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Journal of Virology, July 2003, p. 7401-7410, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7401-7410.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Ex Vivo Analysis of T-Cell Responses to Epstein-Barr Virus-Encoded Oncogene Latent Membrane Protein 1 Reveals Highly Conserved Epitope Sequences in Virus Isolates from Diverse Geographic Regions

Jaikumar Duraiswamy,1 Jacqueline M. Burrows,1 Mandvi Bharadwaj,1 Scott R. Burrows,1 Leanne Cooper,1 Nattiya Pimtanothai,2 and Rajiv Khanna1*

Cooperative Research Centre for Vaccine Technology, Tumour Immunology Laboratory, Division of Infectious Diseases and Immunology, Queensland Institute of Medical Research, and Joint Oncology Program, Department of Molecular and Cellular Pathology, University of Queensland, Brisbane, Australia 4029,1 Immunology Unit, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330 Thailand2

Received 10 October 2002/ Accepted 1 April 2003

Epstein-Barr virus (EBV)-encoded oncogene latent membrane protein (LMP) 1, which is consistently expressed in multiple EBV-associated malignancies, has been proposed as a potential target antigen for any future vaccine designed to control these malignancies. However, the high degree of genetic variation in the LMP1 sequence has been considered a major impediment for its use as a potential immunotherapeutic target for the treatment of EBV-associated malignancies. In the present study, we have employed a highly efficient strategy, based on ex vivo functional assays, to conduct an extensive sequence-wide analysis of LMP1-specific T-cell responses in a large panel of healthy virus carriers of diverse ethnic origin and nasopharyngeal carcinoma patients. By comparing the frequencies of T cells specific for overlapping peptides spanning LMP1, we mapped a number of novel HLA class I- and class II-restricted LMP1 T-cell epitopes, including an epitope with dual HLA class I restriction. More importantly, extensive sequence analysis of LMP1 revealed that the majority of the T-cell epitopes were highly conserved in EBV isolates from Caucasian, Papua New Guinean, African, and Southeast Asian populations, while unique geographically constrained genetic variation was observed within one HLA A2 supertype-restricted epitope. These findings indicate that conserved LMP1 epitopes should be considered in designing epitope-based immunotherapeutic strategies against EBV-associated malignancies in different ethnic populations.

* Corresponding author. Mailing address: Queensland Institute of Medical Research, 300 Herston Rd., Brisbane, Australia 4029. Phone: 61-7-3362 0385. Fax: 61-7-3845 3510. E-mail: rajivK{at}qimr.edu.au.

Journal of Virology, July 2003, p. 7401-7410, Vol. 77, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.13.7401-7410.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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