Abstract
Cytotoxic T lymphocytes (CTLs) which recognize viral antigens in association with human leukocyte antigens (HLAs) play an important role in controlling persistent virus infections. These viruses use several mechanisms to evade the immune response, including mutations that affect either T-cell receptor recognition or binding of viral epitopes to the HLA. It has recently been proposed that the distribution of HLA frequencies and the specific CTL response may influence the long-term evolution of Epstein-Barr virus (EBV) by selecting variants which lack immunodominant CTL epitopes. To test this hypothesis, we have studied EBV isolates from two genetically distinct Papua New Guinea (PNG) populations, residing in coastal and highland regions, for polymorphism within seven viral CTL epitope sequences restricted through several class I HLAs. Surprisingly, all EBV isolates analyzed displayed identical amino acid substitutions within HLA A11-, B35- and B8-restricted CTL epitope sequences which completely abrogated CTL recognition and binding of synthetic peptides to HLA molecules. Furthermore, these substitutions revealed no correlation with the contemporary distribution of HLAs in the different PNG populations, which argues for a minimal influence of immune pressure. The sequence homology between EBV isolates from coastal and highland PNG suggests that the virus may have had a single origin and, more importantly, that these isolates are genetically distinct from those present in a Caucasian population.
Full Text
The Full Text of this article is available as a PDF (198.8 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Aitken C., Sengupta S. K., Aedes C., Moss D. J., Sculley T. B. Heterogeneity within the Epstein-Barr virus nuclear antigen 2 gene in different strains of Epstein-Barr virus. J Gen Virol. 1994 Jan;75(Pt 1):95–100. doi: 10.1099/0022-1317-75-1-95. [DOI] [PubMed] [Google Scholar]
- Bertoletti A., Sette A., Chisari F. V., Penna A., Levrero M., De Carli M., Fiaccadori F., Ferrari C. Natural variants of cytotoxic epitopes are T-cell receptor antagonists for antiviral cytotoxic T cells. Nature. 1994 Jun 2;369(6479):407–410. doi: 10.1038/369407a0. [DOI] [PubMed] [Google Scholar]
- Bhatia K., Jenkins C., Prasad M., Koki G., Lombange J. Immunogenetic studies of two recently contacted populations from Papua New Guinea. Hum Biol. 1989 Feb;61(1):45–64. [PubMed] [Google Scholar]
- Burrows S. R., Gardner J., Khanna R., Steward T., Moss D. J., Rodda S., Suhrbier A. Five new cytotoxic T cell epitopes identified within Epstein-Barr virus nuclear antigen 3. J Gen Virol. 1994 Sep;75(Pt 9):2489–2493. doi: 10.1099/0022-1317-75-9-2489. [DOI] [PubMed] [Google Scholar]
- Burrows S. R., Rodda S. J., Suhrbier A., Geysen H. M., Moss D. J. The specificity of recognition of a cytotoxic T lymphocyte epitope. Eur J Immunol. 1992 Jan;22(1):191–195. doi: 10.1002/eji.1830220128. [DOI] [PubMed] [Google Scholar]
- Byrne J. A., Oldstone M. B. Biology of cloned cytotoxic T lymphocytes specific for lymphocytic choriomeningitis virus: clearance of virus in vivo. J Virol. 1984 Sep;51(3):682–686. doi: 10.1128/jvi.51.3.682-686.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Couillin I., Culmann-Penciolelli B., Gomard E., Choppin J., Levy J. P., Guillet J. G., Saragosti S. Impaired cytotoxic T lymphocyte recognition due to genetic variations in the main immunogenic region of the human immunodeficiency virus 1 NEF protein. J Exp Med. 1994 Sep 1;180(3):1129–1134. doi: 10.1084/jem.180.3.1129. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Crane G., Bhatia K., Honeyman M., Doran T., Messel N., Hakos G., Tarlinton D., Amos D. B., Bashir H. HLA studies of Highland and Coastal New Guineans. Hum Immunol. 1985 Apr;12(4):247–260. doi: 10.1016/0198-8859(85)90340-4. [DOI] [PubMed] [Google Scholar]
- 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]
- Gavioli R., Kurilla M. G., de Campos-Lima P. O., Wallace L. E., Dolcetti R., Murray R. J., Rickinson A. B., Masucci M. G. Multiple HLA A11-restricted cytotoxic T-lymphocyte epitopes of different immunogenicities in the Epstein-Barr virus-encoded nuclear antigen 4. J Virol. 1993 Mar;67(3):1572–1578. doi: 10.1128/jvi.67.3.1572-1578.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hill A., Worth A., Elliott T., Rowland-Jones S., Brooks J., Rickinson A., McMichael A. Characterization of two Epstein-Barr virus epitopes restricted by HLA-B7. Eur J Immunol. 1995 Jan;25(1):18–24. doi: 10.1002/eji.1830250105. [DOI] [PubMed] [Google Scholar]
- 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]
- 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]
- Klenerman P., Rowland-Jones S., McAdam S., Edwards J., Daenke S., Lalloo D., Köppe B., Rosenberg W., Boyd D., Edwards A. Cytotoxic T-cell activity antagonized by naturally occurring HIV-1 Gag variants. Nature. 1994 Jun 2;369(6479):403–407. doi: 10.1038/369403a0. [DOI] [PubMed] [Google Scholar]
- Lang D. J., Garruto R. M., Gajdusek D. C. Early acquisition of cytomegalovirus and Epstein-Barr virus antibody in several isolated Melanesian populations. Am J Epidemiol. 1977 May;105(5):480–487. doi: 10.1093/oxfordjournals.aje.a112407. [DOI] [PubMed] [Google Scholar]
- Lee S. P., Morgan S., Skinner J., Thomas W. A., Jones S. R., Sutton J., Khanna R., Whittle H. C., Rickinson A. B. Epstein-Barr virus isolates with the major HLA B35.01-restricted cytotoxic T lymphocyte epitope are prevalent in a highly B35.01-positive African population. Eur J Immunol. 1995 Jan;25(1):102–110. doi: 10.1002/eji.1830250119. [DOI] [PubMed] [Google Scholar]
- 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]
- Phillips R. E., Rowland-Jones S., Nixon D. F., Gotch F. M., Edwards J. P., Ogunlesi A. O., Elvin J. G., Rothbard J. A., Bangham C. R., Rizza C. R. Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition. Nature. 1991 Dec 12;354(6353):453–459. doi: 10.1038/354453a0. [DOI] [PubMed] [Google Scholar]
- Pircher H., Moskophidis D., Rohrer U., Bürki K., Hengartner H., Zinkernagel R. M. Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo. Nature. 1990 Aug 16;346(6285):629–633. doi: 10.1038/346629a0. [DOI] [PubMed] [Google Scholar]
- Rickinson A. B., Finerty S., Epstein M. A. Comparative studies on adult donor lymphocytes infected by EB virus in vivo or in vitro: origin of transformed cells arising in co-cultures with foetal lymphocytes. Int J Cancer. 1977 Jun 15;19(6):775–782. doi: 10.1002/ijc.2910190606. [DOI] [PubMed] [Google Scholar]
- Sample J., Kieff E. Transcription of the Epstein-Barr virus genome during latency in growth-transformed lymphocytes. J Virol. 1990 Apr;64(4):1667–1674. doi: 10.1128/jvi.64.4.1667-1674.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Serjeantson S., Bryson K., Amato D., Babona D. Malaria and hereditary ovalocytosis. Hum Genet. 1977 Jun 30;37(2):161–167. doi: 10.1007/BF00393579. [DOI] [PubMed] [Google Scholar]
- Smith G. L. Virus strategies for evasion of the host response to infection. Trends Microbiol. 1994 Mar;2(3):81–88. doi: 10.1016/0966-842x(94)90539-8. [DOI] [PubMed] [Google Scholar]
- Thomas J. A., Allday M. J., Crawford D. H. Epstein-Barr virus-associated lymphoproliferative disorders in immunocompromised individuals. Adv Cancer Res. 1991;57:329–380. doi: 10.1016/s0065-230x(08)61003-9. [DOI] [PubMed] [Google Scholar]
- Tsubota H., Lord C. I., Watkins D. I., Morimoto C., Letvin N. L. A cytotoxic T lymphocyte inhibits acquired immunodeficiency syndrome virus replication in peripheral blood lymphocytes. J Exp Med. 1989 Apr 1;169(4):1421–1434. doi: 10.1084/jem.169.4.1421. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Valerio R. M., Benstead M., Bray A. M., Campbell R. A., Maeji N. J. Synthesis of peptide analogues using the multipin peptide synthesis method. Anal Biochem. 1991 Aug 15;197(1):168–177. doi: 10.1016/0003-2697(91)90374-3. [DOI] [PubMed] [Google Scholar]
- de Campos-Lima P. O., Gavioli R., Zhang Q. J., Wallace L. E., Dolcetti R., Rowe M., Rickinson A. B., Masucci M. G. HLA-A11 epitope loss isolates of Epstein-Barr virus from a highly A11+ population. Science. 1993 Apr 2;260(5104):98–100. doi: 10.1126/science.7682013. [DOI] [PubMed] [Google Scholar]
- de Campos-Lima P. O., Levitsky V., Brooks J., Lee S. P., Hu L. F., Rickinson A. B., Masucci M. G. T cell responses and virus evolution: loss of HLA A11-restricted CTL epitopes in Epstein-Barr virus isolates from highly A11-positive populations by selective mutation of anchor residues. J Exp Med. 1994 Apr 1;179(4):1297–1305. doi: 10.1084/jem.179.4.1297. [DOI] [PMC free article] [PubMed] [Google Scholar]