Skip to main content
PMC home page
Elsevier - PMC COVID-19 Collection logoLink to Elsevier - PMC COVID-19 Collection
. 1999 Mar 23;14(16):1485–1494. doi: 10.1016/S0264-410X(96)00117-X

Construction and characterisation of a recombinant vaccinia virus expressing human papillomavirus proteins for immunotherapy of cervical cancer

MEG Boursnell ∗, E Rutherford ∗, JK Hickling ∗, EA Rollinson ∗, AJ Munro ∗, N Rolley ∗, CS McLean ∗, LK Borysiewicz †, K Vousden ‡, SC Inglis ∗,§
PMCID: PMC7130629  PMID: 9014288

Abstract

The presence and consistent expression of the genes encoding the human papillomavirus (HPV) E6 and E7 proteins in the great majority of cervical tumours presents the opportunity for an immunotherapeutic approach for control of the disease. This report describes the construction and characterisation of a recombinant vaccinia virus designed to express modified forms of the E6 and E7 proteins from HPV16 and HPV18, the viruses most commonly associated with cervical cancer. The recombinant virus (designated TA-HPV) was based on the Wyeth vaccine strain of vaccinia, and was shown to express the desired gene products. Studies in mice indicated that the recombinant virus was less neurovirulent than the parental virus and was capable of inducing an HPV-specific CTL response. This pre-clinical evaluation has provided a basis for the initiation of human trials in cervical cancer patients.

Keywords: HPV, vaccinia virus, cervical carcinoma

References

  • 1.zur Hausen H. Viruses in human cancers. Science. 1991;254:1167–1173. doi: 10.1126/science.1659743. [DOI] [PubMed] [Google Scholar]
  • 2.van den Brule A.J.C., Snijders P.J.F., Meijer C.J.L.M., Walboomers J.M.M. PCR based detection of genital HPV genotypes: An update and future perspectives. Papillomavirus Reports. 1993;4:95–99. [Google Scholar]
  • 3.Schwartz E., Freese U.K., Gissman L. Structure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature. 1985;314:111–114. doi: 10.1038/314111a0. [DOI] [PubMed] [Google Scholar]
  • 4.Hawley-Nelson P., Vousden K.H., Hubbert N.L., Lowy D.R., Schiller J.T. HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J. 1989;8:3905–3910. doi: 10.1002/j.1460-2075.1989.tb08570.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Phelps W.C., Yee C.L., Münger K., Howley P.M. The human papillomavirus type 16 E7 gene encodes transactivation and transformation functions similar to those of adenovirus E1A. Cell. 1988;53:539–547. doi: 10.1016/0092-8674(88)90570-3. [DOI] [PubMed] [Google Scholar]
  • 6.Dyson N., Howley P.M., Münger K., Harlow E. The human papillomavirus type 16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science. 1989;243:934–937. doi: 10.1126/science.2537532. [DOI] [PubMed] [Google Scholar]
  • 7.Münger K., Werness B.A., Dyson N., Phelps W.C., Harlow E., Howley P.M. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumour suppressor gene product. EMBO J. 1989;8:4099–4105. doi: 10.1002/j.1460-2075.1989.tb08594.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Werness B.A., Levine A.J., Howley P.M. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science. 1990;248:76–79. doi: 10.1126/science.2157286. [DOI] [PubMed] [Google Scholar]
  • 9.von Knebel Doeberitz M., Ritmuller C., Aengeneyndt P., Jansendurr D., Spitovsky D. Reversible repression of papillomavirus oncogene expression in cervical carcinoma cells. Consequences for the phenotype and E6-p53 and E7-pRb interactions. J Virol. 1994;68:2811–2821. doi: 10.1128/jvi.68.5.2811-2821.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Townsend A.R.M., Rothbard J.B., Gotch F.M., Bahadur G., Wraith D., McMichael A.J. The epitopes of influenza nucleoprotein recognized by cytotoxic T lymphocytes can be defined with short synthetic peptides. Cell. 1986;44:959–968. doi: 10.1016/0092-8674(86)90019-x. [DOI] [PubMed] [Google Scholar]
  • 11.Rooney C.M., Smith C.A., Ng C.Y.C. Use of gene modified virus specific T lymphocytes to control Epstein-Barr virus related lymphoproliferation. Lancet. 1995;345:9–13. doi: 10.1016/s0140-6736(95)91150-2. [DOI] [PubMed] [Google Scholar]
  • 12.Kawakami Y., Eliyahu S., Delgado C.H. 2nd edn. Vol. 91. 1994. Identification of a human melanoma antigen recognized by tumour infiltrating lymphocytes associated with in vivo tumour rejection; pp. 6458–6462. (Proc Natl Acad Sci (USA)). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Feltkamp M.C.W., Smits H.L., Vierboom M.P.M. Vaccination with cytotoxic T lymphocyte epitope containing peptide protects against a tumor induced by human papillomavirus type 16 cells. Eur J Immunol. 1993;23:2242–2249. doi: 10.1002/eji.1830230929. [DOI] [PubMed] [Google Scholar]
  • 14.Meneguzzi G., Cerni C., Kieny M.P., Lathe R. Immunisation against human papillomavirus type 16 tumour cells with recombinant vaccinia viruses expressing E6 and E7. Virology. 1991;181:62–69. doi: 10.1016/0042-6822(91)90470-v. [DOI] [PubMed] [Google Scholar]
  • 15.Chen L.P., Thomas E.K., Hu S.L., Hellstrom I., Hellstrom K.E. 2nd edn. Vol. 88. 1991. Human papillomavirus type 16 nucleoprotein E7 is a tumour rejection antigen; pp. 110–114. (Proc Natl Acad Sci (USA)). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Chen L.P., Mizuno M.T., Singhal M.C. Induction of cytotoxic T lymphocytes specific for a syngeneic tumour expressing the E6 oncoprotein of human papillomavirus type 16. J Immunol. 1992;148:2617–2621. [PubMed] [Google Scholar]
  • 17.Barrany G., Merrifield R. Solid phase peptide synthesis. In: Gross E., Meienhofer J., editors. The Peptides. Academic Press; New York: 1979. pp. 1–284. [Google Scholar]
  • 18.Cole S.T., Danos O. Nucleotide sequence and comparative analysis of the human papillomavirus type 18 genome. J Mol Biol. 1987;193:599–608. doi: 10.1016/0022-2836(87)90343-3. [DOI] [PubMed] [Google Scholar]
  • 19.Brierley I., Digard P., Inglis S.C. Characterisation of an efficient coronavirus ribosomal frameshifting signal: Requirement for an RNA pseudoknot. Cell. 1989;57:537–547. doi: 10.1016/0092-8674(89)90124-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Barbosa M.S., Edmonds C., Fisher C., Schiller J.T., Lowy D.R., Vousden K.H. The region of the HPV E7 oncoprotein homologous to adenovirus E1a and SV40 large T antigen contains separate domains for Rb binding and casein kinase II phosphorylation. EMBO J. 1990;9:153–160. doi: 10.1002/j.1460-2075.1990.tb08091.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Chesters P.M., Edmonds C., Vousden K.H., McCance D.J. Analysis of human papillomavirus type 16 open reading frame E7 immortalizing function in rat embryo fibroblast cells. J Gen Virol. 1990;71:449–453. doi: 10.1099/0022-1317-71-2-449. [DOI] [PubMed] [Google Scholar]
  • 22.Morgenstern J.P., Land H.D. A series of mammalian expression vectors and characterisation of their expression of a reporter gene in stably and transiently transfected cells. Nucleic Acids Res. 1990;18:1068–1072. doi: 10.1093/nar/18.4.1068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Storey A., Pim D., Murray A., Osborn K., Banks L., Crawford L. Comparison of the in vitro transforming activities of human papillomavirus types. EMBO J. 1988;7:1815–1820. doi: 10.1002/j.1460-2075.1988.tb03013.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Shih C., Weinberg R.A. Isolation of a transforming sequence from a human carcinoma cell line. Cell. 1982;29:161–169. doi: 10.1016/0092-8674(82)90100-3. [DOI] [PubMed] [Google Scholar]
  • 25.Venkatesan S., Baroudy B.M., Moss B. Distinctive nucleotide sequences adjacent to multiple initiation and termination sites of an early vaccinia virus gene. Cell. 1981;125:805–813. doi: 10.1016/0092-8674(81)90188-4. [DOI] [PubMed] [Google Scholar]
  • 26.Rosel J.L., Earl P.L., Weir J.P., Moss B. Conserved TAAATG sequence at the transcriptional and translational initiation sites of vaccinia virus late genes deduced by structural and functional analysis of the Hind III H genome fragment. J Virol. 1986;60:436–449. doi: 10.1128/jvi.60.2.436-449.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Falkner F.G., Moss B. Transient dominant selection of recombinant vaccinia viruses. J Virol. 1990;64:3108–3111. doi: 10.1128/jvi.64.6.3108-3111.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Stacey S.N., Eklund C., Jordan D. Scanning the structure and antigenicity of HPV16 E6 and E7 oncoproteins using anti-peptide antibodies. Oncogene. 1994;9:635–645. [PubMed] [Google Scholar]
  • 29.Sadovnikova E., Zhu X., Collins S.M. Limitations of predictive motifs revealed by cytotoxic T lymphocyte epitope mapping of the human papillomavirus E7 protein. Int Immunol. 1994;6:289–296. doi: 10.1093/intimm/6.2.289. [DOI] [PubMed] [Google Scholar]
  • 30.Lane J.M., Ruben F.L., Neff J.M., Milar J.D. Complications of smallpox vaccination 1968. National surveillance in the United States. New Engl J Med. 1969;281:1201–1208. doi: 10.1056/NEJM196911272812201. [DOI] [PubMed] [Google Scholar]
  • 31.Moss B., Flexner C.H. Vaccinia virus expression vectors. Annu Rev Immunol. 1987;5:305–324. doi: 10.1146/annurev.iy.05.040187.001513. [DOI] [PubMed] [Google Scholar]
  • 32.Bennink J.R., Yewdell J.W. Recombinant vaccinia viruses as vectors for studying T lymphocyte specificity and function. Curr Top Microbiol Immunol. 1990;163:153–184. doi: 10.1007/978-3-642-75605-4_6. [DOI] [PubMed] [Google Scholar]
  • 33.Estin C.D., Stevenson U.S., Plowman G.D. 2nd edn. Vol. 85. 1988. Recombinant vaccinia virus vaccine against the human melanoma antigen p97 for use in immunotherapy; pp. 1052–1056. (Proc Natl Acad Sci (USA)). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Hareuveni M., Gautier C., Kieny M.-P., Wreschner D., Chambon P., Lathe R. 2nd edn. Vol. 87. 1990. Vaccination against tumour cells expressing breast cancer epithelial cell antigen; pp. 9498–9502. (Proc Natl Acad Sci (USA)). [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Kantor J., Irvine K., Abrams S., Kaufmann H., DiPietro J., Schlom J. Anti-tumour activity and immune responses induced by a recombinant carcinoembryonic antigen-vaccinia virus vaccine. J Natl Cancer Inst. 1992;84:1084–1091. doi: 10.1093/jnci/84.14.1084. [DOI] [PubMed] [Google Scholar]
  • 36.Rohrmann G., Yuen L., Moss B. Transcription of vaccinia virus early genes by enzymes isolated from vaccinia virions terminates downstream of a regulatory sequence. Cell. 1986;46:1029–1035. doi: 10.1016/0092-8674(86)90702-6. [DOI] [PubMed] [Google Scholar]
  • 37.Edmonds C., Vousden K.H. A point mutational analysis of human papillomavirus type 16 E7 protein. J Virol. 1989;63:2650–2656. doi: 10.1128/jvi.63.6.2650-2656.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Smith G.L., Chan Y.S., Howard S.T. Nucleotide sequence of 42kbp of vaccinia virus strain WR from near the right inverted terminal repeat. J Gen Virol. 1991;72:1349–1376. doi: 10.1099/0022-1317-72-6-1349. [DOI] [PubMed] [Google Scholar]
  • 39.Andrew M.E., Coupar B.E., Boyle D.B., Blanden R.V. Recognition by major histocompatibility class I restricted cytolytic T lymphocytes of vaccinia encoded viral and class I proteins. Eur J Immunol. 1987;17:1515–1518. doi: 10.1002/eji.1830171021. [DOI] [PubMed] [Google Scholar]
  • 40.Schendel D.J., Gansbacher B., Oberneder R. Tumour specific lysis of human renal cell carcinomas by tumour infiltrating lymphocytes. J Immunol. 1993;151:4209–4220. [PubMed] [Google Scholar]

Articles from Vaccine are provided here courtesy of Elsevier

RESOURCES