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. 2006 Mar 3;151(8):1511–1523. doi: 10.1007/s00705-006-0734-y

Identification of type-specific and cross-reactive neutralizing conformational epitopes on the major capsid protein of human papillomavirus type 31

M J J Fleury 1, A Touzé 1, E Alvarez 1, G Carpentier 1, C Clavel 2, J-F Vautherot 3, P Coursaget 1
PMCID: PMC7086758  PMID: 16508703

Summary.

The majority of the neutralizing epitopes of papillomaviruses (PV) are conformation-specific and have not been fully characterised. Studies have, to date, been limited to a few HPV types only. We analysed the epitopes on the major capsid protein (L1) of Human papillomavirus (HPV) type 31 using monoclonal antibodies (MAbs) generated against HPV-31 virus-like particles (VLPs). The type-specific MAbs against HPV-31 were all found to be neutralizing and recognized conformation-dependent epitopes. Two other MAbs directed against a conformational epitope were found to be cross-reactive with other HPV types, and one of them was found to be cross-neutralizing. Cross-reactive antibodies were further investigated using wild-type HPV-16 L1 VLPs and two mutants. The results obtained suggested the existence of a cross-neutralizing conformational epitope at the N-terminal part of the FG loop of the major capsid protein, and the other four cross-reactive MAbs recognized epitopes also located at the N-terminal part of the FG loop.

Keywords: Conformational Epitope, Major Capsid Protein, Linear Epitope, Viruslike Particle, Minor Capsid Protein

References

  1. Bousarghin L, Touzé A, Combita AL, El Mehdaoui S, Sizaret PY, Bravo MM, Coursaget P. Detection of neutralizing antibodies against human papillomaviruses (HPV) by inhibition of gene transfer mediated by HPV pseudovirions. J Clin Microbiol. 2002;40:926–932. doi: 10.1128/JCM.40.3.926-932.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Breitburd F, Kirnbauer R, Hubbert NL, Nonnenmacher B, Trin-Dinh-Desmarquet C, Orth G, Schiller JT, Lowy DR. Immunization with viruslike particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection. J Virol. 1995;69:3959–3963. doi: 10.1128/jvi.69.6.3959-3963.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Brown DR, Fife KH, Wheeler CM, Koutsky LA, Lupinacci LM, Railkar R, Suhr G, Barr E, Dicello A, Li W, Smith JF, Tadesse A, Jansen KU. Early assessment of the efficacy of a human papillomavirus type 16 L1 virus-like particle vaccine. Vaccine. 2004;22:2936–2942. doi: 10.1016/j.vaccine.2003.11.059. [DOI] [PubMed] [Google Scholar]
  4. Carter JJ, Wipf GC, Benki SF, Christensen ND, Galloway DA. Identification of a human papillomavirus type 16-specific epitope on the C-terminal arm of the major capsid protein L1. J Virol. 2003;77:11625–11632. doi: 10.1128/JVI.77.21.11625-11632.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cason J, Patel D, Naylor J, Lunney D, Shepherd PS, Best JM, McCance DJ. Identification of immunogenic regions of the major coat protein of human papillomavirus type 16 that contain type-restricted epitopes. J Gen Virol. 1989;70:2973–2987. doi: 10.1099/0022-1317-70-11-2973. [DOI] [PubMed] [Google Scholar]
  6. Christensen ND, Kreider JW, Cladel NM, Patrick SD, Welsh PA. Monoclonal antibody-mediated neutralization of infectious human papillomavirus type 11. J Virol. 1990;64:5678–5681. doi: 10.1128/jvi.64.11.5678-5681.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Christensen ND, Kirnbauer R, Schiller JT, Ghim SJ, Schlegel R, Jenson AB, Kreider JW. Human papillomavirus types 6 and 11 have antigenically distinct strongly immunogenic conformationally dependent neutralizing epitopes. Virology. 1994a;205:329–335. doi: 10.1006/viro.1994.1649. [DOI] [PubMed] [Google Scholar]
  8. Christensen ND, Hopfl R, DiAngelo SL, Cladel NM, Patrick SD, Welsh PA, Budgeon LR, Reed CA, Kreider JW. Assembled baculovirus-expressed human papillomavirus type 11 L1 capsid protein virus-like particles are recognized by neutralizing monoclonal antibodies and induce high titres of neutralizing antibodies. J Gen Virol. 1994b;75:2271–2276. doi: 10.1099/0022-1317-75-9-2271. [DOI] [PubMed] [Google Scholar]
  9. Christensen ND, Dillner J, Eklund C, Carter JJ, Wipf GC, Reed CA, Cladel NM, Galloway DA. Surface conformational and linear epitopes on HPV-16 and HPV-18 L1 virus-like particles as defined by monoclonal antibodies. Virology. 1996;223:174–184. doi: 10.1006/viro.1996.0466. [DOI] [PubMed] [Google Scholar]
  10. Christensen ND, Reed CA, Cladel NM, Hall K, Leiserowitz GS. Monoclonal antibodies to HPV-6 L1 virus-like particles identify conformational and linear neutralizing epitopes on HPV-11 in addition to type-specific epitopes on HPV-6. Virology. 1996;224:477–486. doi: 10.1006/viro.1996.0554. [DOI] [PubMed] [Google Scholar]
  11. Christensen ND, Cladel NM, Reed CA, Budgeon LR, Embers ME, Skulsky DM, McClements WL, Ludmerer SW, Jansen KU. Hybrid papillomavirus L1 molecules assemble into virus-like particles that reconstitute conformational epitopes and induce neutralizing antibodies to distinct HPV types. Virology. 2001;291:324–334. doi: 10.1006/viro.2001.1220. [DOI] [PubMed] [Google Scholar]
  12. Combita AL, Touzé A, Bousarghin L, Christensen ND, Coursaget P. Identification of two cross-neutralizing linear epitopes within the L1 major capsid protein of human papillomavirus. J Virol. 2002;76:6480–6486. doi: 10.1128/JVI.76.13.6480-6486.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Combita AL, Bravo MM, Touzé A, Orozco O, Coursaget P. Serologic response to human oncogenic papillomavirus types 16, 18, 31, 33, 39, 58 and 59 virus-like particles in colombian women with invasive cervical cancer. Int J Cancer. 2002;97:796–803. doi: 10.1002/ijc.10153. [DOI] [PubMed] [Google Scholar]
  14. Giroglou T, Sapp M, Lane C, Fligge C, Christensen ND, Streek RE, Sapp M. Immunological analyses of human papillomavirus capsids. Vaccine. 2001;19:1783–1793. doi: 10.1016/S0264-410X(00)00370-4. [DOI] [PubMed] [Google Scholar]
  15. Goldborough MD, DiSelvestre D, Temple GF, Lorincz AT. Nucleotide sequence of human papillomavirus type 31: A cervical neoplasia associated virus. Virology. 1989;171:306–311. doi: 10.1016/0042-6822(89)90545-X. [DOI] [PubMed] [Google Scholar]
  16. Harper DM, Franco EL, Wheeler C, Ferris DG, Jenkins D, Schuind A, Zahaf T, Innis B, Naud P, De Carvalho NS, Roteli-Martins CM, Teixeira J, Blatter MM, Korn AP, Quint W, Dubin G, GlaxoSmithKline HPV, Vaccine Study Group Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet. 2004;364:1757–1765. doi: 10.1016/S0140-6736(04)17398-4. [DOI] [PubMed] [Google Scholar]
  17. Harro CD, Pang YY, Roden RB, Hildesheim A, Wang Z, Reynolds MJ, Mast TC, Robinson R, Murphy BR, Karron RA, Dillner J, Schiller JT, Lowy DR. Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst. 2001;93:284–292. doi: 10.1093/jnci/93.4.284. [DOI] [PubMed] [Google Scholar]
  18. Heino P, Skyldberg B, Lehtinen M, Rantala I, Hagmar B, Kreider JW, Kirnbauer R, Dillner J. Human papillomavirus type 16 capsids expose multiple type-restricted and type-common antigenic epitopes. J Gen Virol. 1995;76:1141–1153. doi: 10.1099/0022-1317-76-5-1141. [DOI] [PubMed] [Google Scholar]
  19. Kawana K, Yoshikawa H, Taketani Y, Yoshiike K, Kanda T. Common neutralization epitope in minor capsid protein L2 of human papillomavirus types 16 and 6. J Virol. 1999;73:6188–6190. doi: 10.1128/jvi.73.7.6188-6190.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kirnbauer R, Taub J, Greenstone H, Roden R, Durst M, Gissmann L, Lowy DR, Schiller JT. Efficient self-assembly of human papillomavirus type 16 L1 and L1-L2 into viruslike particles. J Virol. 1993;67:6929–6936. doi: 10.1128/jvi.67.12.6929-6936.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kirnbauer R, Chandrachud LM, O’Neil BW, Wagner ER, Grindlay GJ, Armstrong A, McGarvie GM, Schiller JT, Lowy DR, Campo MS. Virus-like particles of bovine papillomavirus type 4 in prophylactic and therapeutic immunization. Virology. 1996;219:37–44. doi: 10.1006/viro.1996.0220. [DOI] [PubMed] [Google Scholar]
  22. Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, Chiacchierini LM, Jansen KU. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347:1645–1651. doi: 10.1056/NEJMoa020586. [DOI] [PubMed] [Google Scholar]
  23. Kulski JK, Sadleir JW, Kelsall SR, Cicchini MS, Shellam G, Peng SW, Qi YM, Galloway DA, Zhou J, Frazer IH. Type specific and genotype cross reactive B 20 epitopes of the L1 protein of HPV16 defined by a panel of monoclonal antibodies. Virology. 1998;243:275–282. doi: 10.1006/viro.1997.9011. [DOI] [PubMed] [Google Scholar]
  24. Ludmerer SW, Benincasa D, Mark GE., 3rd Two amino acid residues confer type specificity to a neutralizing, conformationally dependent epitope on human papillomavirus type 11. J Virol. 1996;70:4791–4794. doi: 10.1128/jvi.70.7.4791-4794.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ludmerer SW, Benincasa D, Mark GE, 3rd, Christensen ND. A neutralizing epitope of human papillomavirus type 11 is principally described by a continuous set of residues which overlap a distinct linear, surface-exposed epitope. J Virol. 1997;71:3834–3839. doi: 10.1128/jvi.71.5.3834-3839.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ludmerer SW, McClements WL, Wang XM, Ling JC, Jansen KU, Christensen ND. HPV11 mutant virus-like particles elicit immune responses that neutralize virus and delineate a novel neutralizing domain. Virology. 2000;266:237–245. doi: 10.1006/viro.1999.0083. [DOI] [PubMed] [Google Scholar]
  27. McClements WL, Wang XM, Ling JC, Skulsky DM, Christensen ND, Jansen KU, Ludmerer SW. A novel human papillomavirus type 6 neutralizing domain comprising two discrete regions of the major capsid protein L1. Virology. 2001;289:262–268. doi: 10.1006/viro.2001.1146. [DOI] [PubMed] [Google Scholar]
  28. Munoz N, Bosch FX, de Sanjose S, Herrero R, Castellsague X, Shah KV, Snijders PJ, Meijer CJ. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348:518–527. doi: 10.1056/NEJMoa021641. [DOI] [PubMed] [Google Scholar]
  29. Roden RB, Weissinger EM, Henderson DW, Booy F, Kirnbauer R, Mushinski JF, Lowy DR, Schiller JT. Neutralization of bovine papillomavirus by antibodies to L1 and L2 capsid proteins. J Virol. 1994;68:7570–7574. doi: 10.1128/jvi.68.11.7570-7574.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Roden RB, Armstrong A, Haderer P, Christensen ND, Hubbert NL, Lowy DR, Schiller JT, Kirnbauer R. Characterization of a human papillomavirus type 16 variant dependent neutralizing epitope. J Virol. 1997;71:6247–6252. doi: 10.1128/jvi.71.8.6247-6252.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Roden RB, Yutzy WH, 4th, Fallon R, Inglis S, Lowy DR, Schiller JT. Minor capsid protein of human genital papillomaviruses contains subdominant, cross-neutralizing epitopes. Virology. 2000;270:254–257. doi: 10.1006/viro.2000.0272. [DOI] [PubMed] [Google Scholar]
  32. Sadeyen JR, Tourne S, Shkreli M, Sizaret PY, Coursaget P. Insertion of a foreign sequence on capsid surface loops of human papillomavirus type 16 virus-like particles reduced their immunogenicity and delineates a conformational neutralizing epitope. Virology. 2003;309:32–40. doi: 10.1016/S0042-6822(02)00134-4. [DOI] [PubMed] [Google Scholar]
  33. Slupetzky K, Shafti-Keramat S, Lenz P, Brandt S, Grassauer A, Sara M, Kirnbauer R. Chimeric papillomavirus-like particles expressing a foreign epitope on capsid surface loops. J Gen Virol. 2001;82:2799–2804. doi: 10.1099/0022-1317-82-11-2799. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Suzich JA, Ghim SJ, Palmer-Hill FJ, White WI, Tamura JK, Bell JA, Newsome JA, Jenson AB, Schlegel R. Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas. Proc Natl Acad Sci USA. 1995;92:11553–11557. doi: 10.1073/pnas.92.25.11553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Thouvenin E, Laurent S, Madelaine MF, Rasschaert D, Vautherot JF, Hewat EA. Bivalent binding of a neutralising antibody to a calicivirus involves the torsional flexibility of the antibody hinge. J Mol Biol. 1997;270:238–246. doi: 10.1006/jmbi.1997.1095. [DOI] [PubMed] [Google Scholar]
  36. Touzé A, El Mehdaoui S, Sizaret PY, Mougin C, Munoz N, Coursaget P. The L1 major capsid protein of human papillomavirus type 16 variants affects yield of virus-like particles produced in an insect cell expression system. J Clin Microbiol. 1998;36:2046–2051. doi: 10.1128/jcm.36.7.2046-2051.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Vautherot JF, Madelaine MF, Boireau P, Laporte J. Bovine coronavirus peplomer glycoproteins: detail antigenic analyses of S1, S2 and HE. J Gen Virol. 1992;73:1725–1737. doi: 10.1099/0022-1317-73-7-1725. [DOI] [PubMed] [Google Scholar]
  38. Viscidi RP, Snyder B, Cu-Uvin S, Hogan JW, Clayman B, Klein RS, Sobel J, Shah KV. Human papillomavirus capsid antibody response to natural infection and risk of subsequent HPV infection in HIV-positive and HIV-negative women. Cancer Epidemiol Biomarkers Prev. 2005;14:283–288. [PubMed] [Google Scholar]
  39. Volpers C, Sapp M, Snijders PJ, Walboomers JM, Streeck RE. Conformational and linear epitopes on virus-like particles of human papillomavirus type 33 identified by monoclonal antibodies to the minor capsid protein L2. J Gen Virol. 1995;76:2661–2667. doi: 10.1099/0022-1317-76-11-2661. [DOI] [PubMed] [Google Scholar]
  40. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders PJ, Peto J, Meijer CJ, Munoz N. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–19. doi: 10.1002/(SICI)1096-9896(199909)189:1<12::AID-PATH431>3.0.CO;2-F. [DOI] [PubMed] [Google Scholar]
  41. Wang XM, Cook JC, Lee JC, Jansen KU, Christensen ND, Ludmerer SW, McClements WL. Human papillomavirus type 6 virus-like particles present overlapping yet distinct conformational epitopes. J Gen Virol. 2003;84:1493–1497. doi: 10.1099/vir.0.18872-0. [DOI] [PubMed] [Google Scholar]
  42. White WI, Wilson SD, Bonnez W, Rose RC, Koenig S, Suzich JA. In vitro infection and type-restricted antibody-mediated neutralization of authentic human papillomavirus type 16. J Virol. 1998;72:959–964. doi: 10.1128/jvi.72.2.959-964.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. White WI, Wilson SD, Palmer-Hill FJ, Woods RM, Ghim SJ, Hewitt LA, Goldman DM, Burke SJ, Jenson AB, Koenig S, Suzich JA. Characterization of a major neutralizing epitope on human papillomavirus type 16 L1. J Virol. 1999;73:4882–4889. doi: 10.1128/jvi.73.6.4882-4889.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yaegashi N, Jenison SA, Valentine JM, Dunn M, Taichman LB, Baker DA, Galloway DA. Characterization of murine polyclonal antisera and monoclonal antibodies generated against intact and denatured human papillomavirus type 1 virions. J Virol. 1991;65:1578–1583. doi: 10.1128/jvi.65.3.1578-1583.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zhang LF, Zhou J, Chen S, Cai LL, Bao QY, Zheng FY, Lu JQ, Padmanabha J, Hengst K, Malcolm K, Frazer IH. HPV6b virus like particles are potent immunogens without adjuvant in man. Vaccine. 2000;18:1051–1058. doi: 10.1016/S0264-410X(99)00351-5. [DOI] [PubMed] [Google Scholar]

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