1887

Abstract

Persistent infection with oncogenic types of human papillomaviruses (HPV) is the major cause of cervical cancer precursor lesions. Cellular immune responses are considered important in the elimination of HPV infection, but the targets are not well defined. HPV E1 and E2 proteins form a replicative complex necessary for viral genome maintenance. To investigate whether epitopes in the E1 or E2 proteins can serve as targets for cytotoxic T-lymphocyte (CTL)-mediated killing, we identified peptides containing the human leukocyte antigen (HLA)-A*0201 binding motif in the deduced amino acid sequences of the HPV-16 E1 and E2 genes. Binding affinity of the peptides was measured by HLA-A*0201 upregulation on T2 cells. Peptides with high binding-affinity were tested for their ability to elicit peptide-specific CTLs from healthy blood donors. We found one peptide from the E1 and one from the E2 protein sequence that were capable of eliciting peptide-specific CTLs. The E2-specific CTLs lysed an HPV-16-transfected cervical carcinoma cell line, but not the untransfected HPV-negative parental cell line, indicating that the identified E2 epitope can be presented to CTLs in HPV-positive epithelial cells. These findings might have potentially important implications for studies of the natural history of HPV infection in relation to cervical carcinogenesis.

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1997-10-01
2024-11-11
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References

  1. Apple R. J., Erlich H. A., Klitz W., Manos M. M., Becker T. M., Wheeler C. M. 1994; HLA DR-DQ associations with cervical carcinoma show papillomavirus-type specificity. Nature Genetics 6:157–162
    [Google Scholar]
  2. Bartholomew J. S., Stacey S. N., Coles B., Burt D. J., Arrand J. R., Stern P. L. 1994; Identification of a naturally processed HLA A0201- restricted viral peptide from cells expressing human papillomavirus type 16 E6 oncoprotein. European Journal of Immunology 24:3175–3179
    [Google Scholar]
  3. Breitburd F., Kirnbauer R., Hubbert N. L., Nonnenmacher B., Trin-Dinh-Desmarquet C., Orth G., Schiller J. T., Lowy D. R. 1995; Immunization with virus like particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection. Journal of Virology 69:3959–3963
    [Google Scholar]
  4. Croft M. 1994; Activation of naive, memory and effector T cells. Current Opinion in Immunology 6:413–437
    [Google Scholar]
  5. del Guercio M. F., Sidney J., Hermanson G., Perez C., Grey H. M., Kubo R. T., Sette A. 1995; Binding of a peptide antigen to multiple HLA alleles allows definition of an A2-like supertype. Journal of Immunology 154:685–693
    [Google Scholar]
  6. Dillner J. 1995; Serology of human papillomavirus. Cancer Journal 8:264–269
    [Google Scholar]
  7. Dowhanick J. J., McBride A. A., Howley P. M. 1995; Suppression of cellular proliferation by the papillomavirus E2 protein. Journal of Virology 69:7791–7799
    [Google Scholar]
  8. Evander M., Edlund K., Gustafsson A., Jonsson M., Karlsson R., Rylander E., Wadell G. 1995; Human papillomavirus infection is transient in young women: a population-based cohort study. Journal of Infectious Diseases 171:1026–1030
    [Google Scholar]
  9. Feltkamp M. C., Smits H. L., Vierboom M. P., Minnaar R. P., de Jongh B. M., Drijfhout J. W., ter Schegget J., Melief C. J., Kast W. M. 1993; Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumour induced by human papillomavirus type 16-transformed cells. European Journal of Immunology 23:2242–2249
    [Google Scholar]
  10. Gotch F., Rothbard J., Howland K., Townsend A., McMichael A. 1987; Cytotoxic T lymphocytes recognise a fragment of influenza virus matrix protein in association with HLA-A2. Nature 326:881–882
    [Google Scholar]
  11. Hildesheim A., Schiffman M. H., Gravitt P. E., Glass A. G., Greer C. E., Zhang T., Scott D. R., Rush B. B., Lawler P., Sherman M. E. others 1994; Persistence of type-specific human papillomavirus infection among cytologically normal women. Journal of Infectious Diseases 169:235–240
    [Google Scholar]
  12. Houbiers J. G., Nijman H. W., van der Burg S. H., Drijfhout J. W., Kenemans P., van de Velde C. J., Brand A., Momburg F., Kast W. M., Melief C. J. 1993; In vitro induction of human cytotoxic T lymphocyte responses against peptides of mutant and wild-type p53. European Journal of Immunology 23:2072–2077
    [Google Scholar]
  13. Kast W. M., Brandt R. M., Sidney J., Drijfhout J. W., Kubo R. T., Grey H. M., Melief C. J., Sette A. 1994; Role of HLA-A motifs in identification of potential CTL epitopes in human papillomavirus type 16 E6 and E7 proteins. Journal of Immunology 152:3904–3912
    [Google Scholar]
  14. Keating P. J., Cromme F. V., Duggan-Keen M., Snijders P. J., Walboomers J. M., Hunter R. D., Dyer P. A., Stern P. L. 1995; Frequency of down-regulation of individual HLA-A and -B alleles in cervical carcinomas in relation to TAP-1 expression. British Journal of Cancer 72:405–411
    [Google Scholar]
  15. 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. Journal ofthe National Cancer Institute 86:494–499
    [Google Scholar]
  16. Kónya J., Stuber G., Björndal Å., Fenyö E. M., Dillner J. 1997; Primary induction of human cytotoxic lymphocytes against a synthetic peptide of the human immunodeficiency virus type 1 protease. Journal of General Virology 78:2217–2224
    [Google Scholar]
  17. Koutsky L. A., Holmes K. K., Critchlow C. W., Stevens C. E., Paavonen J., Beckmann A. M., DeRouen T. A., Galloway D. A., Vernon D., Kiviat N. B. 1992; A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. New England Journal of Medicine 327:1272–1278
    [Google Scholar]
  18. 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. Biochemical and Biophysical Research Communications 209:541–546
    [Google Scholar]
  19. Myers G., Bernard H. U., Delius H., Baker C., Icenogle J., Halpern A., Wheeler C. 1995 Human papillomaviruses: a compilation and analysis of nucleic acid and amino acid sequences Los Alamos National Laboratory, Los Alamos, New Mexico, USA:
    [Google Scholar]
  20. Petry K. U., Scheffel D., Bode U., Gabrysiak T., Kochel H., Kupsch E., Niesert S., Kuhnle H., Schedel I. 1994; Cellular immunodeficiency enhances the progression of human papillomavirus- associated cervical lesions. International Journal of Cancer 57:836–840
    [Google Scholar]
  21. Ponten J., Adami H. O., Bergstrom R., Dillner J., Friberg L. G., Gustafsson L., Miller A. B., Parkin D. M., Sparen P., Trichopoulos D. 1995; Strategies for global control of cervical cancer. International Journal of Cancer 60:1–26
    [Google Scholar]
  22. Ressing M. E., Sette A., Brandt R. M., Ruppert J., Wentworth P. A., Hartman M., Oseroff C., Grey H. M., Melief C. J., Kast W. M. 1995; Human CTL epitopes encoded by human papillomavirus type 16 E6 and E7 identified through in vivo and in vitro immunogenicity studies of HLA-A*0201-binding peptides. Journal of Immunology 154:5934–5943
    [Google Scholar]
  23. Ressing M. E., van Driel W. J., Celis E., Sette A., Brandt M. P., Hartman M., Anholts J. D., Schreuder G. M., terHarmsel W. B., Fleuren G. J., Trimbos B. J., Kast W. M., Melief C. J. 1996; Occasional memory cytotoxic T-cell responses of patients with human papillomavirus type 16-positive cervical lesions against a human leukocyte antigen-A*0201-restricted E7-encoded epitope. Cancer Research 56:582–588
    [Google Scholar]
  24. Sanjeevi C. B., Hjelmdahl P., Lenner P., Wiklund F., Hallmas G., Dillner J., Lernmark A. 1996; Different DR-DQ haplotypes are associated with cervical neoplasia among human papillomavirus type 16 seropositive and negative subjects. International Journal of Cancer 68:409–414
    [Google Scholar]
  25. Seedorf K., Krammer G., Durst M., Suhai S., Rowekamp W. G. 1985; Human papillomavirus type 16 DNA sequence. Virology 145:181–185
    [Google Scholar]
  26. Sette A., Vitiello A., Reherman B., Fowler P., Nayersina R., Kast W. M., Melief C. J., Oseroff C., Yuan L., Ruppert J. others 1994; The relationship between class I binding affinity and immunogenicity of potential cytotoxic T cell epitopes. Journal of Immunology 153:5586–5592
    [Google Scholar]
  27. Sherman L., Alloul N. 1992; Human papillomavirus type 16 expresses a variety of alternatively spliced mRNAs putatively encoding the E2 protein. Virology 191:953–959
    [Google Scholar]
  28. Stoler M. H., Rhodes C. R., Whitbeck A., Wolinsky S. M., Chow L. T., Broker T. R. 1992; Human papillomavirus type 16 and 18 gene expression in cervical neoplasias. Human Pathology 23:117–128
    [Google Scholar]
  29. Stuber G., Dillner J., Modrow S., Wolf H., Szekely L., Klein G., Klein E. 1995; HLA-A0201 and HLA-B7 binding peptides in the EBV- encoded EBNA-1, EBNA-2 and BZLF-1 proteins detected in the MHC class I stabilization assay. Low proportion of binding motifs for several HLA class I alleles in EBNA-1. International Immunology 7:653–663
    [Google Scholar]
  30. Tindle R. W., Fernando G. J., Sterling J. C., Frazer I. H. 1991; A ‘public’ T-helper epitope of the E7 transforming protein of human papillomavirus 16 provides cognate help for several E7 B-cell epitopes from cervical cancer-associated human papillomavirus genotypes. Proceedings of the National Academy of Sciences USA: 885887–5891
    [Google Scholar]
  31. Turek L. P. 1994; The structure, function, and regulation of papillo- maviral genes in infection and cervical cancer. Advances in Virus Research 44:305–356
    [Google Scholar]
  32. Vanderburg S. H., Klein M. R., Vandevelde C., Kast W. M., Miedema F., Melief C. 1995; Induction of a primary human cytotoxic T- lymphocyte response against a novel conserved epitope in a functional sequence of HIV-1 reverse transcriptase. AIDS 9:121–127
    [Google Scholar]
  33. Vitiello A., Ishioka G., Grey H. M., Rose R., Farness P., LaFond R., Yuan L., Chisari F. V., Furze J., Bartholomeuz R. others 1995; Development of a lipopeptide-based therapeutic vaccine to treat chronic HBV infection. I. Induction of a primary cytotoxic T lymphocyte response in humans. Journal of Clinical Investigation 95:341–349
    [Google Scholar]
  34. Woodworth C. D., Bowden P. E., Doniger J., Pirisi L., Barnes W., Lancaster W. D., DiPaolo J. A. 1988; Characterization of normal human exocervical epithelial cells immortalized in vitro by papillomavirus types 16 and 18 DNA. Cancer Research 48:4620–4628
    [Google Scholar]
  35. zur Hausen H., de Villiers E. M. 1994; Human papillomaviruses. Annual Review of Microbiology 48:427–447
    [Google Scholar]
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