Epstein–Barr virus strain heterogeneity impairs human T-cell immunity
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The Epstein–Barr virus (EBV) establishes lifelong infections in > 90% of the human population. Although contained as asymptomatic infection by the immune system in most individuals, EBV is associated with the pathogenesis of approximately 1.5% of all cancers in humans. Some of these EBV-associated tumors have been successfully treated by the infusion of virus-specific T-cell lines. Recent sequence analyses of a large number of viral isolates suggested that distinct EBV strains have evolved in different parts of the world. Here, we assessed the impact of such sequence variations on EBV-specific T-cell immunity. With the exceptions of EBNA2 and the EBNA3 family of proteins, an overall low protein sequence disparity of about 1% was noted between Asian viral isolates, including the newly characterized M81 strain, and the prototypic EBV type 1 and type 2 strains. However, when T-cell epitopes including their flanking regions were compared, a substantial proportion was found to be polymorphic in different EBV strains. Importantly, CD4+ and CD8+ T-cell clones specific for viral epitopes from one strain often showed diminished recognition of the corresponding epitopes in other strains. In addition, T-cell recognition of a conserved epitope was affected by amino acid exchanges within the epitope flanking region. Moreover, the CD8+ T-cell response against polymorphic epitopes varied between donors and often ignored antigen variants. These results demonstrate that viral strain heterogeneity may impair antiviral T-cell immunity and suggest that immunotherapeutic approaches against EBV should preferably target broad sets of conserved epitopes including their flanking regions.
KeywordsT-cell therapy Epstein–Barr virus Strain variation Epitope Immunity
Epstein–Barr virus nuclear antigen
Lymphoblastoid B-cell line
Latent membrane protein
Post-transplant lymphoproliferative disease
The excellent technical support by Grit Müller-Neumann and Dorothea Seubert is greatly appreciated.
U. Behrends and J. Mautner conceived and designed the study. A. Cirac, S. Stützle, M. Dieckmeyer, and D. Adhikary contributed to the acquisition, analysis, and interpretation of data. A. Cirac and M. Dieckmeyer performed the statistical analysis. A. Moosmann, N. Körber, T. Bauer, K. Witter, and H-J. Delecluse provided essential reagents and technical and material support. A. Cirac, U. Behrends and J. Mautner wrote the paper and all authors made substantial contributions to data analysis and interpretation, manuscript editing, review and approval.
This study was supported by the German Center for Infection Research - DZIF (TTU 07.804). A. Cirac was supported by the Technische Universität München (TUM) Graduate School.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Informed consent was obtained from all individual participants included in the study. All procedures involving human participants were in accordance with the ethical standards of the institutional research committee of the Technische Universität München and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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