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. 1996 Dec;70(12):8858–8864. doi: 10.1128/jvi.70.12.8858-8864.1996

Identification of type B-specific and cross-reactive cytotoxic T-lymphocyte responses to Epstein-Barr virus.

B M Kerr 1, N Kienzle 1, J M Burrows 1, S Cross 1, S L Silins 1, M Buck 1, E M Benson 1, B Coupar 1, D J Moss 1, T B Sculley 1
PMCID: PMC190982  PMID: 8971014

Abstract

Persistent Epstein-Barr virus (EBV) infection is primarily controlled by HLA class I-restricted memory cytotoxic T-cell (CTL) responses which can be reactivated in vitro by stimulation of peripheral blood lymphocytes with autologous lymphoblastoid cell lines. During an investigation of a donor infected by both type A and type B EBV, CTL specific for type B EBV were isolated. The CTL were found to recognize an epitope encoded by the EBNA-6B gene. The minimal epitope sequence was identified as QNGALAINTF, corresponding to residues 213 to 222 in the EBNA-6B protein, and presentation of this epitope was shown to be via HLA B62 (B15). This is the first report of the characterization of an epitope that is EBV type B specific. CTL recognizing sequences common to type A and type B EBV were identified as well. A cross-reactive epitope recognized by these CTL was encoded within the EBNA-6 gene of both type A and type B. This minimal sequence for this epitope was LLDFVRFMGV (residues 284 to 293 in both types), and the epitope was restricted through HLA A*0201. This second epitope sequence overlaps with a published EBV B44-restricted epitope (EENLLDFVRF). The implications of these findings are discussed with respect to the design and efficacy of epitope-based vaccines.

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Selected References

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  1. Andrew M. E., Coupar B. E., Boyle D. B., Ada G. L. The roles of influenza virus haemagglutinin and nucleoprotein in protection: analysis using vaccinia virus recombinants. Scand J Immunol. 1987 Jan;25(1):21–28. doi: 10.1111/j.1365-3083.1987.tb01042.x. [DOI] [PubMed] [Google Scholar]
  2. Apolloni A., Sculley T. B. Detection of A-type and B-type Epstein-Barr virus in throat washings and lymphocytes. Virology. 1994 Aug 1;202(2):978–981. doi: 10.1006/viro.1994.1422. [DOI] [PubMed] [Google Scholar]
  3. Bogedain C., Wolf H., Modrow S., Stuber G., Jilg W. Specific cytotoxic T lymphocytes recognize the immediate-early transactivator Zta of Epstein-Barr virus. J Virol. 1995 Aug;69(8):4872–4879. doi: 10.1128/jvi.69.8.4872-4879.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Buisson M., Morand P., Genoulaz O., Bourgeat M. J., Micoud M., Seigneurin J. M. Changes in the dominant Epstein-Barr virus type during human immunodeficiency virus infection. J Gen Virol. 1994 Feb;75(Pt 2):431–437. doi: 10.1099/0022-1317-75-2-431. [DOI] [PubMed] [Google Scholar]
  5. Burrows S. R., Fernan A., Argaet V., Suhrbier A. Bystander apoptosis induced by CD8+ cytotoxic T cell (CTL) clones: implications for CTL lytic mechanisms. Int Immunol. 1993 Sep;5(9):1049–1058. doi: 10.1093/intimm/5.9.1049. [DOI] [PubMed] [Google Scholar]
  6. Burrows S. R., Misko I. S., Sculley T. B., Schmidt C., Moss D. J. An Epstein-Barr virus-specific cytotoxic T-cell epitope present on A- and B-type transformants. J Virol. 1990 Aug;64(8):3974–3976. doi: 10.1128/jvi.64.8.3974-3976.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Crawford D. H., Thomas J. A., Janossy G., Sweny P., Fernando O. N., Moorhead J. F., Thompson J. H. Epstein Barr virus nuclear antigen positive lymphoma after cyclosporin A treatment in patient with renal allograft. Lancet. 1980 Jun 21;1(8182):1355–1356. doi: 10.1016/s0140-6736(80)91800-0. [DOI] [PubMed] [Google Scholar]
  8. Dambaugh T., Hennessy K., Chamnankit L., Kieff E. U2 region of Epstein-Barr virus DNA may encode Epstein-Barr nuclear antigen 2. Proc Natl Acad Sci U S A. 1984 Dec;81(23):7632–7636. doi: 10.1073/pnas.81.23.7632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Doherty P. C., Hou S., Tripp R. A. CD8+ T-cell memory to viruses. Curr Opin Immunol. 1994 Aug;6(4):545–552. doi: 10.1016/0952-7915(94)90139-2. [DOI] [PubMed] [Google Scholar]
  10. Gratama J. W., Oosterveer M. A., Weimar W., Sintnicolaas K., Sizoo W., Bolhuis R. L., Ernberg I. Detection of multiple 'Ebnotypes' in individual Epstein-Barr virus carriers following lymphocyte transformation by virus derived from peripheral blood and oropharynx. J Gen Virol. 1994 Jan;75(Pt 1):85–94. doi: 10.1099/0022-1317-75-1-85. [DOI] [PubMed] [Google Scholar]
  11. Gregory C. D., Rowe M., Rickinson A. B. Different Epstein-Barr virus-B cell interactions in phenotypically distinct clones of a Burkitt's lymphoma cell line. J Gen Virol. 1990 Jul;71(Pt 7):1481–1495. doi: 10.1099/0022-1317-71-7-1481. [DOI] [PubMed] [Google Scholar]
  12. Khanna R., Burrows S. R., Kurilla M. G., Jacob C. A., Misko I. S., Sculley T. B., Kieff E., Moss D. J. Localization of Epstein-Barr virus cytotoxic T cell epitopes using recombinant vaccinia: implications for vaccine development. J Exp Med. 1992 Jul 1;176(1):169–176. doi: 10.1084/jem.176.1.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Khanna R., Burrows S. R., Moss D. J. Immune regulation in Epstein-Barr virus-associated diseases. Microbiol Rev. 1995 Sep;59(3):387–405. doi: 10.1128/mr.59.3.387-405.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Khanna R., Jacob C. A., Burrows S. R., Kurilla M. G., Kieff E., Misko I. S., Sculley T. B., Moss D. J. Expression of Epstein-Barr virus nuclear antigens in anti-IgM-stimulated B cells following recombinant vaccinia infection and their recognition by human cytotoxic T cells. Immunology. 1991 Nov;74(3):504–510. [PMC free article] [PubMed] [Google Scholar]
  15. Kyaw M. T., Hurren L., Evans L., Moss D. J., Cooper D. A., Benson E., Esmore D., Sculley T. B. Expression of B-type Epstein-Barr virus in HIV-infected patients and cardiac transplant recipients. AIDS Res Hum Retroviruses. 1992 Nov;8(11):1869–1874. doi: 10.1089/aid.1992.8.1869. [DOI] [PubMed] [Google Scholar]
  16. Lear A. L., Rowe M., Kurilla M. G., Lee S., Henderson S., Kieff E., Rickinson A. B. The Epstein-Barr virus (EBV) nuclear antigen 1 BamHI F promoter is activated on entry of EBV-transformed B cells into the lytic cycle. J Virol. 1992 Dec;66(12):7461–7468. doi: 10.1128/jvi.66.12.7461-7468.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lewin N., Aman P., Masucci M. G., Klein E., Klein G., Oberg B., Strander H., Henle W., Henle G. Characterization of EBV-carrying B-cell populations in healthy seropositive individuals with regard to density, release of transforming virus and spontaneous outgrowth. Int J Cancer. 1987 Apr 15;39(4):472–476. doi: 10.1002/ijc.2910390411. [DOI] [PubMed] [Google Scholar]
  18. Lung M. L., Chang R. S., Huang M. L., Guo H. Y., Choy D., Sham J., Tsao S. Y., Cheng P., Ng M. H. Epstein-Barr virus genotypes associated with nasopharyngeal carcinoma in southern China. Virology. 1990 Jul;177(1):44–53. doi: 10.1016/0042-6822(90)90458-4. [DOI] [PubMed] [Google Scholar]
  19. Miller W. E., Edwards R. H., Walling D. M., Raab-Traub N. Sequence variation in the Epstein-Barr virus latent membrane protein 1. J Gen Virol. 1994 Oct;75(Pt 10):2729–2740. doi: 10.1099/0022-1317-75-10-2729. [DOI] [PubMed] [Google Scholar]
  20. Misko I. S., Soszynski T. D., Kane R. G., Pope J. H. Factors influencing the human cytotoxic T cell response to autologous lymphoblastoid cell lines in vitro. Clin Immunol Immunopathol. 1984 Sep;32(3):285–297. doi: 10.1016/0090-1229(84)90273-3. [DOI] [PubMed] [Google Scholar]
  21. Miyashita E. M., Yang B., Lam K. M., Crawford D. H., Thorley-Lawson D. A. A novel form of Epstein-Barr virus latency in normal B cells in vivo. Cell. 1995 Feb 24;80(4):593–601. doi: 10.1016/0092-8674(95)90513-8. [DOI] [PubMed] [Google Scholar]
  22. Moss D. J., Misko I. S., Burrows S. R., Burman K., McCarthy R., Sculley T. B. Cytotoxic T-cell clones discriminate between A- and B-type Epstein-Barr virus transformants. Nature. 1988 Feb 25;331(6158):719–721. doi: 10.1038/331719a0. [DOI] [PubMed] [Google Scholar]
  23. Moss D. J., Rickinson A. B., Pope J. H. Long-term T-cell-mediated immunity to Epstein-Barr virus in man. I. Complete regression of virus-induced transformation in cultures of seropositive donor leukocytes. Int J Cancer. 1978 Dec;22(6):662–668. doi: 10.1002/ijc.2910220604. [DOI] [PubMed] [Google Scholar]
  24. Murray R. J., Kurilla M. G., Brooks J. M., Thomas W. A., Rowe M., Kieff E., Rickinson A. B. Identification of target antigens for the human cytotoxic T cell response to Epstein-Barr virus (EBV): implications for the immune control of EBV-positive malignancies. J Exp Med. 1992 Jul 1;176(1):157–168. doi: 10.1084/jem.176.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Murray R. J., Kurilla M. G., Griffin H. M., Brooks J. M., Mackett M., Arrand J. R., Rowe M., Burrows S. R., Moss D. J., Kieff E. Human cytotoxic T-cell responses against Epstein-Barr virus nuclear antigens demonstrated by using recombinant vaccinia viruses. Proc Natl Acad Sci U S A. 1990 Apr;87(8):2906–2910. doi: 10.1073/pnas.87.8.2906. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Nilsson K., Klein G., Henle W., Henle G. The establishment of lymphoblastoid lines from adult and fetal human lymphoid tissue and its dependence on EBV. Int J Cancer. 1971 Nov 15;8(3):443–450. doi: 10.1002/ijc.2910080312. [DOI] [PubMed] [Google Scholar]
  27. Pope J. H., Achong B. G., Epstein M. A., Biddulph J. Burkitt lymphoma in New Guinea: establishment of a line of lymphoblasts in vitro and description of their fine structure. J Natl Cancer Inst. 1967 Nov;39(5):933–945. [PubMed] [Google Scholar]
  28. Pope J. H., Horne M. K., Scott W. Transformation of foetal human keukocytes in vitro by filtrates of a human leukaemic cell line containing herpes-like virus. Int J Cancer. 1968 Nov 15;3(6):857–866. doi: 10.1002/ijc.2910030619. [DOI] [PubMed] [Google Scholar]
  29. Rammensee H. G., Friede T., Stevanoviíc S. MHC ligands and peptide motifs: first listing. Immunogenetics. 1995;41(4):178–228. doi: 10.1007/BF00172063. [DOI] [PubMed] [Google Scholar]
  30. 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. 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. J Immunol. 1995 Jun 1;154(11):5934–5943. [PubMed] [Google Scholar]
  31. Rickinson A. B., Rowe M., Hart I. J., Yao Q. Y., Henderson L. E., Rabin H., Epstein M. A. T-cell-mediated regression of "spontaneous" and of Epstein-Barr virus-induced B-cell transformation in vitro: studies with cyclosporin A. Cell Immunol. 1984 Sep;87(2):646–658. doi: 10.1016/0008-8749(84)90032-7. [DOI] [PubMed] [Google Scholar]
  32. Rooney C. M., Rickinson A. B., Moss D. J., Lenoir G. M., Epstein M. A. Paired Epstein-Barr virus-carrying lymphoma and lymphoblastoid cell lines from Burkitt's lymphoma patients: comparative sensitivity to non-specific and to allo-specific cytotoxic responses in vitro. Int J Cancer. 1984 Sep 15;34(3):339–348. doi: 10.1002/ijc.2910340310. [DOI] [PubMed] [Google Scholar]
  33. Rooney C. M., Rowe M., Wallace L. E., Rickinson A. B. Epstein-Barr virus-positive Burkitt's lymphoma cells not recognized by virus-specific T-cell surveillance. Nature. 1985 Oct 17;317(6038):629–631. doi: 10.1038/317629a0. [DOI] [PubMed] [Google Scholar]
  34. Rosenberg S. A., Grimm E. A., McGrogan M., Doyle M., Kawasaki E., Koths K., Mark D. F. Biological activity of recombinant human interleukin-2 produced in Escherichia coli. Science. 1984 Mar 30;223(4643):1412–1414. doi: 10.1126/science.6367046. [DOI] [PubMed] [Google Scholar]
  35. Sample J., Young L., Martin B., Chatman T., Kieff E., Rickinson A., Kieff E. Epstein-Barr virus types 1 and 2 differ in their EBNA-3A, EBNA-3B, and EBNA-3C genes. J Virol. 1990 Sep;64(9):4084–4092. doi: 10.1128/jvi.64.9.4084-4092.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Sculley T. B., Apolloni A., Hurren L., Moss D. J., Cooper D. A. Coinfection with A- and B-type Epstein-Barr virus in human immunodeficiency virus-positive subjects. J Infect Dis. 1990 Sep;162(3):643–648. doi: 10.1093/infdis/162.3.642. [DOI] [PubMed] [Google Scholar]
  37. Sculley T. B., Apolloni A., Stumm R., Moss D. J., Mueller-Lantczh N., Misko I. S., Cooper D. A. Expression of Epstein-Barr virus nuclear antigens 3, 4, and 6 are altered in cell lines containing B-type virus. Virology. 1989 Aug;171(2):401–408. doi: 10.1016/0042-6822(89)90608-9. [DOI] [PubMed] [Google Scholar]
  38. Selin L. K., Nahill S. R., Welsh R. M. Cross-reactivities in memory cytotoxic T lymphocyte recognition of heterologous viruses. J Exp Med. 1994 Jun 1;179(6):1933–1943. doi: 10.1084/jem.179.6.1933. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Silins S. L., Argaet V. P., Sculley T. B. Isolation of Epstein-Barr virus genomes using pulse-field gel electrophoresis. Nucleic Acids Res. 1992 Jun 11;20(11):2901–2901. doi: 10.1093/nar/20.11.2901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sixbey J. W., Shirley P., Chesney P. J., Buntin D. M., Resnick L. Detection of a second widespread strain of Epstein-Barr virus. Lancet. 1989 Sep 30;2(8666):761–765. doi: 10.1016/s0140-6736(89)90829-5. [DOI] [PubMed] [Google Scholar]
  41. Sumaya C. V., Ench Y. Epstein-Barr virus infectious mononucleosis in children. I. Clinical and general laboratory findings. Pediatrics. 1985 Jun;75(6):1003–1010. [PubMed] [Google Scholar]
  42. Tomkinson B. E., Wagner D. K., Nelson D. L., Sullivan J. L. Activated lymphocytes during acute Epstein-Barr virus infection. J Immunol. 1987 Dec 1;139(11):3802–3807. [PubMed] [Google Scholar]
  43. Tussey L. G., Rowland-Jones S., Zheng T. S., Androlewicz M. J., Cresswell P., Frelinger J. A., McMichael A. J. Different MHC class I alleles compete for presentation of overlapping viral epitopes. Immunity. 1995 Jul;3(1):65–77. doi: 10.1016/1074-7613(95)90159-0. [DOI] [PubMed] [Google Scholar]
  44. Wagner H. J., Bein G., Bitsch A., Kirchner H. Detection and quantification of latently infected B lymphocytes in Epstein-Barr virus-seropositive, healthy individuals by polymerase chain reaction. J Clin Microbiol. 1992 Nov;30(11):2826–2829. doi: 10.1128/jcm.30.11.2826-2829.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Walling D. M., Edmiston S. N., Sixbey J. W., Abdel-Hamid M., Resnick L., Raab-Traub N. Coinfection with multiple strains of the Epstein-Barr virus in human immunodeficiency virus-associated hairy leukoplakia. Proc Natl Acad Sci U S A. 1992 Jul 15;89(14):6560–6564. doi: 10.1073/pnas.89.14.6560. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Wang A., Lu S. D., Mark D. F. Site-specific mutagenesis of the human interleukin-2 gene: structure-function analysis of the cysteine residues. Science. 1984 Jun 29;224(4656):1431–1433. doi: 10.1126/science.6427925. [DOI] [PubMed] [Google Scholar]
  47. Yao Q. Y., Rickinson A. B., Epstein M. A. A re-examination of the Epstein-Barr virus carrier state in healthy seropositive individuals. Int J Cancer. 1985 Jan 15;35(1):35–42. doi: 10.1002/ijc.2910350107. [DOI] [PubMed] [Google Scholar]

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