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. 1994 Oct;145(4):969–978.

Latent Epstein-Barr virus infection in cottontop tamarins. A possible model for Epstein-Barr virus infection in humans.

G Niedobitek 1, A Agathanggelou 1, S Finerty 1, R Tierney 1, P Watkins 1, E L Jones 1, A Morgan 1, L S Young 1, N Rooney 1
PMCID: PMC1887315  PMID: 7943186

Abstract

The association of Epstein-Barr virus (EBV) with a growing number of human malignancies underlines the importance of efforts aimed at preventing the infection with this potential carcinogen and of establishing animal models for human virus-associated tumors. Cottontop tamarins have been used in EBV vaccine studies because virus infection regularly induces lymphomas similar to those seen in human immunocompromised individuals. In recent years, several vaccines based on the gp340/220 envelope protein of EBV have been developed and shown to prevent the development of EBV-associated lymphomas in this model. Using in situ hybridization and immunohistology, we have characterized EBV infection in one nonimmunized and three immunized animals after challenge with a standard tumorigenic dose of EBV. In the nonimmunized animal, EBV-infected lymphoid cells were detected in numerous tissues showing no obvious lymphoma infiltration. Surprisingly, variable numbers of virus-carrying cells were also found in all three immunized animals that were protected against the development of virus-associated lymphoma. This observation demonstrates that vaccination does not induce sterilizing immunity against EBV infection in this model. Double labeling suggested a B cell phenotype of the majority of these cells. EBV infection of nonlymphoid cells was not observed. Analysis of viral gene expression in immunized animals suggested a restricted form of virus latency different from that seen in EBV-driven lymphomas in nonimmunized cottontop tamarins. These results raise the possibility that immunized cottontop tamarins protected against the development of EBV-driven lymphoma or animals exposed to a sublymphomagenic dose of virus may serve as a model for EBV infection in humans.

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Selected References

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  1. Cleary M. L., Epstein M. A., Finerty S., Dorfman R. F., Bornkamm G. W., Kirkwood J. K., Morgan A. J., Sklar J. Individual tumors of multifocal EB virus-induced malignant lymphomas in tamarins arise from different B-cell clones. Science. 1985 May 10;228(4700):722–724. doi: 10.1126/science.2986287. [DOI] [PubMed] [Google Scholar]
  2. Deacon E. M., Pallesen G., Niedobitek G., Crocker J., Brooks L., Rickinson A. B., Young L. S. Epstein-Barr virus and Hodgkin's disease: transcriptional analysis of virus latency in the malignant cells. J Exp Med. 1993 Feb 1;177(2):339–349. doi: 10.1084/jem.177.2.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Deamant F. D., Albújar P. F., Chen Y. Y., Weiss L. M. Epstein-Barr virus distribution in nonneoplastic lymph nodes. Mod Pathol. 1993 Nov;6(6):729–732. [PubMed] [Google Scholar]
  4. Emini E. A., Luka J., Armstrong M. E., Banker F. S., Provost P. J., Pearson G. R. Establishment and characterization of a chronic infectious mononucleosislike syndrome in common marmosets. J Med Virol. 1986 Apr;18(4):369–379. doi: 10.1002/jmv.1890180410. [DOI] [PubMed] [Google Scholar]
  5. Finerty S., Scullion F. T., Morgan A. J. Demonstration in vitro of cell mediated immunity to Epstein-Barr virus in cotton-top tamarins. Clin Exp Immunol. 1988 Aug;73(2):181–185. [PMC free article] [PubMed] [Google Scholar]
  6. Fåhraeus R., Fu H. L., Ernberg I., Finke J., Rowe M., Klein G., Falk K., Nilsson E., Yadav M., Busson P. Expression of Epstein-Barr virus-encoded proteins in nasopharyngeal carcinoma. Int J Cancer. 1988 Sep 15;42(3):329–338. doi: 10.1002/ijc.2910420305. [DOI] [PubMed] [Google Scholar]
  7. Greenspan J. S., Greenspan D., Lennette E. T., Abrams D. I., Conant M. A., Petersen V., Freese U. K. Replication of Epstein-Barr virus within the epithelial cells of oral "hairy" leukoplakia, an AIDS-associated lesion. N Engl J Med. 1985 Dec 19;313(25):1564–1571. doi: 10.1056/NEJM198512193132502. [DOI] [PubMed] [Google Scholar]
  8. Hamilton-Dutoit S. J., Rea D., Raphael M., Sandvej K., Delecluse H. J., Gisselbrecht C., Marelle L., van Krieken H. J., Pallesen G. Epstein-Barr virus-latent gene expression and tumor cell phenotype in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. Correlation of lymphoma phenotype with three distinct patterns of viral latency. Am J Pathol. 1993 Oct;143(4):1072–1085. [PMC free article] [PubMed] [Google Scholar]
  9. Herbst H., Dallenbach F., Hummel M., Niedobitek G., Pileri S., Müller-Lantzsch N., Stein H. Epstein-Barr virus latent membrane protein expression in Hodgkin and Reed-Sternberg cells. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4766–4770. doi: 10.1073/pnas.88.11.4766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Herbst H., Stein H., Niedobitek G. Epstein-Barr virus and CD30+ malignant lymphomas. Crit Rev Oncog. 1993;4(2):191–239. [PubMed] [Google Scholar]
  11. Herbst H., Steinbrecher E., Niedobitek G., Young L. S., Brooks L., Müller-Lantzsch N., Stein H. Distribution and phenotype of Epstein-Barr virus-harboring cells in Hodgkin's disease. Blood. 1992 Jul 15;80(2):484–491. [PubMed] [Google Scholar]
  12. Kawaguchi H., Miyashita T., Herbst H., Niedobitek G., Asada M., Tsuchida M., Hanada R., Kinoshita A., Sakurai M., Kobayashi N. Epstein-Barr virus-infected T lymphocytes in Epstein-Barr virus-associated hemophagocytic syndrome. J Clin Invest. 1993 Sep;92(3):1444–1450. doi: 10.1172/JCI116721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kikuta H., Taguchi Y., Tomizawa K., Kojima K., Kawamura N., Ishizaka A., Sakiyama Y., Matsumoto S., Imai S., Kinoshita T. Epstein-Barr virus genome-positive T lymphocytes in a boy with chronic active EBV infection associated with Kawasaki-like disease. Nature. 1988 Jun 2;333(6172):455–457. doi: 10.1038/333455a0. [DOI] [PubMed] [Google Scholar]
  14. Locker J., Nalesnik M. Molecular genetic analysis of lymphoid tumors arising after organ transplantation. Am J Pathol. 1989 Dec;135(6):977–987. [PMC free article] [PubMed] [Google Scholar]
  15. Morgan A. J. Epstein-Barr virus vaccines. Vaccine. 1992;10(9):563–571. doi: 10.1016/0264-410x(92)90434-l. [DOI] [PubMed] [Google Scholar]
  16. Niedobitek G., Herbst H., Young L. S., Brooks L., Masucci M. G., Crocker J., Rickinson A. B., Stein H. Patterns of Epstein-Barr virus infection in non-neoplastic lymphoid tissue. Blood. 1992 May 15;79(10):2520–2526. [PubMed] [Google Scholar]
  17. Niedobitek G., Young L. S. Epstein-Barr virus persistence and virus-associated tumours. Lancet. 1994 Feb 5;343(8893):333–335. doi: 10.1016/s0140-6736(94)91167-3. [DOI] [PubMed] [Google Scholar]
  18. Niedobitek G., Young L. S., Lau R., Brooks L., Greenspan D., Greenspan J. S., Rickinson A. B. Epstein-Barr virus infection in oral hairy leukoplakia: virus replication in the absence of a detectable latent phase. J Gen Virol. 1991 Dec;72(Pt 12):3035–3046. doi: 10.1099/0022-1317-72-12-3035. [DOI] [PubMed] [Google Scholar]
  19. Raab-Traub N. Epstein-Barr virus and nasopharyngeal carcinoma. Semin Cancer Biol. 1992 Oct;3(5):297–307. [PubMed] [Google Scholar]
  20. Ragot T., Finerty S., Watkins P. E., Perricaudet M., Morgan A. J. Replication-defective recombinant adenovirus expressing the Epstein-Barr virus (EBV) envelope glycoprotein gp340/220 induces protective immunity against EBV-induced lymphomas in the cottontop tamarin. J Gen Virol. 1993 Mar;74(Pt 3):501–507. doi: 10.1099/0022-1317-74-3-501. [DOI] [PubMed] [Google Scholar]
  21. Rowe M., Evans H. S., Young L. S., Hennessy K., Kieff E., Rickinson A. B. Monoclonal antibodies to the latent membrane protein of Epstein-Barr virus reveal heterogeneity of the protein and inducible expression in virus-transformed cells. J Gen Virol. 1987 Jun;68(Pt 6):1575–1586. doi: 10.1099/0022-1317-68-6-1575. [DOI] [PubMed] [Google Scholar]
  22. Rowe M., Rowe D. T., Gregory C. D., Young L. S., Farrell P. J., Rupani H., Rickinson A. B. Differences in B cell growth phenotype reflect novel patterns of Epstein-Barr virus latent gene expression in Burkitt's lymphoma cells. EMBO J. 1987 Sep;6(9):2743–2751. doi: 10.1002/j.1460-2075.1987.tb02568.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sample J., Brooks L., Sample C., Young L., Rowe M., Gregory C., Rickinson A., Kieff E. Restricted Epstein-Barr virus protein expression in Burkitt lymphoma is due to a different Epstein-Barr nuclear antigen 1 transcriptional initiation site. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):6343–6347. doi: 10.1073/pnas.88.14.6343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Schaefer B. C., Woisetschlaeger M., Strominger J. L., Speck S. H. Exclusive expression of Epstein-Barr virus nuclear antigen 1 in Burkitt lymphoma arises from a third promoter, distinct from the promoters used in latently infected lymphocytes. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6550–6554. doi: 10.1073/pnas.88.15.6550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Shibata D., Weiss L. M., Hernandez A. M., Nathwani B. N., Bernstein L., Levine A. M. Epstein-Barr virus-associated non-Hodgkin's lymphoma in patients infected with the human immunodeficiency virus. Blood. 1993 Apr 15;81(8):2102–2109. [PubMed] [Google Scholar]
  26. Wedderburn N., Edwards J. M., Desgranges C., Fontaine C., Cohen B., de Thé G. Infectious mononucleosis-like response in common marmosets infected with Epstein-Barr virus. J Infect Dis. 1984 Dec;150(6):878–882. doi: 10.1093/infdis/150.6.878. [DOI] [PubMed] [Google Scholar]
  27. Weiss L. M., Movahed L. A., Warnke R. A., Sklar J. Detection of Epstein-Barr viral genomes in Reed-Sternberg cells of Hodgkin's disease. N Engl J Med. 1989 Feb 23;320(8):502–506. doi: 10.1056/NEJM198902233200806. [DOI] [PubMed] [Google Scholar]
  28. Young L. S., Dawson C. W., Clark D., Rupani H., Busson P., Tursz T., Johnson A., Rickinson A. B. Epstein-Barr virus gene expression in nasopharyngeal carcinoma. J Gen Virol. 1988 May;69(Pt 5):1051–1065. doi: 10.1099/0022-1317-69-5-1051. [DOI] [PubMed] [Google Scholar]
  29. Young L. S., Finerty S., Brooks L., Scullion F., Rickinson A. B., Morgan A. J. Epstein-Barr virus gene expression in malignant lymphomas induced by experimental virus infection of cottontop tamarins. J Virol. 1989 May;63(5):1967–1974. doi: 10.1128/jvi.63.5.1967-1974.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Young L. S., Lau R., Rowe M., Niedobitek G., Packham G., Shanahan F., Rowe D. T., Greenspan D., Greenspan J. S., Rickinson A. B. Differentiation-associated expression of the Epstein-Barr virus BZLF1 transactivator protein in oral hairy leukoplakia. J Virol. 1991 Jun;65(6):2868–2874. doi: 10.1128/jvi.65.6.2868-2874.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Young L. S., Rowe M. Epstein-Barr virus, lymphomas and Hodgkin's disease. Semin Cancer Biol. 1992 Oct;3(5):273–284. [PubMed] [Google Scholar]
  32. Young L., Alfieri C., Hennessy K., Evans H., O'Hara C., Anderson K. C., Ritz J., Shapiro R. S., Rickinson A., Kieff E. Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med. 1989 Oct 19;321(16):1080–1085. doi: 10.1056/NEJM198910193211604. [DOI] [PubMed] [Google Scholar]
  33. zur Hausen H., Schulte-Holthausen H., Klein G., Henle W., Henle G., Clifford P., Santesson L. EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the nasopharynx. Nature. 1970 Dec 12;228(5276):1056–1058. doi: 10.1038/2281056a0. [DOI] [PubMed] [Google Scholar]

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