1887

Abstract

The hepatitis B virus (HBV) surface antigen (HBsAg) is a complex protein, and understanding accurately the impact of amino acid changes on the antigenicity of the immunodominant determinant must take this complexity into consideration. Epitope mapping with four mAbs was used to phenotype HBsAg directly from patients’ sera to investigate the effect of mutations in their native genetic backbone. The expected mAb reactivity was established initially for samples harbouring ‘wild-type’ HBsAg sequences across genotypes A–E. The alteration of HBsAg antigenicity, defined by mAb epitope loss, was demonstrated in a number of samples with sequence-inferred amino acid changes. Individual mutations within the mapped epitopes to which the mAbs were directed usually affected their binding. However, the loss of more than one epitope was observed as the number of mutations within a sequence increased. Conversely, not all mutations occurring in the determinant altered the HBsAg conformation. The genotype backbone, the specific amino acid substitution and amino acid changes occurring outside the major antigenic region appeared to be important in determining expression of the predicted epitope loss. These data clearly demonstrate that sequence-based methods alone may not accurately define HBsAg phenotype. This phenotyping methodology allows for the rapid and accurate identification of antigenically altered viruses and will greatly enhance current HBV surveillance, research and diagnostic activities. The data generated can be used to inform on public health issues relating to prevalence, transmission and impact of HBsAg mutants in HBV-infected populations.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.044305-0
2012-11-01
2019-12-11
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/11/2473.html?itemId=/content/journal/jgv/10.1099/vir.0.044305-0&mimeType=html&fmt=ahah

References

  1. Beale M. A., Ijaz S., Tedder R. S.. ( 2010;). The genetic backbone modulates the phenotype of hepatitis B surface antigen mutants. . J Gen Virol 91:, 68–73. [CrossRef][PubMed]
    [Google Scholar]
  2. Carman W. F.. ( 1997;). The clinical significance of surface antigen variants of hepatitis B virus. . J Viral Hepat 4: (Suppl. 1), 11–20. [CrossRef][PubMed]
    [Google Scholar]
  3. Chen Y.-C., Delbrook K., Dealwis C., Mimms L., Mushahwar I. K., Mandecki W.. ( 1996;). Discontinuous epitopes of hepatitis B surface antigen derived from a filamentous phage peptide library. . Proc Natl Acad Sci U S A 93:, 1997–2001. [CrossRef][PubMed]
    [Google Scholar]
  4. Clements C. J., Coghlan B., Creati M., Locarnini S., Tedder R. S., Torresi J.. ( 2010;). Global control of hepatitis B virus: does treatment-induced antigenic change affect immunization?. Bull World Health Organ 88:, 66–73. [CrossRef][PubMed]
    [Google Scholar]
  5. Coleman P. F., Chen Y.-C., Mushahwar I. K.. ( 1999;). Immunoassay detection of hepatitis B surface antigen mutants. . J Med Virol 59:, 19–24. [CrossRef][PubMed]
    [Google Scholar]
  6. Couroucé A. M., Holland P. V., Muller J. Y., Soulier J. P.. ( 1976;). HBs Antigen Subtypes. International Workshop, Paris, April 1975. Current Studies in Hematology and Blood Transfusion, No. 42. Basel: Karger..
    [Google Scholar]
  7. Hsu H.-Y., Chang M.-H., Liaw S.-H., Ni Y.-H., Chen H.-L.. ( 1999;). Changes of hepatitis B surface antigen variants in carrier children before and after universal vaccination in Taiwan. . Hepatology 30:, 1312–1317. [CrossRef][PubMed]
    [Google Scholar]
  8. Ijaz S., Ferns R. B., Tedder R. S.. ( 2003;). A ‘first loop’ linear epitope accessible on native hepatitis B surface antigen that persists in the face of ‘second loop’ immune escape. . J Gen Virol 84:, 269–275. [CrossRef][PubMed]
    [Google Scholar]
  9. Ijaz S., Arnold C., Dervisevic S., Mechurova J., Tatman N., Tedder R. S., Naoumov N. V.. ( 2008;). Dynamics of lamivudine-resistant hepatitis B virus during adefovir monotherapy versus lamivudine plus adefovir combination therapy. . J Med Virol 80:, 1160–1170. [CrossRef][PubMed]
    [Google Scholar]
  10. Le Bouvier G. L., McCollum R. W., Hierholzer W. J. Jr, Irwin G. R., Krugman S., Giles J. P.. ( 1972;). Subtypes of Australia antigen and hepatitis-B virus. . JAMA 222:, 928–930. [CrossRef][PubMed]
    [Google Scholar]
  11. Prange R., Streeck R. E.. ( 1995;). Novel transmembrane topology of the hepatitis B virus envelope proteins. . EMBO J 14:, 247–256.[PubMed]
    [Google Scholar]
  12. Rice S. J.. ( 1988;). False negativity with one-step monoclonal assay for hepatitis B surface antigen. . Lancet 311:, 598–599. [CrossRef][PubMed]
    [Google Scholar]
  13. Rousseeuw P. J., Croux C.. ( 1993;). Alternatives to the median absolute deviation. . J Am Stat Assoc 88:, 1273–1283. [CrossRef]
    [Google Scholar]
  14. Servant-Delmas A., Mercier-Darty M., Ly T. D., Wind F., Alloui C., Sureau C., Laperche S.. ( 2012;). Variable capacity of 13 hepatitis B virus surface antigen assays for the detection of HBsAg mutants in blood samples. . J Clin Virol 53:, 338–345. [CrossRef][PubMed]
    [Google Scholar]
  15. Sloan R. D., Ijaz S., Moore P. L., Harrison T. J., Teo C. G., Tedder R. S.. ( 2008;). Antiviral resistance mutations potentiate hepatitis B virus immune evasion through disruption of its surface antigen a determinant. . Antivir Ther 13:, 439–447.[PubMed]
    [Google Scholar]
  16. Tedder R. S., Guarascio P., Yao J. L., Lord R. B., Eddleston A. L.. ( 1983;). Production of monoclonal antibodies to hepatitis B surface and core antigens, and use in the detection of viral antigens in liver biopsies. . J Hyg (Lond) 90:, 135–142. [CrossRef][PubMed]
    [Google Scholar]
  17. Torresi J., Earnest-Silveira L., Deliyannis G., Edgtton K., Zhuang H., Locarnini S. A., Fyfe J., Sozzi T., Jackson D. C.. ( 2002;). Reduced antigenicity of the hepatitis B virus HBsAg protein arising as a consequence of sequence changes in the overlapping polymerase gene that are selected by lamivudine therapy. . Virology 293:, 305–313. [CrossRef][PubMed]
    [Google Scholar]
  18. Zoulim F., Locarnini S.. ( 2009;). Hepatitis B virus resistance to nucleos(t)ide analogues. . Gastroenterology 137:, 1593–1608. [CrossRef][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.044305-0
Loading
/content/journal/jgv/10.1099/vir.0.044305-0
Loading

Data & Media loading...

Most Cited This Month

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