Evidence for reduced selection pressure on the hepatitis B virus core gene in hepatitis B e antigen-negative chronic hepatitis B Free

Abstract

The mechanisms underlying the high levels of hepatitis B virus (HBV) replication that cause hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (e−CHB) are unknown. Impaired anti-HBV immunity, which may be measurable as a relaxation of selection pressure on the virus, is possible. A group of Tongans ( = 345) with a chronic HBV infection, including seven with e−CHB, were genotyped at HLA class I. The repertoire of HBV core-gene codons under positive selection pressure was defined by phylogenetic analysis (by using the program) of 708 cloned sequences extracted from the 67 of these 345 subjects with the same repertoire of HLA class I alleles as the seven e−CHB individuals and matched controls (see below). The frequency of non-synonymous mutations at these codons was measured in longitudinal data from 15 subjects. Finally, the number of non-synonymous mutations at these codons was compared in seven groups comprised of one subject with e−CHB and 1–3 HLA class I-matched controls with an inactive, HBeAg-negative chronic HBV infection (e−InD). Nineteen codons in the core gene were under positive selection pressure. There was a high frequency of new non-synonymous mutations at these codons (<0.0001) in longitudinal data. The mean number of these 19 codons with non-synonymous mutations was lower ( = 0.02) in HBV from subjects with e−CHB (4.4±0.5 codons per subject) versus those with e−InD (6.4±0.4 codons per subject). There is a subtle relaxation in selection pressure on the HBV core gene in e−CHB. This may be due to impaired antiviral immunity, and could contribute to the high levels of viral replication that cause liver inflammation in this disease.

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2011-08-01
2024-03-29
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References

  1. Abbott W. G., Tukuitonga C. F., Ofanoa M., Munn S. R., Gane E. J. 2006a; Low-cost, simultaneous, single-sequence genotyping of the HLA-A, HLA-B and HLA-C loci. Tissue Antigens 68:28–37 [View Article][PubMed]
    [Google Scholar]
  2. Abbott W. G., Winship I. M., Gane E. J., Finau S. A., Munn S. R., Tukuitonga C. E. 2006b; Genetic diversity and linkage disequilibrium in the Polynesian population of Niue Island. Hum Biol 78:131–145 [View Article][PubMed]
    [Google Scholar]
  3. Abbott W. G., Tsai P., Leung E., Trevarton A., Ofanoa M., Hornell J., Gane E. J., Munn S. R., Rodrigo A. G. 2010; Associations between HLA class I alleles and escape mutations in the hepatitis B virus core gene in New Zealand-resident Tongans. J Virol 84:621–629 [View Article][PubMed]
    [Google Scholar]
  4. Akarca U. S., Lok A. S. 1995; Naturally occurring hepatitis B virus core gene mutations. Hepatology 22:50–60[PubMed]
    [Google Scholar]
  5. Bertoletti A., Costanzo A., Chisari F. V., Levrero M., Artini M., Sette A., Penna A., Giuberti T., Fiaccadori F., Ferrari C. 1994; Cytotoxic T lymphocyte response to a wild type hepatitis B virus epitope in patients chronically infected by variant viruses carrying substitutions within the epitope. J Exp Med 180:933–943 [View Article][PubMed]
    [Google Scholar]
  6. Boni C., Fisicaro P., Valdatta C., Amadei B., Di Vincenzo P., Giuberti T., Laccabue D., Zerbini A., Cavalli A. et al. 2007; Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 81:4215–4225 [View Article][PubMed]
    [Google Scholar]
  7. Chin R., Locarnini S. 2003; Treatment of chronic hepatitis B: current challenges and future directions. Rev Med Virol 13:255–272 [View Article][PubMed]
    [Google Scholar]
  8. Crawford H., Prado J. G., Leslie A., Hué S., Honeyborne I., Reddy S., van der Stok M., Mncube Z., Brander C. et al. 2007; Compensatory mutation partially restores fitness and delays reversion of escape mutation within the immunodominant HLA-B*5703-restricted Gag epitope in chronic human immunodeficiency virus type 1 infection. J Virol 81:8346–8351 [View Article][PubMed]
    [Google Scholar]
  9. del Guercio M. F., Sidney J., Hermanson G., Perez C., Grey H. M., Kubo R. T., Sette A. 1995; Binding of a peptide antigen to multiple HLA alleles allows definition of an A2-like supertype. J Immunol 154:685–693[PubMed]
    [Google Scholar]
  10. Durantel D., Zoulim F. 2009; Innate response to hepatitis B virus infection: observations challenging the concept of a stealth virus. Hepatology 50:1692–1695 [View Article][PubMed]
    [Google Scholar]
  11. Guindon S., Rodrigo A. G., Dyer K. A., Huelsenbeck J. P. 2004; Modeling the site-specific variation of selection patterns along lineages. Proc Natl Acad Sci U S A 101:12957–12962 [View Article][PubMed]
    [Google Scholar]
  12. Günther S. 2006; Genetic variation in HBV infection: genotypes and mutants. J Clin Virol 36:Suppl. 1S3–S11 [View Article][PubMed]
    [Google Scholar]
  13. Hannoun C., Horal P., Lindh M. 2000; Long-term mutation rates in the hepatitis B virus genome. J Gen Virol 81:75–83[PubMed]
    [Google Scholar]
  14. Hirankarn N., Manonom C., Tangkijvanich P., Poovorawan Y. 2007; Association of interleukin-18 gene polymorphism (–607A/A genotype) with susceptibility to chronic hepatitis B virus infection. Tissue Antigens 70:160–163 [View Article][PubMed]
    [Google Scholar]
  15. Hsu H. Y., Chang M. H., Ni Y. H., Chen H. L. 2004; Survey of hepatitis B surface variant infection in children 15 years after a nationwide vaccination programme in Taiwan. Gut 53:1499–1503 [View Article][PubMed]
    [Google Scholar]
  16. Liaw Y. F. 2009; Natural history of chronic hepatitis B virus infection and long-term outcome under treatment. Liver Int 29:Suppl. 1100–107 [View Article][PubMed]
    [Google Scholar]
  17. Liaw Y. F., Leung N., Kao J. H., Piratvisuth T., Gane E., Han K. H., Guan R., Lau G. K., Locarnini S. for the Chronic Hepatitis B Guideline Working Party of the Asian-Pacific Association for the Study of the Liver 2008; Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2008 update. Hepatol Int 2:263–283 [View Article][PubMed]
    [Google Scholar]
  18. Lim S. G., Cheng Y., Guindon S., Seet B. L., Lee L. Y., Hu P., Wasser S., Peter F. J., Tan T. et al. 2007; Viral quasi-species evolution during hepatitis Be antigen seroconversion. Gastroenterology 133:951–958 [View Article][PubMed]
    [Google Scholar]
  19. Lin T. M., Chen C. J., Wu M. M., Yang C. S., Chen J. S., Lin C. C., Kwang T. Y., Hsu S. T., Lin S. Y., Hsu L. C. 1989; Hepatitis B virus markers in Chinese twins. Anticancer Res 9:737–741[PubMed]
    [Google Scholar]
  20. Lok A. S., McMahon B. J. 2007; Chronic hepatitis B. Hepatology 45:507–539 [View Article][PubMed]
    [Google Scholar]
  21. Lok A. S., Heathcote E. J., Hoofnagle J. H. 2001; Management of hepatitis B: 2000–summary of a workshop. Gastroenterology 120:1828–1853 [View Article][PubMed]
    [Google Scholar]
  22. Lok A. S., Zoulim F., Locarnini S., Bartholomeusz A., Ghany M. G., Pawlotsky J. M., Liaw Y. F., Mizokami M., Kuiken C. Hepatitis B Virus Drug Resistance Working Group 2007; Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology 46:254–265 [View Article][PubMed]
    [Google Scholar]
  23. Lucifora J., Durantel D., Testoni B., Hantz O., Levrero M., Zoulim F. 2010; Control of hepatitis B virus replication by innate response of HepaRG cells. Hepatology 51:63–72[PubMed] [CrossRef]
    [Google Scholar]
  24. Milich D., Liang T. J. 2003; Exploring the biological basis of hepatitis B e antigen in hepatitis B virus infection. Hepatology 38:1075–1086 [View Article][PubMed]
    [Google Scholar]
  25. Missale G., Redeker A., Person J., Fowler P., Guilhot S., Schlicht H. J., Ferrari C., Chisari F. V. 1993; 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 177:751–762 [View Article][PubMed]
    [Google Scholar]
  26. Publicover J., Goodsell A., Nishimura S., Vilarinho S., Wang Z. E., Avanesyan L., Spolski R., Leonard W. J., Cooper S., Baron J. L. 2011; IL-21 is pivotal in determining age-dependent effectiveness of immune responses in a mouse model of human hepatitis B. J Clin Invest 121:1154–1162 [View Article][PubMed]
    [Google Scholar]
  27. Reijnders J. G., Perquin M. J., Zhang N., Hansen B. E., Janssen H. L. 2010; Nucleos(t)ide analogues only induce temporary hepatitis B e antigen seroconversion in most patients with chronic hepatitis B. Gastroenterology 139:491–498 [View Article][PubMed]
    [Google Scholar]
  28. Scheuer P. J. 1970; Liver biopsy in the diagnosis of cirrhosis. Gut 11:275–278 [View Article][PubMed]
    [Google Scholar]
  29. Sendi H., Mehrab-Mohseni M., Shahraz S., Norder H., Alavian S. M., Noorinayer B., Zali M. R., Pumpens P., Bonkovsky H. L., Magnius L. O. 2009; CTL escape mutations of core protein are more frequent in strains of HBeAg negative patients with low levels of HBV DNA. J Clin Virol 46:259–264 [View Article][PubMed]
    [Google Scholar]
  30. Sobao Y., Sugi K., Tomiyama H., Saito S., Fujiyama S., Morimoto M., Hasuike S., Tsubouchi H., Tanaka K., Takiguch M. 2001; Identification of hepatitis B virus-specific CTL epitopes presented by HLA-A*2402, the most common HLA class I allele in East Asia. J Hepatol 34:922–929 [View Article][PubMed]
    [Google Scholar]
  31. Visvanathan K., Skinner N. A., Thompson A. J., Riordan S. M., Sozzi V., Edwards R., Rodgers S., Kurtovic J., Chang J. et al. 2007; Regulation of Toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology 45:102–110 [View Article][PubMed]
    [Google Scholar]
  32. Whalley S. A., Brown D., Webster G. J., Jacobs R., Reignat S., Bertoletti A., Teo C. G., Emery V., Dusheiko G. M. 2004; Evolution of hepatitis B virus during primary infection in humans: transient generation of cytotoxic T-cell mutants. Gastroenterology 127:1131–1138 [View Article][PubMed]
    [Google Scholar]
  33. Wu J. F., Wu T. C., Chen C. H., Ni Y. H., Chen H. L., Hsu H. Y., Chang M. H. 2010; Serum levels of interleukin-10 and interleukin-12 predict early, spontaneous hepatitis B virus e antigen seroconversion. Gastroenterology 138:165–172, e1–e3 [View Article][PubMed]
    [Google Scholar]
  34. Wu S., Imazeki F., Kurbanov F., Fukai K., Arai M., Kanda T., Yonemitsu Y., Tanaka Y., Mizokami M., Yokosuka O. 2011; Evolution of hepatitis B genotype C viral quasi-species during hepatitis B e antigen seroconversion. J Hepatol 54:19–25 [View Article][PubMed]
    [Google Scholar]
  35. Yamashiro T., Nagayama K., Enomoto N., Watanabe H., Miyagi T., Nakasone H., Sakugawa H., Watanabe M. 2004; Quantitation of the level of hepatitis delta virus RNA in serum, by real-time polymerase chain reaction and its possible correlation with the clinical stage of liver disease. J Infect Dis 189:1151–1157 [View Article][PubMed]
    [Google Scholar]
  36. Yang Z., Wong W. S., Nielsen R. 2005; Bayes empirical bayes inference of amino acid sites under positive selection. Mol Biol Evol 22:1107–1118 [View Article][PubMed]
    [Google Scholar]
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