Digestive Diseases and Sciences

, Volume 39, Issue 9, pp 2000–2006 | Cite as

Nucleotide sequence analysis of the precore region in patients with spontaneous reactivation of chronic hepatitis B

  • Tomasz Laskus
  • Jorge Rakela
  • Myron J. Tong
  • David H. Persing
Liver: Infectious, Inflammatory, And Metabolic Disorders

Abstract

The role of HBV precore mutations in the spontaneous reactivation of chronic hepatitis B (CHB) is currently unknown. We studied 10 patients with CHB; five were HBeAg+ (group I) and five were anti-HBe+ (group II). All 10 had spontaneous reactivation of CHB as defined by the appearance of clinical symptoms along with an increase of serum ALT activity at least 5× above baseline values, in the absence of any other known causes of liver disease or CHB reactivation. The precore (87 nt) and proximal core (81 nt) regions were sequenced after PCR amplification. From each patient three serum samples were studied: one 3–12 months before, one during, and one six months after reactivation. Prior to reactivation, none of the group I patients harbored an HBV strain having a mutation that prevented HBeAg synthesis; however, 2/5 developed such a mutation during reactivation (G to A transition at nt 1896). Among the group II patients, three harbored an HBeAg defective mutant both before and during reactivation; after six months, two of these three patients were HBV DNA negative in serum by PCR. Several other sequence polymorphisms, some of which changed the predicted amino acid sequence, were either present initially or developed during reactivation. In conclusion, in this small group of CHB patients who were HBeAg+ spontaneous reactivation was accompanied in some cases by a shift to an HBeAg defective mutant, while in patients who were anti-HBe+, such mutations were frequently present prior to reactivation. In patients already harboring precore defective mutants, spontaneous reactivation may precede an attenuation of viral replication.

Key words

chronic hepatitis B precore region mutation nucleotide sequence 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Wands JR, Chura CM, Roll FJ, Maddrey WC: Serial studies of hepatitis-associated antigen and antibody in patients receiving antitumor chemotherapy for myeloproferative and lymphoproliferative disorders. Gastroenterology 68:105–112, 1975PubMedGoogle Scholar
  2. 2.
    Rakela J, Redeker AG, Weliky B: Effect of short-term prednisone therapy on aminotransferase levels and hepatitis B virus markers in chronic type B hepatitis. Gastroenterology 84:956–960, 1983PubMedGoogle Scholar
  3. 3.
    Vento S, Di Perri G, Luzzati R, Cruciani M, Garofano T, Mengoli C, Concia E, Bassett D: Clinical reactivation of hepatitis B in anti-HBs positive patients with AIDS. Lancet 1:332–333, 1989Google Scholar
  4. 4.
    Tassopoulos NC, Papaevangelou GJ, Roumeliotou-Karayannis A: Reactivation of chronic hepatitis B as acute viral hepatitis. Ann Intern Med 103:481, 1985Google Scholar
  5. 5.
    Davis GL, Hoofnagle JH, Waggoner JG: Spontaneous reactivation of chronic hepatitis B virus infection. Gastroenterology 86:230–235, 1984PubMedGoogle Scholar
  6. 6.
    Levy P, Marcellin P, Martinot-Peignoux M, Degott C, Nataf J, Benhamou J-P: Clinical course of spontaneous reactivation of hepatitis B virus infection in patients with chronic hepatitis B. Hepatology 12:570–574, 1990PubMedGoogle Scholar
  7. 7.
    Gupta S, Govindarajan S, Fong T-L, Redeker AG: Spontaneous reactivation in chronic hepatitis B: Patterns and natural history. J Clin Gastroenterol 12:562–568, 1990PubMedGoogle Scholar
  8. 8.
    Tong MJ, Sampliner RE, Govindarajan S, Co RL: Spontaneous reactivation of hepatitis B in Chinese patients with HBsAg-positive chronic active hepatitis. Hepatology 7:713–718, 1987PubMedGoogle Scholar
  9. 9.
    Liaw YF, Yang SS, Chen TJ, Chu CM: Acute exacerbation in hepatitis Be antigen positive chronic type B hepatitis. J Hepatol 1:227–233, 1985PubMedGoogle Scholar
  10. 10.
    Liaw YF, Tai D-I, Chu CM, Chen T-J: The development of cirrhosis in patients with chronic type B hepatitis: A prospective study. Hepatology 8:493–496, 1988PubMedGoogle Scholar
  11. 11.
    Liaw YF, Pao CC, Chu CM: Changes in serum HBV-DNA in relation to serum transaminase level during acute exacerbation in patients with chronic type B hepatitis. Liver 8:231–235, 1988PubMedGoogle Scholar
  12. 12.
    Gayno S, Marcellin P, Loriot MA, Martinot-Peignoux M, Levy P, Erlinger S, Benhamou JP: Detection of serum HBV-DNA by polymerase chain reaction (PCR) in patients before reactivation of chronic hepatitis B. J Hepatol 14:357–360, 1992PubMedGoogle Scholar
  13. 13.
    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. N Engl J Med 324:1699–1704, 1991PubMedGoogle Scholar
  14. 14.
    Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, McGarvey MJ, Makris A: Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 2:588–590, 1989PubMedGoogle Scholar
  15. 15.
    Naumov NV, Schneider R, Grotzinger T, Jung MC, Miska S, Pape GR, Will H: Precore mutant hepatitis B virus infection and liver disease. Gastroenterology 102:538–543, 1992PubMedGoogle Scholar
  16. 16.
    Liang TJ, Hasegawa K, Rimon N, Wands JR, Ben-Porath E: A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. N Engl J Med 324:1705–1709, 1991PubMedGoogle Scholar
  17. 17.
    Carman W, Thomas H, Domingo E: Viral genetic variation: Hepatitis B virus as a clinical example. Lancet 1:349–353, 1993Google Scholar
  18. 18.
    Okamoto H, Yotsumoto S, Akahane Y, Yamanaka T, Miyazaki Y, Sugai Y, Tsuda F, Tanaka T, Miyakawa Y, Mayumi M: Hepatitis B viruses in precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen. J Virol 64:1298–1303, 1990PubMedGoogle Scholar
  19. 19.
    Santantonio T, Jung M-C, Miska S, Pastore G, Pape GR, 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, 1991PubMedGoogle Scholar
  20. 20.
    Nair PV, Tong MJ, Stevenson D, Roskamp D, Boone C: A pilot study on the effects of prednisone withdrawal on serum hepatitis B virus, DNA and HBeAg in chronic active hepatitis B. Hepatology 6:1319–1324, 1986PubMedGoogle Scholar
  21. 21.
    Laskus T, Persing DH, Nowicki M, Mosley JW, Rakela J: Nucleotide sequence analysis of the precore region in patients with fulminant hepatitis B in the United States. Gastroenterology 105:1173–1178, 1993PubMedGoogle Scholar
  22. 22.
    Rys PN, Persing DH: Preventing false positives: Quantitative comparison of three PCR product inactivation assays. J Clin Microbiol 31:2356–2360, 1993PubMedGoogle Scholar
  23. 23.
    Thomas HC, Montano L, Goodall A, De Koning R, Oladapo J, Wiedman KH: Immunological mechanisms in chronic B virus infection. Hepatology 2:116S-121S, 1982Google Scholar
  24. 24.
    Chisari FV, Ferrari C, Mondelli MU: Hepatitis B virus structure and biology. Microb Pathog 6:311–325, 1989PubMedGoogle Scholar
  25. 25.
    Lok ASF, Lai C-L: Acute exacerbations in Chinese patients with chronic hepatitis B virus (HBV) infection. J Hepatol 10:29–34, 1990PubMedGoogle Scholar
  26. 26.
    Brunetto MR, Giarin MM, Olivieri F, Chiaberge E, Baldi M, Alfarano A, Serra A, Saracco G, Verme G, Will H, Bonino F: Wild-type and e antigen-minus hepatitis B viruses and course of chronic hepatitis. Proc Natl Acad Sci USA 88:4186–4190, 1991PubMedGoogle Scholar
  27. 27.
    Raimondo G, Schneider R, Stemler M, Smedile V, Rodino G, Will H: A new hepatitis B virus variant in a chronic carrier with multiple episodes of viral reactivation and acute hepatitis. Virology 179:64–68, 1990PubMedGoogle Scholar
  28. 28.
    Blum HE, Offensperger W-B, Walter E, Offensperger S, Gerok W: Latent hepatitis B virus infection with full-length viral genome in a patient serologically immune to hepatitis B virus infection. Liver 8:307–316, 1988PubMedGoogle Scholar
  29. 29.
    Raimondo G, Burk RD, Lieberman HM, Muschel J, Hadziyannis SJ, Will H, Kew MC, Dusheiko GM, Shafritz DA: Interrupted replication of hepatitis B virus in liver tissue of HBsAg carriers with hepatocellular carcinoma. Virology 166:103–112, 1988PubMedGoogle Scholar
  30. 30.
    Hasegawa K, Huang J, Wands JR, Obata H, Liang TJ: Association of hepatitis B viral precore mutations with fulminant hepatitis B in Japan. Virology 185:460–463, 1991PubMedGoogle Scholar
  31. 31.
    Carman WF, Jacyna MR, Hadziyannis S, Karayiannis P, McGarvey MJ, Makris A: Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet 2:588–590, 1989PubMedGoogle Scholar
  32. 32.
    Kozak M: Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes. Cell 44:283–292, 1986PubMedGoogle Scholar
  33. 33.
    Pollack JR, Ganem D: An RNA stem-loop structure directs hepatitis B virus genomic RNA encapsidation. J Virol 67:3254–3263, 1993PubMedGoogle Scholar
  34. 34.
    Junker-Niepmann M, Bartenschlager R, Schaller H: A shortcis-acting sequence is required for hepatitis B virus pregenome encapsidation and sufficient for packaging of foreign RNA. EMBO J 9:3389–3396, 1990PubMedGoogle Scholar
  35. 35.
    Yuh C-H, Chang Y-L, Ting L-P: Transcriptional regulation of precore and pregenomic RNAs of hepatitis B virus. J Virol 66:4073–4084, 1992PubMedGoogle Scholar
  36. 36.
    Bertoletti A, Ferrari C, Fiaccadori F, Penna A, Margolskee R, Schlicht HJ, Fowler P, Guilhot S, Chisari FV: HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen. Proc Natl Acad Sci USA 88:10445–10449, 1991PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 1994

Authors and Affiliations

  • Tomasz Laskus
    • 1
    • 2
  • Jorge Rakela
    • 1
    • 2
  • Myron J. Tong
    • 1
    • 2
  • David H. Persing
    • 1
    • 2
  1. 1.From the Mayo ClinicRochester
  2. 2.Liver CenterHuntington Memorial HospitalPasadena

Personalised recommendations