Skip to main content
NCBI home page
Journal of Virology logoLink to Journal of Virology
. 1997 Nov;71(11):8340–8346. doi: 10.1128/jvi.71.11.8340-8346.1997

Evolutionary dynamics of genetic variation in Epstein-Barr virus isolates of diverse geographical origins: evidence for immune pressure-independent genetic drift.

R Khanna 1, R W Slade 1, L Poulsen 1, D J Moss 1, S R Burrows 1, J Nicholls 1, J M Burrows 1
PMCID: PMC192293  PMID: 9343187

Abstract

The question whether immune pressure exerted by cytotoxic T lymphocytes (CTLs) can influence the long-term evolution of genetically stable viruses such as Epstein-Barr virus (EBV) has generated considerable scientific interest, primarily due to its important implications for the overall biology of the virus. While arguing for a role of CTLs in the evolution of viruses, it is important to differentiate between genetic variation in virus and immune recognition of these variant virus by CTLs. To assess the role of genetic selection in the long-term evolution of EBV, we have analyzed a large panel of type 1 EBV isolates from African, Southeast Asian, Papua-New Guinean (PNG), and Australian Caucasian individuals. Seven different regions of the EBV genome, which include nine CTL epitopes restricted through a range of HLA class I alleles, were sequenced and compared. Although numerous nucleotide changes were identified within these isolates, comparison of synonymous and nonsynonymous substitutions in the CTL epitope indicated that the genetic variation was generated mostly independently of immune selection pressure. Surprisingly, an inverse correlation between genetic variation within certain CTL epitopes and the frequency distribution of HLA alleles that present the CTL epitopes was seen, suggesting that the evolutionary pressures on the CTL epitopes of the virus may be toward their conservation rather than their inactivation. Furthermore, molecular evolutionary genetic analysis of nucleotide sequences revealed that viral isolates from PNG are evolving as a lineage distinct from isolates from African, Southeast Asian, and Australian Caucasian individuals.

Full Text

The Full Text of this article is available as a PDF (1.3 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Burrows J. M., Burrows S. R., Poulsen L. M., Sculley T. B., Moss D. J., Khanna R. Unusually high frequency of Epstein-Barr virus genetic variants in Papua New Guinea that can escape cytotoxic T-cell recognition: implications for virus evolution. J Virol. 1996 Apr;70(4):2490–2496. doi: 10.1128/jvi.70.4.2490-2496.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. 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]
  3. Crow J. F., Aoki K. Group selection for a polygenic behavioral trait: estimating the degree of population subdivision. Proc Natl Acad Sci U S A. 1984 Oct;81(19):6073–6077. doi: 10.1073/pnas.81.19.6073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Franken M., Annis B., Ali A. N., Wang F. 5' Coding and regulatory region sequence divergence with conserved function of the Epstein-Barr virus LMP2A homolog in herpesvirus papio. J Virol. 1995 Dec;69(12):8011–8019. doi: 10.1128/jvi.69.12.8011-8019.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Fu Y. X., Li W. H. Statistical tests of neutrality of mutations. Genetics. 1993 Mar;133(3):693–709. doi: 10.1093/genetics/133.3.693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hudson R. R., Slatkin M., Maddison W. P. Estimation of levels of gene flow from DNA sequence data. Genetics. 1992 Oct;132(2):583–589. doi: 10.1093/genetics/132.2.583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hughes A. L., Nei M. Pattern of nucleotide substitution at major histocompatibility complex class I loci reveals overdominant selection. Nature. 1988 Sep 8;335(6186):167–170. doi: 10.1038/335167a0. [DOI] [PubMed] [Google Scholar]
  8. 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]
  9. 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]
  10. 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]
  11. Khanna R., Jacob C. A., Burrows S. R., Moss D. J. Presentation of endogenous viral peptide epitopes by anti-CD40 stimulated human B cells following recombinant vaccinia infection. J Immunol Methods. 1993 Aug 26;164(1):41–49. doi: 10.1016/0022-1759(93)90274-b. [DOI] [PubMed] [Google Scholar]
  12. Kimura M. A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J Mol Evol. 1980 Dec;16(2):111–120. doi: 10.1007/BF01731581. [DOI] [PubMed] [Google Scholar]
  13. 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]
  14. McElroy D., Moran P., Bermingham E., Kornfield I. REAP: an integrated environment for the manipulation and phylogenic analysis of restriction data. J Hered. 1992 Mar-Apr;83(2):157–158. doi: 10.1093/oxfordjournals.jhered.a111180. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Nei M., Gojobori T. Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol. 1986 Sep;3(5):418–426. doi: 10.1093/oxfordjournals.molbev.a040410. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. 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]
  19. 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]
  20. 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]
  21. Saitou N., Nei M. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol. 1987 Jul;4(4):406–425. doi: 10.1093/oxfordjournals.molbev.a040454. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Sculley T. B., Sculley D. G., Pope J. H., Bornkamm G. W., Lenoir G. M., Rickinson A. B. Epstein-Barr virus nuclear antigens 1 and 2 in Burkitt lymphoma cell lines containing either 'A'- or 'B'-type virus. Intervirology. 1988;29(2):77–85. doi: 10.1159/000150032. [DOI] [PubMed] [Google Scholar]
  24. Wright S. Evolution in Mendelian Populations. Genetics. 1931 Mar;16(2):97–159. doi: 10.1093/genetics/16.2.97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. 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]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES