Implications of genetic variation on the pathogenesis of hepatitis B virus infection

  • W. F. Carman
  • H. C. Thomas
Conference paper
Part of the Archives of Virology Supplementum book series (ARCHIVES SUPPL, volume 8)


It is now well established that sequence variation of hepatitis B virus (HBV) occurs worldwide. Although variants have been classified into subtypes by means of antigenic specificities of the surface proteins, it may be that HBV can be better classified into genotypes by means of percentage nucleotide difference. HBV can be classified into at least four genotypes based on a divergence of >7% at the nucleotide level [1] and it is clear that, based on this definition, other genotypes will be described in the future. Whether genotyping in this fashion is a satisfactory method of classifying HBV, and whether this has any relevance to the pathogenesis of the liver disease, infectivity or spread remains to be seen. Subtypes, defined by antigens associated with specific amino acid changes, are distributed geographically and have no apparent ink with disease. Whether one subtype can infect a person previously infected with a different subtype is unclear; at least, it would seem to be quite uncommon.


Fulminant Hepatitis HBeAg Positive Patient preC Mutant Core Epitope HBeAg Positive Group 
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  1. 1.
    Okamoto H, Tsuda F, Sakugawa H, Sastrosoewignjo RI, Imai M, Miyakawa Y, Mayumi M (1988) Typing hepatitis B virus by homology in nucleotide sequence: comparison of surface antigen subtypes. J Gen Virol 69: 2575–2583PubMedCrossRefGoogle Scholar
  2. 2.
    Junker-Niepmann M, Bartenschlager R, Schaller H (1990) A short cis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA. EMBO J 9: 3389–3396PubMedGoogle Scholar
  3. 3.
    Salfeld J, Pfaff E, Noah M, Schaller H (1989) Antigenic determinants and functional domains in core antigen and e antigen from hepatitis B virus. J Virol 63: 798–808PubMedGoogle Scholar
  4. 4.
    Milich DR, McLachlan A, Moriarty A, Thornton GB (1987) Immune response to hepatitis B virus core antigen (HBcAg): localisation of T cell recognition sites with HBcAg/HBeAg. J Immunol 139: 1223–1231PubMedGoogle Scholar
  5. 5.
    Waters JA, Jowett TP, Thomas HC (1986) Identification of a dominant epitope of the nucleocapsid ( HBc) of the hepatitis B virus. J Med Virol 19: 79–86PubMedCrossRefGoogle Scholar
  6. 6.
    Bertoletti A, Ferrari C, Fiaccadori F, Penna A, Margolskee R, Schlicht HJ, Fowler P, Guilhot S, Chisari FV (1991) HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized HBV core antigens. Proc Natl Acad Sci USA 88: 10445–10449PubMedCrossRefGoogle Scholar
  7. 7.
    Ferrari C, Bertoletti A, Penna A, Cavalli A, Valli A, Missale G, Pilli M, Fowler P, Giuberti T, Chisari FV, Fiaccadori F (1991) Identification of immunodominant T cell epitopes of the hepatitis B virus nucleocapsid antigen. J Clin Invest 88: 214–222PubMedCrossRefGoogle Scholar
  8. 8.
    Bonino F, Rosina F, Rizzetto M, Rizzi R, Chiaberge E, Tardanico R, Callea F, Verme G (1986) chronic hepatitis in HBsAg carriers with serum HBV-DNA and anti-HBe. Gastroenterology 90: 1268–1273Google Scholar
  9. 9.
    Hadziyannis SJ, Lieberman HM, Karvountzis MG, Shafritz D (1983) Analysis of liver disease, nuclear HBcAg, viral replication and hepatitis B virus in liver and serum of HBeAg vs anti-HBe positive chronic hepatitis B virus infection. Hepatology 3: 652–662Google Scholar
  10. 10.
    Chu C-M, Karayiannis P, Fowler MJF, Monjardino J, Liaw Y-F, Thomas HC (1985) Natural history of chronic hepatitis B virus infection in Taiwan: studies of hepatitis B virus DNA in serum. Hepatology 5: 431–434PubMedCrossRefGoogle Scholar
  11. 11.
    Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, McGarvey M, Makris A, Thomas HC (1989) Mutation preventing formation of e antigen in patients with chronic HBV infection. Lancet ii: 588–591Google Scholar
  12. 12.
    Brunetto MR, Stemmler M, Schodel F, Will H, Ottobrelli A, Rizzetto M, Bonino F (1989) Identification of HBV variants which cannot produce precore-derived HBeAg and may be responsible for severe hepatitis. Ital J Gastroenterol 21: 151–154Google Scholar
  13. 13.
    Okamoto H, Yotsumoto S, Akahane Y, Yamanaka T, Miyazaki Y, Sugai Y, Tsuda F, Tanaka T, Miyakawa Y, Mayumi M (1990) Hepatitis B viruses with pre-core region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen. J Virol 64: 1298–1303PubMedGoogle Scholar
  14. 14.
    Fiordalisi G, Cariani E, Mantero G, Zanetti A, Tanzi E, Chiaramonte M, Primi D (1990) High genomic variability in the pre-C region of hepatitis B virus in anti- HBe, HBV-DNA positive chronic hepatitis. J Med Virol 31: 297–300PubMedCrossRefGoogle Scholar
  15. 15.
    Tong S, Li J, Vitvitski L, Trepo C (1990) Active hepatitis B virus replication in the presence of anti-HBe is associated with viral variants containing an inactive pre-C region. Virology 176: 596–603PubMedCrossRefGoogle Scholar
  16. 16.
    Carman WF, Ferrao M, Lok ASF, Ma OCK, Lai CL, Thomas HC (1992) Pre-core sequence variation in Chinese isolates of hepatitis B virus. J Infect Dis 165: 127–133PubMedCrossRefGoogle Scholar
  17. 17.
    Pircher H, Moskophidis D, Rohrer U, Burki K, Hengartner H, Zinkernagel RM (1990) Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature 346: 629–633PubMedCrossRefGoogle Scholar
  18. 18.
    Phillips RE, Rowland-Jones S, Nixon DF, Gotch FM, Edwards JP, Ogunlesi AO, Elvin JG, Rothbard JA, Bangham CRM, Rizza C, McMichael AJ (1991) Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature 354: 453–459PubMedCrossRefGoogle Scholar
  19. 19.
    Johnson RP, Trocha A, Buchanan TM, Walker BD (1992) Identification of overlapping HLA class I-restricted cytotoxic T cell epitopes in a conserved region of the human immunodeficiency virus type 1 envelope glycoprotein: definition of minimum epitopes and analysis of the effects of sequence variation. J Exp Med 175: 961–971PubMedCrossRefGoogle Scholar
  20. 20.
    Chen HS, Kew MC, Hornbuckle WE, Tennant BC, Cote PJ, Gerin JL, Purcell RH, Miller RH (1992) The precore gene of the woodchuck hepatitis virus genome is not essential for viral replication in the natural host. J Virol 66: 5682–5684PubMedGoogle Scholar
  21. 21.
    Carman WF, Hadziyannis S, Karayiannis P, Fagan EA, Tassopoulos NC, Williams R, Thomas HC (1991) Association of the precore variant of HBV with acute and fulminant hepatitis B infection. In: Hollinger FB, Lemon SM, Margolis H (eds) Viral hepatitis and liver diseases. Williams and Wilkins, Baltimore, pp 216–219Google Scholar
  22. 22.
    Kosaka Y, Takase K, Kojima M, Shimizu M, Inoue K, Yoshiba M, Tanaka S, Akahane Y, Okamoto H, Tsuda F, Miyakawa Y, Mayumi M (1991) Fulminant hepatitis B: induction by hepatitis B virus mutants defective in the precore region and incapable of encoding e antigen. Gastroenterology 324: 1087–1094Google Scholar
  23. 23.
    Liang TJ, Hasegawa K, Rimon N, Wands JR, Ben-Porath E (1991) A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. N Engl J Med 324: 1705–1709PubMedCrossRefGoogle Scholar
  24. 24.
    Omata M, Ehata T, Yokosuka O, Hosoda K, Ohto M (1991) Mutations in the precore region of hepatitis B virus DNA in patients with fulminant and severe hepatitis. N Engl J Med 324: 1699–1704PubMedCrossRefGoogle Scholar
  25. 25.
    Lo ES-F, Lo Y-MD, Tse CH, Fleming KA (1992) Detection of hepatitis B pre-core mutant by allele specific polymerase chain reaction. J Clin Pathol 45: 689–692PubMedCrossRefGoogle Scholar
  26. 26.
    Fattovich G, Farci P, Rugge M (1992) Chronic hepatitis B positive for antiHBe and with hepatitis B viral DNA in serum can be successfully treated with alpha interferon. Hepatology 5: 584–589CrossRefGoogle Scholar
  27. 27.
    Carman WF, Fattovich G, Mclntyre G, Alberti A, Thomas HC (1991) Pre-core HBV mutants: response to interferon therapy. J Hepatol 13: S16CrossRefGoogle Scholar
  28. 28.
    Brunetto MR, Saracco G, Oliveri F, Demartini A, Giarin MM, Manzini P, Calvo PL, Verme G, Bonino F (1991) HBV heterogeneity and response to interferon. J Hepatol 13: S15CrossRefGoogle Scholar
  29. 29.
    Takeda K, Akahane Y, Suzuki H, Okamoto H, Tsuda F, Miyakawa, Mayumi M (1990) 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 12: 1284–1289PubMedCrossRefGoogle Scholar
  30. 30.
    Xu J, Brown D, Harrison T, Lin Y, Dusheiko G (1992) Absence of hepatitis B virus precore mutants in patients with chronic hepatitis B responding to interferon- alpha. Hepatology 15: 1002–1006PubMedCrossRefGoogle Scholar
  31. 31.
    Liang TJ, Blum HE, Wands JR (1990) Characterisation and biological properties of a hepatitis B virus isolated from a patient without hepatitis B virus serologic markers. Hepatology 12: 204–212PubMedCrossRefGoogle Scholar
  32. 32.
    Tran A, Kremsdorf D, Capel F, Housset C, Dauguet C, Petit M-A, Brechot C (1991) 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 65: 3566–3574PubMedGoogle Scholar
  33. 33.
    Bhat RA, Ulrich PP, Vyas GN (1990) Molecular characterisation of a new variant of hepatitis B virus in a persistently infected homosexual man. Hepatology 11: 271–276PubMedCrossRefGoogle Scholar
  34. 34.
    Milich DR, Jones JE, Hughes JL, Price J, Raney AK, McLachlan A (1990) Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero? Proc Natl Acad Sci USA 87: 6599–6603PubMedCrossRefGoogle Scholar
  35. 35.
    Ehata T, Omata M, Yokosuka O, Hosodo K, Ohto M (1992) Variations in codons 84-101 in the core nucleotide sequence correlate with hepatocellular injury in chronic hepatitis B virus infection. J Clin Invest 89: 332–338PubMedCrossRefGoogle Scholar
  36. 36.
    Wakita T, Kakumu S, Shibata M, Yoskioka K, Ito Y, Shinagawa T, Ishikawa T, Takayanagi M, Morishima T (1991) Detection of pre-C and core region mutants of hepatitis B virus in chronic hepatitis B virus carriers. J Clin Invest 88: 1793–1801PubMedCrossRefGoogle Scholar
  37. 37.
    Ackrill AM, Naomov NV, Eddieston ALWF, Williams R (1993) Specific deletions in the hepatitis B virus core open reading frame in patients with chronic active hepatitis B. J Med Virol (in press)Google Scholar
  38. 38.
    Carman W, Thomas H, Domingo E (1993) Viral genetic variation: hepatitis B virus as a clinical example. Lancet 341: 349–354PubMedCrossRefGoogle Scholar
  39. 39.
    Carman WF, Mclntyre G, Hadziyannis S, Fattovich G, Alberti A, Thomas HC (1993) The development of multiple HBV core gene mutations after loss of HBeAg is associated with severe chronic hepatitis. Lancet (in press)Google Scholar
  40. 40.
    Feitelson M, Mclntyre G, McCruden EAB, Blumberg B, Thomas HC, Carman WF (1992) Mutated HBV DNA in HBsAg negative dialysis patients. J Hepatol 16: S11CrossRefGoogle Scholar
  41. 41.
    Blum HE, Galun E, Liang J, von Weizsäcker F, Wands JR (1991) Naturally occurring missense mutation in the polymerase gene terminating hepatitis B virus replication. J Virol 65: 1836–1842PubMedGoogle Scholar
  42. 42.
    Carman WF, Zanetti AR, Karayiannis P, Waters J, Manzillo G, Tanzi E, Zuckerman AJ, Thomas HC (1990) Vaccine-induced escape mutant of hepatitis B virus. Lancet 336: 325–329PubMedCrossRefGoogle Scholar
  43. 43.
    Santantonio T, Jung MC, Schneider R, Pastore G, Pape GR, Will H (1992) Hepatitis- B virus genomes that cannot synthesise pre-S2 proteins occur frequently and as dominant virus populations in chronic carriers in Italy. Virology 188: 948–952PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • W. F. Carman
    • 1
  • H. C. Thomas
    • 2
    • 3
  1. 1.Institute of VirologyUniversity of GlasgowGlasgowScotland, UK
  2. 2.Department of MedicineSt Mary’s Hospital Medical SchoolLondonUK
  3. 3.Imperial College of Science, Technology and MedicineLondonUK

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