1887

Abstract

The ‘high-risk’ human papillomaviruses (HPVs) cause persistent infections of the anogenital region that may resolve spontaneously following activation of a protective immune response. The aim of this study was to determine whether cell-mediated immunity (CMI) to the early protein E2 was associated with disease regression and to establish whether E2 CMI and antibodies to L1 virus-like particles (VLPs) were associated markers of immunity to HPV. Lymphoproliferative responses to histidine-tagged E2 and antibody responses to VLPs were measured in patients with persistent cervical dysplasia, those whose disease had recently resolved and normal controls. Resolvers had significantly higher E2-specific lymphoproliferative responses when compared with normal controls or persisters, whereas there was no significant difference between the persisters and the normal controls. The T cells stimulated by E2 secreted high levels of gamma interferon (IFN-), consistent with a type 1 helper (Th1) phenotype. VLP IgG responses were associated with current or previous HPV infection, but not with disease regression or a lymphoproliferative response to E2. Major histocompatibility complex class I-restricted T cells secreted IFN- following stimulation with E1, and E2 peptides were detected more frequently in the persister group. The data showed that lymphoproliferative responses to E2 with a cytokine profile indicative of Th1 are associated with disease resolution, supporting the development of a therapeutic vaccine that activates this type of response for the treatment of individuals with pre-existing disease.

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2007-03-01
2024-04-26
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References

  1. Amella C. A., Lofgren L. A., Ronn A. M., Nouri M., Shikowitz M. J., Steinberg B. M. 1994; Latent infection induced with cottontail rabbit papillomavirus. A model for human papillomavirus latency. Am J Pathol 144:1167–1171
    [Google Scholar]
  2. Appay V. 2004; The physiological role of cytotoxic CD4+ T-cells: the holy grail?. Clin Exp Immunol 138:10–13 [CrossRef]
    [Google Scholar]
  3. Benito J. M., Lopez M., Soriano V. 2004; The role of CD8+ T-cell response in HIV infection. AIDS Rev 6:79–88
    [Google Scholar]
  4. Bontkes H. J., de Gruijl T. D., Bijl A., Verheijen R. H., Meijer C. J., Scheper R. J., Stern P. L., Burns J. E., Maitland N. J., Walboomers J. M. 1999; a Human papillomavirus type 16 E2-specific T-helper lymphocyte responses in patients with cervical intraepithelial neoplasia. J Gen Virol 80:2453–2459
    [Google Scholar]
  5. Bontkes H. J., de Gruijl T. D., Walboomers J. M., Schiller J. T., Dillner J., Helmerhorst T. J., Verheijen R. H., Scheper R. J., Meijer C. J. 1999; b Immune responses against human papillomavirus (HPV) type 16 virus-like particles in a cohort study of women with cervical intraepithelial neoplasia. II. Systemic but not local IgA responses correlate with clearance of HPV-16. J Gen Virol 80:409–417
    [Google Scholar]
  6. Brown D. M., Roman E., Swain S. L. 2004; CD4 T cell responses to influenza infection. Semin Immunol 16:171–177 [CrossRef]
    [Google Scholar]
  7. Chiang C. M., Ustav M., Stenlund A., Ho T. F., Broker T. R., Chow L. T. 1992; Viral E1 and E2 proteins support replication of homologous and heterologous papillomaviral origins. Proc Natl Acad Sci U S A 89:5799–5803 [CrossRef]
    [Google Scholar]
  8. Clerici M., Merola M., Ferrario E., Trabattoni D., Villa M. L., Stefanon B., Venzon D. J., Shearer G. M., De Palo G., Clerici E. 1997; Cytokine production patterns in cervical intraepithelial neoplasia: association with human papillomavirus infection. J Natl Cancer Inst 89:245–250 [CrossRef]
    [Google Scholar]
  9. Clifford G. M., Smith J. S., Plummer M., Muñoz N., Franceschi S. 2003; Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer 88:63–73 [CrossRef]
    [Google Scholar]
  10. Coleman N., Birley H. D., Renton A. M., Hanna N. F., Ryait B. K., Byrne M., Taylor-Robinson D., Stanley M. A. 1994; Immunological events in regressing genital warts. Am J Clin Pathol 102:768–774
    [Google Scholar]
  11. Conley L. J., Ellerbrock T. V., Bush T. J., Chiasson M. A., Sawo D., Wright T. C. 2002; HIV-1 infection and risk of vulvovaginal and perianal condylomata acuminata and intraepithelial neoplasia: a prospective cohort study. Lancet 359:108–113 [CrossRef]
    [Google Scholar]
  12. Davidson E. J., Brown M. D., Burt D. J., Parish J. L., Gaston K., Kitchener H. C., Stacey S. N., Stern P. L. 2001; Human T cell responses to HPV 16 E2 generated with monocyte-derived dendritic cells. Int J Cancer 94:807–812 [CrossRef]
    [Google Scholar]
  13. Davidson E. J., Sehr P., Faulkner R. L., Parish J. L., Gaston K., Moore R. A., Pawlita M., Kitchener H. C., Stern P. L. 2003; Human papillomavirus type 16 E2- and L1-specific serological and T-cell responses in women with vulval intraepithelial neoplasia. J Gen Virol 84:2089–2097 [CrossRef]
    [Google Scholar]
  14. de Jong A., van der Burg S. H., Kwappenberg K. M., van der Hulst J. M., Franken K. L., Geluk A., van Meijgaarden K. E., Drijfhout J. W., Kenter G. 2002; Frequent detection of human papillomavirus 16 E2-specific T-helper immunity in healthy subjects. Cancer Res 62:472–479
    [Google Scholar]
  15. de Jong A., van Poelgeest M. I., van der Hulst J. M., Drijfhout J. W., Fleuren G. J., Melief C. J., Kenter G., Offringa R., van der Burg S. H. 2004; Human papillomavirus type 16-positive cervical cancer is associated with impaired CD4+ T-cell immunity against early antigens E2 and E6. Cancer Res 64:5449–5455 [CrossRef]
    [Google Scholar]
  16. Ferenczy A., Mitao M., Nagai N., Silverstein S. J., Crum C. P. 1985; Latent papillomavirus and recurring genital warts. N Engl J Med 313:784–788 [CrossRef]
    [Google Scholar]
  17. Filippova M., Parkhurst L., Duerksen-Hughes P. J. 2004; The human papillomavirus 16 E6 protein binds to Fas-associated death domain and protects cells from Fas-triggered apoptosis. J Biol Chem 279:25729–25744 [CrossRef]
    [Google Scholar]
  18. Frazer I. H. 2004; Prevention of cervical cancer through papillomavirus vaccination. Nat Rev Immunol 4:46–54 [CrossRef]
    [Google Scholar]
  19. Giroglou T., Sapp M., Lane C., Fligge C., Christensen N. D., Streeck R. E., Rose R. C. 2001; Immunological analyses of human papillomavirus capsids. Vaccine 19:1783–1793 [CrossRef]
    [Google Scholar]
  20. Heard I., Tassie J. M., Schmitz V., Mandelbrot L., Kazatchkine M. D., Orth G. 2000; Increased risk of cervical disease among human immunodeficiency virus-infected women with severe immunosuppression and high human papillomavirus load. Obstet Gynecol 96:403–409 [CrossRef]
    [Google Scholar]
  21. Heinemann L., Dillon S., Crawford A., Backstrom B. T., Hibma M. H. 2004; Flow cytometric quantitation of the protective efficacy of dendritic cell based vaccines in a human papillomavirus type 16 murine challenge model. J Virol Methods 117:9–18 [CrossRef]
    [Google Scholar]
  22. Hilders C. G., Houbiers J. G., Krul E. J., Fleuren G. J. 1994; The expression of histocompatibility-related leukocyte antigens in the pathway to cervical carcinoma. Am J Clin Pathol 101:5–12
    [Google Scholar]
  23. Hilders C. G., Munoz I. M., Nooyen Y., Fleuren G. J. 1995; Altered HLA expression by metastatic cervical carcinoma cells as a factor in impaired immune surveillance. Gynecol Oncol 57:366–375 [CrossRef]
    [Google Scholar]
  24. Jeon S., Allen-Hoffmann B. L., Lambert P. F. 1995; Integration of human papillomavirus type 16 into the human genome correlates with a selective growth advantage of cells. J Virol 69:2989–2997
    [Google Scholar]
  25. Johnston K. B., Monteiro J. M., Schultz L. D., Chen L., Wang F., Ausensi V. A., Dell E. C., Santos E. B., Moore R. A. other authors 2005; Protection of beagle dogs from mucosal challenge with canine oral papillomavirus by immunization with recombinant adenoviruses expressing codon-optimized early genes. Virology 336:208–218 [CrossRef]
    [Google Scholar]
  26. Kadish A. S., Timmins P., Wang Y., Ho G. Y., Burk R. D., Ketz J., He W., Romney S. L., Johnson A. other authors 2002; Regression of cervical intraepithelial neoplasia and loss of human papillomavirus (HPV) infection is associated with cell-mediated immune responses to an HPV type 16 E7 peptide. Cancer Epidemiol Biomarkers Prev 11:483–488
    [Google Scholar]
  27. Kirnbauer R., Hubbert N. L., Wheeler C. M., Becker T. M., Lowy D. R., Schiller J. T. 1994; A virus-like particle enzyme-linked immunosorbent assay detects serum antibodies in a majority of women infected with human papillomavirus type 16. J Natl Cancer Inst 86:494–499 [CrossRef]
    [Google Scholar]
  28. Knowles G., O’Neil B. W., Campo M. S. 1996; Phenotypical characterization of lymphocytes infiltrating regressing papillomas. J Virol 70:8451–8458
    [Google Scholar]
  29. Konya J., Eklund C., af Geijersstam V., Yuan F., Stuber G., Dillner J. 1997; Identification of a cytotoxic T-lymphocyte epitope in the human papillomavirus type 16 E2 protein. J Gen Virol 78:2615–2620
    [Google Scholar]
  30. Koutsky L. A., Ault K. A., Wheeler C. M., Brown D. R., Barr E., Alvarez F. B., Chiacchierini L. M., Jansen K. U. 2002; A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 347:1645–1651 [CrossRef]
    [Google Scholar]
  31. Lehtinen M., Hibma M. H., Stellato G., Kuoppala T., Paavonen J. 1995; Human T helper cell epitopes overlap B cell and putative cytotoxic T cell epitopes in the E2 protein of human papillomavirus type 16. Biochem Biophys Res Commun 209:541–546 [CrossRef]
    [Google Scholar]
  32. Middleton K., Peh W., Southern S., Griffin H., Sotlar K., Nakahara T., El-Sherif A., Morris L., Seth R. other authors 2003; Organization of human papillomavirus productive cycle during neoplastic progression provides a basis for selection of diagnostic markers. J Virol 77:10186–10201 [CrossRef]
    [Google Scholar]
  33. Milde-Langosch K., Riethdorf S., Loning T. 2000; Association of human papillomavirus infection with carcinoma of the cervix uteri and its precursor lesions: theoretical and practical implications. Virchows Arch 437:227–233 [CrossRef]
    [Google Scholar]
  34. Miskovsky E. P., Liu A. Y., Pavlat W., Viveen R., Stanhope P. E., Finzi D., Fox W. M., Hruban R. H., Podack E. R., Siliciano R. F. 1994; Studies of the mechanism of cytolysis by HIV-1-specific CD4+ human CTL clones induced by candidate AIDS vaccines. J Immunol 153:2787–2799
    [Google Scholar]
  35. Moss P., Khan N. 2004; CD8+ T-cell immunity to cytomegalovirus. Hum Immunol 65:456–464 [CrossRef]
    [Google Scholar]
  36. Muñoz N., Bosch F. X., de Sanjosé S., Herrero R., Castellsagué X., Shah K. V., Snijders P. J., Meijer C. J. 2003; Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 348:518–527 [CrossRef]
    [Google Scholar]
  37. Nicholls P. K., Doorbar J., Moore R. A., Peh W., Anderson D. M., Stanley M. A. 2001; Detection of viral DNA and E4 protein in basal keratinocytes of experimental canine oral papillomavirus lesions. Virology 284:82–98 [CrossRef]
    [Google Scholar]
  38. Paludan C., Bickham K., Nikiforow S., Tsang M. L., Goodman K., Hanekom W. A., Fonteneau J. F., Stevanovic S., Münz C. 2002; Epstein–Barr nuclear antigen 1-specific CD4+ Th1 cells kill Burkitt’s lymphoma cells. J Immunol 169:1593–1603 [CrossRef]
    [Google Scholar]
  39. Petry K. U., Scheffel D., Bode U., Gabrysiak T., Kochel H., Kupsch E., Glaubitz M., Niesert S., Kuhnle H., Schedel I. 1994; Cellular immunodeficiency enhances the progression of human papillomavirus-associated cervical lesions. Int J Cancer 57:836–840 [CrossRef]
    [Google Scholar]
  40. Pisani P., Parkin D. M., Ferlay J. 1993; Estimates of the worldwide mortality from eighteen major cancers in; 1985; Implications for prevention and projections of future burden. Int J Cancer 55:891–903 [CrossRef]
    [Google Scholar]
  41. Qian J., Dong Y., Pang Y. Y., Ibrahim R., Berzofsky J. A., Schiller J. T., Khleif S. N. 2006; Combined prophylactic and therapeutic cancer vaccine: enhancing CTL responses to HPV16 E2 using a chimeric VLP in HLA-A2 mice. Int J Cancer 118:3022–3029 [CrossRef]
    [Google Scholar]
  42. Rose R. C., Bonnez W., Da Rin C., McCance D. J., Reichman R. C. 1994; Serological differentiation of human papillomavirus types 11, 16 and 18 using recombinant virus-like particles. J Gen Virol 75:2445–2449 [CrossRef]
    [Google Scholar]
  43. Rudlinger R., Smith I. W., Bunney M. H., Hunter J. A. 1986; Human papillomavirus infections in a group of renal transplant recipients. Br J Dermatol 115:681–692 [CrossRef]
    [Google Scholar]
  44. Sarkar A. K., Tortolero-Luna G., Follen M., Sastry K. J. 2005; Inverse correlation of cellular immune responses specific to synthetic peptides from the E6 and E7 oncoproteins of HPV-16 with recurrence of cervical intraepithelial neoplasia in a cross-sectional study. Gynecol Oncol 99:S251–S261 [CrossRef]
    [Google Scholar]
  45. Sasagawa T., Rose R. C., Azar K. K., Sakai A., Inoue M. 2003; Mucosal immunoglobulin-A and -G responses to oncogenic human papilloma virus capsids. Int J Cancer 104:328–335 [CrossRef]
    [Google Scholar]
  46. Schiffman M., Herrero R., Desalle R., Hildesheim A., Wacholder S., Rodriguez A. C., Bratti M. C., Sherman M. E., Morales J. other authors 2005; The carcinogenicity of human papillomavirus types reflects viral evolution. Virology 337:76–84 [CrossRef]
    [Google Scholar]
  47. Schlecht N. F., Platt R. W., Duarte-Franco E., Costa M. C., Sobrinho J. P., Prado J. C., Ferenczy A., Rohan T. E., Villa L. L., Franco E. L. 2003; Human papillomavirus infection and time to progression and regression of cervical intraepithelial neoplasia. J Natl Cancer Inst 95:1336–1343 [CrossRef]
    [Google Scholar]
  48. Selvakumar R., Ahmed R., Wettstein F. O. 1995; a Tumor regression is associated with a specific immune response to the E2 protein of cottontail rabbit papillomavirus. Virology 208:298–302 [CrossRef]
    [Google Scholar]
  49. Selvakumar R., Borenstein L. A., Lin Y. L., Ahmed R., Wettstein F. O. 1995; b Immunization with nonstructural proteins E1 and E2 of cottontail rabbit papillomavirus stimulates regression of virus-induced papillomas. J Virol 69:602–605
    [Google Scholar]
  50. Sun Y., Eluf-Neto J., Bosch F. X., Muñoz N., Walboomers J. M., Meijer C. J., Shah K. V., Clayman B., Viscidi R. P. 1999; Serum antibodies to human papillomavirus 16 proteins in women from Brazil with invasive cervical carcinoma. Cancer Epidemiol Biomarkers Prev 8:935–940
    [Google Scholar]
  51. Tagami H., Oguchi M., Ofuji S. 1980; The phenomenon of spontaneous regression of numerous flat warts: immunohistological studies. Cancer 45:2557–2563 [CrossRef]
    [Google Scholar]
  52. Thompson D. A., Zacny V., Belinsky G. S., Classon M., Jones D. L., Schlegel R., Münger K. 2001; The HPV E7 oncoprotein inhibits tumor necrosis factor α -mediated apoptosis in normal human fibroblasts. Oncogene 20:3629–3640 [CrossRef]
    [Google Scholar]
  53. Vambutas A., DeVoti J., Pinn W., Steinberg B. M., Bonagura V. R. 2001; Interaction of human papillomavirus type 11 E7 protein with TAP-1 results in the reduction of ATP-dependent peptide transport. Clin Immunol 101:94–99 [CrossRef]
    [Google Scholar]
  54. van Poelgeest M. I., Nijhuis E. R., Kwappenberg K. M., Hamming I. E., Wouter Drijfhout J., Fleuren G. J., van der Zee A. G., Melief C. J., Kenter G. G. other authors 2006; Distinct regulation and impact of type 1 T-cell immunity against HPV16 L1, E2 and E6 antigens during HPV16-induced cervical infection and neoplasia. Int J Cancer 118:675–683 [CrossRef]
    [Google Scholar]
  55. Vayrynen M., Syrjanen K., Mantyjarvi R., Castren O., Saarikoski S. 1984; Langerhans cells in human papillomavirus (HPV) lesions of the uterine cervix identified by the monoclonal antibody OKT-6. Int J Gynaecol Obstet 22:375–383 [CrossRef]
    [Google Scholar]
  56. Vayrynen M., Syrjanen K., Mantyjarvi R., Castren O., Saarikoski S. 1985; Immunophenotypes of lymphocytes in prospectively followed up human papillomavirus lesions of the cervix. Genitourin Med 61:190–196
    [Google Scholar]
  57. Viscidi R. P., Schiffman M., Hildesheim A., Herrero R., Castle P. E., Bratti M. C., Rodriguez A. C., Sherman M. E., Wang S. 2004; Seroreactivity to human papillomavirus (HPV) types 16, 18, or 31 and risk of subsequent HPV infection: results from a population-based study in Costa Rica. Cancer Epidemiol Biomarkers Prev 13:324–327 [CrossRef]
    [Google Scholar]
  58. Walboomers J. M., Jacobs M. V., Manos M. M., Bosch F. X., Kummer J. A., Shah K. V., Snijders P. J., Peto J., Meijer C. J., Muñoz N. 1999; Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol 189:12–19 [CrossRef]
    [Google Scholar]
  59. Wick M. J., Pfeifer J. D. 1996; Major histocompatibility complex class I presentation of ovalbumin peptide 257–264 from exogenous sources: protein context influences the degree of TAP-independent presentation. Eur J Immunol 26:2790–2799 [CrossRef]
    [Google Scholar]
  60. Zagury D. 1991; Anti-HIV cellular immunotherapy in AIDS. Lancet 338:694–695
    [Google Scholar]
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