sera of a later period. Furthermore, there was a tendency of concentrating missense mutations in clones derived from the progressive liver disease patient. These data suggested that missense mutations in the core gene that occurred at an earlier phase might evoke an immune response to eliminate mutated virus and that concentrating missense mutations during a phase of exacerbation might be a result of adaptive mutation.
Similar content being viewed by others
References
Mondelli M, Vergani GM, Alberti A, Vergani D, Portmann B, Eddleston ALWF, Williams R: Specificity of lymphocytes cytotoxicity to autologous hepatocytes in chronic hepatitis B virus infection: Evidence that T cells are directed against HBV core antigen expressed on hepatocytes. J Immunol 129:2773–2778, 1982
Vento S, Hegarty JE, Alberti A, O'Brien CJ, Alexander GJM, Eddleston ALWF, Williams R: T lymphocytes sensitization to HBcAg and T cell-mediated unresponsiveness to HBsAg in hepatitis B virus-related chronic liver disease. Hepatology 5:192–197, 1985
Thomas HC, Jacyna M, Waters J, Main J: Virus-host interaction in chronic hepatitis B virus infection. Semin Liver Dis 8:342–349, 1988
Van Bleek GM, Nathenson SG: Isolation of an endogenously processed immunodominant viral peptide from the class I H-2Kb molecule. Nature 348:213–216, 1990
Rotzschke O, Falk K, Deres K, Shild H, Norda M, Metzger J, Jung G, Rammensee HG: Isolation and analysis of naturally processed viral peptides as recognized by cytotoxic T cells. Nature 348:252–254, 1990
Culmann B, Gomard E, Kieny MP, Guy B, Dreyfus F, Saimot AG, Sereni D, Sicard D, Levy JP: Six epitopes reacting with human cytotoxic CD8+ T cells in the central region of the HIV-1 NEF protein. J Immunol 146:1560–1565, 1991
Oldstone MBA, Tishon A, Geckeler R, Lewicki H, Whitton JL: A common antiviral cytotoxic T-lymphocyte epitope for diverse major histocompatibility complex haplotypes: Implications for vaccination. Proc Natl Acad Sci USA 89:2752–2755, 1992
Ehata T, Omata M, Yokosuka O, Hosoda K, Ohto M: Variations in codons 84–101 in core nucleotide sequence correlate with hepatocellular injury in chronic hepatitis B virus infection. J Clin Invest 89:332–338, 1992
Matsuyama Y, Omata M, Yokosuka O, Imazeki F, Ito Y, Okuda K: Discordance of hepatitis B e antigen/antibody and hepatitis B virus deoxyribonucleic acid in serum: analysis of 1063 specimens. Gastroenterology 89:1104–1108, 1985
Kobayashi M, Koike K: Complete nucleotide sequence of hepatitis B virus DNA of subtype adr and its conserved gene organization. Gene 30:227–232, 1984
Saiki RK, Scharf S, Faloona F, Mullis KB, Horn GT, Erlich HA, Arnheim N: Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science 230:1350–1354, 1985
Yokosuka O, Omata M, Hosoda K, Tada M, Ehata T, Ohto M: Detection and direct sequencing of hepatitis B virus genome by DNA amplification method. Gastroenterology 100:175–181, 1991
Tada M, Omata M, Ohto M: Analysis of ras gene mutations in human hepatic malignant tumors by polymerase chain reaction and direct sequencing. Cancer Res 50:1121–1124, 1990
Hoofnagle JH: Chronic hepatitis B. N Engl J Med 323:337–339, 1990
Kinoyama S, Yamada G, Tsuji T: Analysis of antigen-specific immune response in peripheral blood mononuclear cells (PBMC) from patients with hepatitis B virus infection. Acta Hepatol Jpn 31:1031–1037, 1990
Shirai M, Watanabe S, Nishioka M: Hepatitis B core antigen specific CD4 response in peripheral blood. Jpn J Exp Med 60:93–96, 1990
Ferrari C, Penna A, Bertoletti A, Valli A, Antoni AD, Giuberti T, Cavalli A, Petit MA, Fiaccadori F: Cellular immune response to hepatitis B virus-encoded antigens in acute and chronic hepatitis B virus infection. J Immunol 145:3442–3449, 1990
Chu CM, Shyu WC, Kuo RW, Liaw YF: HLA class I antigen display on hepatocyte membrane in chronic hepatitis B virus infection: Its role in the pathogenesis of chronic type B hepatitis. Hepatology 7:1311–1316, 1987
Mota AH, Fainboim H, Terg R, Fainboim L: Association of chronic active hepatitis and HLA B35 in patients with hepatitis B virus. Tissue Antigens 30:238–240, 1987
Milich DR, McLachlan A, Stahl S, Wingfield P, Thornton GB, Hughes JL, Jones JE: Comparative immunogenicity of hepatitis B virus core and e antigen. J Immunol 141:3617–3624, 1988
Milich DR, Jones JE, Hughes JL, Price J, Raney AK, McLachlan A: Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero. Proc Natl Acad Sci USA 87:6599–6603, 1990
Elliott T, Townsend A, Cerundolo V: Naturally processed peptides. Nature 348:195–197, 1990
Townsend A, Bastin J, Gould K, Brownlee G, Andrew M, Coupar B, Boyle D, Chan S, Smith G: Defective presentation of class I-restricted cytotoxic T lymphocytes in vaccinia-infected cells is overcome by enhanced degradation of antigen. J Exp Med 168:1211–1224, 1988
Falk K, Rotzschke O, Stevanovic S, Jung G, Rammensee HG: Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351:290–296, 1991
Rothbard JB, Taylor WR: A sequence pattern common to T cell epitopes. EMBO J 7:93–100, 1988
Hill AVS, Allsopp CEM, Kwiatkowski D, Anstey NM, Twumasi P, Rowe PA, Bennett S, Brewster D, McMichael AJ, Greenwood BM: Common west African HLA antigens are associated with protection from severe malaria. Nature 352:595–600, 1991
Pircher H, Moskophidis D, Rohrer U, Burki K, Hengartner H, Zinkernagel RM: Viral escape by selection of cytotoxic T cell-resistant virus variantsin vivo. Nature 346:629–633, 1990
Carman WF, Zanetti AR, Karayiannis P, Waters J, Manzillo G, Tanzi E, Zuckerman AJ, Thomas HC: Vaccine-induced escape mutant of hepatitis B virus. Lancet 336:325–329, 1990
Okamoto H, Imai M, Kametani M, Nakamura T, Mayumi M: Genomic heterogeneity of hepatitis B virus in a 54-year-old woman who contracted the infection through materno-fetal transmission. Jpn J Exp Med 57:231–236, 1987
Hall BG: Adaptive evolution that requires multiple spontaneous mutations: Mutations involving base substitutions. Proc Natl Acad Sci USA 88:5882–5886, 1991
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Chuang, WL., Omata, M., Ehata, T. et al. Concentrating missense mutations in core gene of hepatitis B virus. Digest Dis Sci 38, 594–600 (1993). https://doi.org/10.1007/BF01316786
Received:
Revised:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01316786