1887

Journal of General Virology header logo

Volume 81, Issue 1

Long-term mutation rates in the hepatitis B virus genome Free

Abstract

Mutations in the hepatitis B virus (HBV) genome have so far been investigated in cross-sectional or short-term longitudinal studies. Information about long-term changes is lacking due to the difficulty of sampling over long observation periods. In this study, a retrospective approach was used that allowed the analysis of changes in the viral genome from transmission to late stages of infection without the requirement for sampling early during this period. The entire viral genome was sequenced from serum samples of three mothers and their 10 adult children, who presumably had been infected vertically. The emergence of mutations between birth and sampling (mean 26·5 years) was assessed by comparing the individual sequences with the sequence of the strain assumed to have been transmitted. The mean differences from this sequence were 0·02 and 0·28% in seven asymptomatic and one symptomatic hepatitis B e antigen (HBeAg)-positive carriers, respectively, and 0·62 % in five HBeAg-negative carriers. Mutations occurred throughout the genome and 88% of the mutations caused amino acid substitutions spread over all genes. In HBeAg-negative carriers, the number of nucleotide and amino acid changes was independent of the severity of liver disease and, except the AGG→TGA changes, no specific mutation was associated with liver disease. In conclusion, by using a novel method it was found that the entire HBV genome is extremely stable over long periods of time during the HBeAg-positive phase if the immune response (inflammation) is weak, whereas an average of 20 mutations emerged after development of hepatitis and/or loss of HBeAg without association with clinical outcome.

  • Received:
  • Accepted:
  • Published Online:
© Microbiology Society
Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-81-1-75
2000-01-01
2024-04-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/81/1/0810075a.html?itemId=/content/journal/jgv/10.1099/0022-1317-81-1-75&mimeType=html&fmt=ahah

References

  1. Akarca, U. S. & Lok, A. S. (1995). Naturally occurring hepatitis B virus core gene mutations. Hepatology 22, 50-60. [Google Scholar]
  2. Bozkaya, H., Akarca, U. S., Ayola, B. & Lok, A. S. (1997). High degree of conservation in the hepatitis B virus core gene during the immune tolerant phase in perinatally acquired chronic hepatitis B virus infection. Journal of Hepatology 26, 508-516.[CrossRef] [Google Scholar]
  3. Buckwold, V. E., Xu, Z., Yen, T. S. B. & Ou, J.-h. (1997). 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. Journal of General Virology 78, 2055-2065. [Google Scholar]
  4. Carman, W. F., Jacyna, M. R., Hadziyannis, S., Karayiannis, P., McGarvey, M. J., Makris, A. & Thomas, H. C. (1989). Mutation preventing formation of hepatitis B e antigen in patients with chronic hepatitis B infection. Lancet ii, 588–591.
  5. Carman, W. F., Zanetti, A. R., Karayiannis, P., Waters, J., Manzillo, G., Tanzi, E., Zuckerman, A. J. & Thomas, H. C. (1990). Vaccine-induced escape mutant of hepatitis B virus. Lancet 336, 325-329.[CrossRef] [Google Scholar]
  6. Carman, W. F., Boner, W., Fattovich, G., Colman, K., Dornan, E. S., Thursz, M. & Hadziyannis, S. (1997). Hepatitis B virus core protein mutations are concentrated in B cell epitopes in progressive disease and in T helper cell epitopes during clinical remission. Journal of Infectious Diseases 175, 1093-1100.[CrossRef] [Google Scholar]
  7. Felsenstein, J. (1993). PHYLIP (Phylogeny Inference Package) version 3.5c. Distributed by the author. Department of Genetics, University of Washington, Seattle, WA, USA.
  8. Günther, S., Paulij, W., Meisel, H. & Will, H. (1998a). Analysis of hepatitis B virus populations in an interferon-α-treated patient reveals predominant mutations in the C-gene and changing e-antigenicity. Virology 244, 146-160.[CrossRef] [Google Scholar]
  9. Günther, S., Piwon, N. & Will, H. (1998b). Wild-type levels of pregenomic RNA and replication but reduced 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. Journal of General Virology 79, 375-380. [Google Scholar]
  10. Günther, S., Sommer, G., Von Breunig, F., Iwanska, A., Kalinina, T., Sterneck, M. & Will, H. (1998c). Amplification of full-length hepatitis B virus genomes from samples from patients with low levels of viremia: frequency and functional consequences of PCR-introduced mutations. Journal of Clinical Microbiology 36, 531-538. [Google Scholar]
  11. Günther, S., Fischer, L., Pult, I., Sterneck, M. & Will, H. (1999). Naturally occurring variants of hepatitis B virus. Advances in Virus Research 52, 25-137. [Google Scholar]
  12. Horikita, M., Itoh, S., Yamamoto, K., Shibayama, T., Tsuda, F. & Okamoto, H. (1994). Differences in the entire nucleotide sequence between hepatitis B virus genomes from carriers positive for antibody to hepatitis B e antigen with and without active disease. Journal of Medical Virology 44, 96-103.[CrossRef] [Google Scholar]
  13. Karasawa, T., Shirasawa, T., Okawa, Y., Kuramoto, A., Shimada, N., Aizawa, Y., Zeniya, M. & Toda, G. (1997). Association between frequency of amino acid changes in core region of hepatitis B virus (HBV) and the presence of precore mutation in Japanese HBV carriers. Journal of Gastroenterology 32, 611-622.[CrossRef] [Google Scholar]
  14. Knodell, R. G., Ishak, K. G., Black, W. C., Chen, T. S., Craig, R., Kaplowitz, N., Kiernan, T. W. & Wollman, J. (1981). Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1, 431-435.[CrossRef] [Google Scholar]
  15. Li, J., Buckwold, V. E., Hon, M. W. & Ou, J. H. (1999). Mechanism of suppression of hepatitis B virus precore RNA transcription by a frequent double mutation. Journal of Virology 73, 1239-1244. [Google Scholar]
  16. Lindh, M., Horal, P., Dhillon, A. P., Furuta, Y. & Norkrans, G. (1996). Hepatitis B virus carriers without precore mutations in hepatitis B e antigen-negative stage show more severe liver damage. Hepatology 24, 494-501.[CrossRef] [Google Scholar]
  17. Lindh, M., Andersson, A. S. & Gusdal, A. (1997). Genotypes, nt 1858 variants, and geographic origin of hepatitis B virus – large-scale analysis using a new genotyping method. Journal of Infectious Diseases 175, 1285-1293.[CrossRef] [Google Scholar]
  18. Lindh, M., Hannoun, C., Dhillon, A. P., Norkrans, G. & Horal, P. (1999). Core promoter mutations and genotypes in relation to viral replication and liver damage in East Asian hepatitis B virus carriers. Journal of Infectious Diseases 179, 775-782.[CrossRef] [Google Scholar]
  19. Lok, A. S., Akarca, U. & Greene, S. (1994). Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal. Proceedings of the National Academy of Sciences, USA 91, 4077-4081.[CrossRef] [Google Scholar]
  20. Moriyama, K., Okamoto, H., Tsuda, F. & Mayumi, M. (1996). 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 antigen-seronegative persistent infections. Virology 226, 269-280.[CrossRef] [Google Scholar]
  21. Neurath, A. R., Kent, S. B., Strick, N. & Parker, K. (1986). Identification and chemical synthesis of a host cell receptor binding site on hepatitis B virus. Cell 46, 429-436.[CrossRef] [Google Scholar]
  22. Okamoto, H., Imai, M., Shimozaki, M., Hoshi, Y., Iizuka, H., Gotanda, T., Tsuda, F., Miyakawa, Y. & Mayumi, M. (1986). Nucleotide sequence of a cloned hepatitis B virus genome, subtype ayr: comparison with genomes of the other three subtypes. Journal of General Virology 67, 2305-2314.[CrossRef] [Google Scholar]
  23. Okamoto, H., Imai, M., Tsuda, F., Tanaka, T., Miyakawa, Y. & Mayumi, M. (1987). Point mutation in the S gene of hepatitis B virus for a d/y or w/r subtypic change in two blood donors carrying a surface antigen of compound subtype adyr or adwr. Journal of Virology 61, 3030-3034. [Google Scholar]
  24. Okamoto, H., Tsuda, F., Akahane, Y., Sugai, Y., Yoshiba, M., Moriyama, K., Tanaka, T., Miyakawa, Y. & Mayumi, M. (1994). Hepatitis B virus with mutations in the core promoter for an e antigen-negative phenotype in carriers with antibody to e antigen. Journal of Virology 68, 8102-8110. [Google Scholar]
  25. Radziwill, G., Tucker, W. & Schaller, H. (1990). Mutational analysis of the hepatitis B virus P gene product: domain structure and RNase H activity. Journal of Virology 64, 613-620. [Google Scholar]
  26. Tai, P. C., Banik, D., Lin, G. I., Pai, S., Pai, K., Lin, M. H., Yuoh, G., Che, S., Hsu, S. H., Chen, T. C., Kuo, T. T., Lee, C. S., Yang, C. S. & Shih, C. (1997). Novel and frequent mutations of hepatitis B virus coincide with a major histocompatibility complex class I-restricted T-cell epitope of the surface antigen. Journal of Virology 71, 4852-4856. [Google Scholar]
  27. Takahashi, K., Aoyama, K., Ohno, N., Iwata, K., Akahane, Y., Baba, K., Yoshizawa, H. & Mishiro, S. (1995). The precore/core promoter mutant (T1762A1764) of hepatitis B virus: clinical significance and an easy method for detection. Journal of General Virology 76, 3159-3164.[CrossRef] [Google Scholar]
  28. Uchida, T., Saitoh, T. & Shinzawa, H. (1997). Mutations of the X region of hepatitis B virus and their clinical implications. Pathology International 47, 183-193.[CrossRef] [Google Scholar]
  29. Zhang, Y. Y., Nordenfelt, E. & Hansson, B. G. (1996). Increasing heterogeneity of the ‘a’ determinant of HBsAg found in the presumed late phase of chronic hepatitis B virus infection. Scandinavian Journal of Infectious Diseases 28, 9-15.[CrossRef] [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-81-1-75
Loading
Long-term mutation rates in the hepatitis B virus genome
J. Gen. Virol. 81, 75 (2000); https://doi.org/10.1099/0022-1317-81-1-75
/content/journal/jgv/10.1099/0022-1317-81-1-75
/content/journal/jgv/10.1099/0022-1317-81-1-75
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error