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Journal of Virology, November 2003, p. 11507-11516, Vol. 77, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.21.11507-11516.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

HLA-A11-Restricted Epitope Polymorphism among Epstein-Barr Virus Strains in the Highly HLA-A11-Positive Chinese Population: Incidence and Immunogenicity of Variant Epitope Sequences

R. S. Midgley,1 A. I. Bell,1 Q. Y. Yao,1 D. Croom-Carter,1 A. D. Hislop,1 B. M. Whitney,2 A. T. C. Chan,2 P. J. Johnson,1,2 and A. B. Rickinson1*

CRUK Institute for Cancer Studies, The University of Birmingham, Birmingham, United Kingdom,1 Department of Clinical Oncology and Sir Y. K. Pao Cancer Centre, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong2

Received 24 March 2003/ Accepted 30 July 2003

An individual's CD8+-cytotoxic-T-lymphocyte (CTL) response to Epstein-Barr virus (EBV) latent cycle antigens focuses on a small number of immunodominant epitopes often presented by just one of the available HLA class I alleles; for example, HLA-A11-positive Caucasians frequently respond to two immunodominant HLA A11 epitopes, IVTDFSVIK (IVT) and AVFDRKSDAK (AVF), within the nuclear antigen EBNA3B. Here, we reexamine the spectrum of EBV strains present in the highly HLA-A11-positive Chinese population for sequence changes in these epitopes relative to the Caucasian type 1 prototype strain B95.8. The IVT epitope was altered in 61 of 64 Chinese type 1 viruses, with four different sequence variants being observed, and the AVF epitope was altered in 46 cases with six different sequence variants; by contrast, all 10 Chinese type 2 viruses retained the prototype 2 epitope sequences. All but one of the type 1 epitope variants were poorly recognized by IVT- or AVF-specific CTLs in pulse-chase assays of peptide-mediated target cell lysis. More importantly, we screened HLA-A11-positive Chinese donors carrying viruses with known epitope mutations for evidence of epitope-specific CTL memory by enzyme-linked immunospot assays: none of the type 1 variants tested, nor the type 2 prototype, appeared to be immunogenic in vivo. The data remain consistent with the possibility that, during virus-host coevolution, pressure from the host CTL-mediated immune response has given A11 epitope-loss viruses a selective advantage.

* Corresponding author. Mailing address: Cancer Research United Kingdom Institute for Cancer Studies, The University of Birmingham, Vincent Dr., Edgbaston, Birmingham B15 2TT, United Kingdom. Phone: 44-121-414-4492. Fax: 44-121-414-4486. E-mail: A.B.Rickinson{at}bham.ac.uk.

Journal of Virology, November 2003, p. 11507-11516, Vol. 77, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.21.11507-11516.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





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