1887

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Volume 94, Issue 8

Mutations in human papillomavirus type 16 L1 hypervariable surface-exposed loops affect L2 binding and DNA encapsidation Free

Abstract

Prophylactic vaccines against human papillomavirus (HPV) based on virus-like particles (VLP) induce type-specific neutralizing antibodies against a small number of hypervariable residues positioned in surface-exposed loops of the major capsid protein L1. To investigate the importance of these residues for neutralization, cross-neutralization, L2 incorporation and genome encapsidation, ten surface-exposed amino acid residues in four hypervariable loops of L1 were mutated. VLPs containing mutated or WT L1, with or without WT L2, were produced in 293TT cells using pseudovirion expression vectors. The mutations reduced the ability to induce neutralizing antibodies and to incorporate the L2 protein in the capsid. Ability to induce cross-neutralizing antibodies and to encapsidate pseudogenomes were completely abrogated. In summary, the surface-exposed L1 loops are important for the function of the HPV particle.

  • Received:
  • Accepted:
  • Published Online:
© 2013 SGM
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2013-08-01
2024-04-25
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References

  1. Bishop B., Dasgupta J., Klein M., Garcea R. L., Christensen N. D., Zhao R., Chen X. S. 2007; Crystal structures of four types of human papillomavirus L1 capsid proteins: understanding the specificity of neutralizing monoclonal antibodies. J Biol Chem 282:31803–31811 [View Article][PubMed]
     [Google Scholar]
  2. Buck C. B., Pastrana D. V., Lowy D. R., Schiller J. T. 2004; Efficient intracellular assembly of papillomaviral vectors. J Virol 78:751–757 [View Article][PubMed]
     [Google Scholar]
  3. Buck C. B., Thompson C. D., Pang Y. Y., Lowy D. R., Schiller J. T. 2005; Maturation of papillomavirus capsids. J Virol 79:2839–2846 [View Article][PubMed]
     [Google Scholar]
  4. Buck C. B., Cheng N., Thompson C. D., Lowy D. R., Steven A. C., Schiller J. T., Trus B. L. 2008; Arrangement of L2 within the papillomavirus capsid. J Virol 82:5190–5197 [View Article][PubMed]
     [Google Scholar]
  5. Carter J. J., Wipf G. C., Benki S. F., Christensen N. D., Galloway D. A. 2003; Identification of a human papillomavirus type 16-specific epitope on the C-terminal arm of the major capsid protein L1. J Virol 77:11625–11632 [View Article][PubMed]
     [Google Scholar]
  6. Carter J. J., Wipf G. C., Madeleine M. M., Schwartz S. M., Koutsky L. A., Galloway D. A. 2006; Identification of human papillomavirus type 16 L1 surface loops required for neutralization by human sera. J Virol 80:4664–4672 [View Article][PubMed]
     [Google Scholar]
  7. Chen X. S., Garcea R. L., Goldberg I., Casini G., Harrison S. C. 2000; Structure of small virus-like particles assembled from the L1 protein of human papillomavirus 16. Mol Cell 5:557–567 [View Article][PubMed]
     [Google Scholar]
  8. Christensen N. D., Dillner J., Eklund C., Carter J. J., Wipf G. C., Reed C. A., Cladel N. M., Galloway D. A. 1996; Surface conformational and linear epitopes on HPV-16 and HPV-18 L1 virus-like particles as defined by monoclonal antibodies. Virology 223:174–184 [View Article][PubMed]
     [Google Scholar]
  9. Christensen N. D., Cladel N. M., Reed C. A., Budgeon L. R., Embers M. E., Skulsky D. M., McClements W. L., Ludmerer S. W., Jansen K. U. 2001; Hybrid papillomavirus L1 molecules assemble into virus-like particles that reconstitute conformational epitopes and induce neutralizing antibodies to distinct HPV types. Virology 291:324–334 [View Article][PubMed]
     [Google Scholar]
  10. Day P. M., Gambhira R., Roden R. B., Lowy D. R., Schiller J. T. 2008a; Mechanisms of human papillomavirus type 16 neutralization by l2 cross-neutralizing and 11 type-specific antibodies. J Virol 82:4638–4646 [View Article][PubMed]
     [Google Scholar]
  11. Day P. M., Lowy D. R., Schiller J. T. 2008b; Heparan sulfate-independent cell binding and infection with furin-precleaved papillomavirus capsids. J Virol 82:12565–12568 [View Article][PubMed]
     [Google Scholar]
  12. Dillner L., Heino P., Moreno-Lopez J., Dillner J. 1991; Antigenic and immunogenic epitopes shared by human papillomavirus type 16 and bovine, canine, and avian papillomaviruses. J Virol 65:6862–6871[PubMed]
     [Google Scholar]
  13. Embers M. E., Budgeon L. R., Pickel M., Christensen N. D. 2002; Protective immunity to rabbit oral and cutaneous papillomaviruses by immunization with short peptides of L2, the minor capsid protein. J Virol 76:9798–9805 [View Article][PubMed]
     [Google Scholar]
  14. Finnen R. L., Erickson K. D., Chen X. S., Garcea R. L. 2003; Interactions between papillomavirus L1 and L2 capsid proteins. J Virol 77:4818–4826 [View Article][PubMed]
     [Google Scholar]
  15. Gambhira R., Karanam B., Jagu S., Roberts J. N., Buck C. B., Bossis I., Alphs H., Culp T., Christensen N. D., Roden R. B. 2007; A protective and broadly cross-neutralizing epitope of human papillomavirus L2. J Virol 81:13927–13931 [View Article][PubMed]
     [Google Scholar]
  16. Holmgren S. C., Patterson N. A., Ozbun M. A., Lambert P. F. 2005; The minor capsid protein L2 contributes to two steps in the human papillomavirus type 31 life cycle. J Virol 79:3938–3948 [View Article][PubMed]
     [Google Scholar]
  17. Kawana K., Yoshikawa H., Taketani Y., Yoshiike K., Kanda T. 1999; Common neutralization epitope in minor capsid protein L2 of human papillomavirus types 16 and 6. J Virol 73:6188–6190[PubMed]
     [Google Scholar]
  18. Lowe J., Panda D., Rose S., Jensen T., Hughes W. A., Tso F. Y., Angeletti P. C. 2008; Evolutionary and structural analyses of alpha-papillomavirus capsid proteins yields novel insights into L2 structure and interaction with L1. Virol J 5:150 [View Article][PubMed]
     [Google Scholar]
  19. Palmer K. E., Jenson A. B., Kouokam J. C., Lasnik A. B., Ghim S. J. 2009; Recombinant vaccines for the prevention of human papillomavirus infection and cervical cancer. Exp Mol Pathol 86:224–233 [View Article][PubMed]
     [Google Scholar]
  20. Pastrana D. V., Buck C. B., Pang Y. Y., Thompson C. D., Castle P. E., FitzGerald P. C., Krüger Kjaer S., Lowy D. R., Schiller J. T. 2004; Reactivity of human sera in a sensitive, high-throughput pseudovirus-based papillomavirus neutralization assay for HPV16 and HPV18. Virology 321:205–216 [View Article][PubMed]
     [Google Scholar]
  21. Rubio I., Seitz H., Canali E., Sehr P., Bolchi A., Tommasino M., Ottonello S., Müller M. 2011; The N-terminal region of the human papillomavirus L2 protein contains overlapping binding sites for neutralizing, cross-neutralizing and non-neutralizing antibodies. Virology 409:348–359 [View Article][PubMed]
     [Google Scholar]
  22. Ryding J., Dahlberg L., Wallen-Ohman M., Dillner J. 2007; Deletion of a major neutralizing epitope of human papillomavirus type 16 virus-like particles. J Gen Virol 88:792–802 [View Article][PubMed]
     [Google Scholar]
  23. Schäfer F., Florin L., Sapp M. 2002; DNA binding of L1 is required for human papillomavirus morphogenesis in vivo . Virology 295:172–181 [View Article][PubMed]
     [Google Scholar]
  24. Schiller J. T., Lowy D. R. 2009; Immunogenicity testing in human papillomavirus virus-like-particle vaccine trials. J Infect Dis 200:166–171 [View Article][PubMed]
     [Google Scholar]
  25. Schiller J. T., Day P. M., Kines R. C. 2010; Current understanding of the mechanism of HPV infection. Gynecol Oncol 118:SupplS12–S17 [View Article][PubMed]
     [Google Scholar]
  26. Unckell F., Streeck R. E., Sapp M. 1997; Generation and neutralization of pseudovirions of human papillomavirus type 33. J Virol 71:2934–2939[PubMed]
     [Google Scholar]
  27. Wang X., Wang Z., Christensen N. D., Dillner J. 2003; Mapping of human serum-reactive epitopes in virus-like particles of human papillomavirus types 16 and 11. Virology 311:213–221 [View Article][PubMed]
     [Google Scholar]
  28. White W. I., Wilson S. D., Palmer-Hill F. J., Woods R. M., Ghim S. J., Hewitt L. A., Goldman D. M., Burke S. J., Jenson A. B.& other authors ( 1999; Characterization of a major neutralizing epitope on human papillomavirus type 16 L1. J Virol 73:4882–4889[PubMed]
     [Google Scholar]
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Mutations in human papillomavirus type 16 L1 hypervariable surface-exposed loops affect L2 binding and DNA encapsidation
J. Gen. Virol. 94, 1841 (2013); https://doi.org/10.1099/vir.0.054205-0
/content/journal/jgv/10.1099/vir.0.054205-0
/content/journal/jgv/10.1099/vir.0.054205-0
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