Hepatitis B virus (HBV) vaccine and diagnostic escape mutants are a growing concern. The principle target of detection, hepatitis B surface antigen (HBsAg), encoded by S, is completely overlapped by the reverse transcriptase encoding P. With the increased incidence of nucleos(t)ide analogue resistance altering P, the concurrent impact on S must be assessed. HBV DNA from 59 HBsAg-positive plasma samples was sequenced across the polymerase/surface region and the amino acid sequence of HBsAg was inferred. ELISAs were formatted containing individually bound monoclonal antibodies directed against three discrete epitopes on HBsAg. Similar point mutations occurring in different genotypes were shown to influence epitope conformation differently, indicating that the genetic backbone is a major factor in predicting phenotype. C-terminal changes associated with antiviral resistance were found to modulate epitope profiles of HBsAg. Treatment options which may promote drug resistance should be avoided to both protect antiviral treatment and prevent facilitation of vaccine and diagnostic escape mutants.
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. Lancet336, 325–329.[CrossRef][Google Scholar]
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 A93, 1997–2001.[CrossRef][Google Scholar]
Cooreman, M. P., Leroux-Roels, G. & Paulij, W. P.(2001). Vaccine- and hepatitis B immune globulin-induced escape mutations of hepatitis B virus surface antigen. J Biomed Sci8, 237–247.[CrossRef][Google Scholar]
Datta, S., Banerjee, A., Chandra, P. K., Chowdhury, A. & Chakravarty, R.(2006). Genotype, phylogenetic analysis, and transmission pattern of occult hepatitis B virus (HBV) infection in families of asymptomatic HBsAg carriers. J Med Virol78, 53–59.[CrossRef][Google Scholar]
Hadziyannis, S. J., Tassopoulos, N. C., Heathcote, E. J., Chang, T., Kitis, G., Rizzetto, M., Marcellin, P., Lim, S. G., Goodman, Z. & other authors(2005). Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med352, 2673–2681.[CrossRef][Google Scholar]
Hou, J., Wang, Z., Cheng, J., Lin, Y., Lau, G. K., Sun, J., Zhou, F., Waters, J., Karayiannis, P. & Luo, K.(2001). Prevalence of naturally occurring surface gene variants of hepatitis B virus in nonimmunized surface antigen-negative Chinese carriers. Hepatology34, 1027–1034.[CrossRef][Google Scholar]
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. Gut53, 1499–1503.[CrossRef][Google Scholar]
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 Virol84, 269–275.[CrossRef][Google Scholar]
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 Virol80, 1160–1170.[CrossRef][Google Scholar]
Norder, H., Couroucé, A., Coursaget, P., Echevarria, J. M., Lee, S., Mushahwar, I. K., Robertson, B. H., Locarnini, S. & Magnius, L. O.(2004). Genetic diversity of hepatitis B virus strains derived worldwide: genotypes, subgenotypes, and HBsAg subtypes. Intervirology47, 289–309.[CrossRef][Google Scholar]
Osiowy, C., Villeneuve, J., Heathcote, E. J., Giles, E. & Borlang, J.(2006). Detection of rtN236T and rtA181V/T mutations associated with resistance to adefovir dipivoxil in samples from patients with chronic hepatitis B virus infection by the INNO-LiPA HBV DR line probe assay (version 2). J Clin Microbiol44, 1994–1997.[CrossRef][Google Scholar]
Paulij, W. P., de Wit, P. L., Sünnen, C. M., van Roosmalen, M. H., Petersen-van Ettekoven, A., Cooreman, M. P. & Heijtink, R. A.(1999). Localization of a unique hepatitis B virus epitope sheds new light on the structure of hepatitis B virus surface antigen. J Gen Virol80, 2121–2126.
[Google Scholar]
Protzer-Knolle, U., Naumann, U., Bartenschlager, R., Berg, T., Hopf, U., Meyer zum Büschenfelde, K. H., Neuhaus, P. & Gerken, G.(1998). Hepatitis B virus with antigenically altered hepatitis B surface antigen is selected by high-dose hepatitis B immune globulin after liver transplantation. Hepatology27, 254–263.[CrossRef][Google Scholar]
Salisse, J. & Sureau, C.(2009). A function essential to viral entry underlies the hepatitis B virus “a” determinant. J Virol83, 9321–9328.[CrossRef][Google Scholar]
Seeger, C., Zoulim, F. & Mason, W. S.(2007). Hepadnaviruses. Fields Virology, 5th edn, pp. 2977–3029. Edited by D. M. Knipe & P. M. Howley. Philadelphia: Lippincott Williams & Wilkins.
Sloan, R. D., Ijaz, S., Moore, P. L., Harrison, T. J., Teo, C. & Tedder, R. S.(2008). Antiviral resistance mutations potentiate hepatitis B virus immune evasion through disruption of its surface antigen a determinant. Antivir Ther13, 439–447.
[Google Scholar]
Stirk, H. J., Thornton, J. M. & Howard, C. R.(1992). A topological model for hepatitis B surface antigen. Intervirology33, 148–158.
[Google Scholar]
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][Google Scholar]
Torresi, J., Earnest-Silveira, L., Civitico, G., Walters, T. E., Lewin, S. R., Fyfe, J., Locarnini, S. A., Manns, M., Trautwein, C. & Bock, T. C.(2002a). Restoration of replication phenotype of lamivudine-resistant hepatitis B virus mutants by compensatory changes in the “fingers” subdomain of the viral polymerase selected as a consequence of mutations in the overlapping S gene. Virology299, 88–99.[CrossRef][Google Scholar]
Torresi, J., Earnest-Silveira, L., Deliyannis, G., Edgtton, K., Zhuang, H., Locarnini, S. A., Fyfe, J., Sozzi, T. & Jackson, D. C.(2002b). 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. Virology293, 305–313.[CrossRef][Google Scholar]
van Hemert, F. J., Zaaijer, H. L., Berkhout, B. & Lukashov, V. V.(2008). Mosaic amino acid conservation in 3D-structures of surface protein and polymerase of hepatitis B virus. Virology370, 362–372.[CrossRef][Google Scholar]
Warner, N. & Locarnini, S.(2008). The antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound. Hepatology48, 88–98.[CrossRef][Google Scholar]
Ziermann, R. & Ganem, D.(1996). Homologous and heterologous complementation of HBV and WHV capsid and polymerase functions in RNA encapsidation. Virology219, 350–356.[CrossRef][Google Scholar]