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Epstein–Barr virus strain heterogeneity impairs human T-cell immunity

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Abstract

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.

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Abbreviations

EBNA:

Epstein–Barr virus nuclear antigen

EBV:

Epstein–Barr virus

GA:

Glycine–alanine

His6 :

Hexahistidine tag

IFN-γ:

Interferon-gamma

LCL:

Lymphoblastoid B-cell line

LMP:

Latent membrane protein

NPC:

Nasopharyngeal carcinoma

PTLD:

Post-transplant lymphoproliferative disease

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Acknowledgements

The excellent technical support by Grit Müller-Neumann and Dorothea Seubert is greatly appreciated.

Funding

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.

Author information

Authors and Affiliations

  1. Children’s Hospital, Technische Universität München, Munich, Germany

    Ana Cirac, Dinesh Adhikary, Uta Behrends & Josef Mautner

  2. Research Unit Gene Vectors, Helmholtz Zentrum München, Marchionini Strasse 25, 81377, Munich, Germany

    Ana Cirac, Dinesh Adhikary, Uta Behrends & Josef Mautner

  3. German Centre for Infection Research (DZIF), Partner Site Munich, Munich, Germany

    Ana Cirac, Dinesh Adhikary, Nina Körber, Tanja Bauer, Henri-Jacques Delecluse, Uta Behrends & Josef Mautner

  4. Institute of Virology, Technische Universität München/Helmholtz Zentrum München, Munich, Germany

    Simon Stützle, Nina Körber & Tanja Bauer

  5. Department of Diagnostic and Interventional Radiology, Technische Universität München, Munich, Germany

    Michael Dieckmeyer

  6. DZIF Research Group Host Control of Viral Latency and Reactivation, Helmholtz Zentrum München, Munich, Germany

    Andreas Moosmann

  7. Laboratory of Immunogenetics, Ludwig-Maximilians Universität, Munich, Germany

    Klaus Witter

  8. German Cancer Research Center (DKFZ) Unit F100 and Institut National de la Santé et de la Recherche Médicale Unit U1074, Heidelberg, Germany

    Henri-Jacques Delecluse

Authors
  1. Ana Cirac
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  2. Simon Stützle
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  3. Michael Dieckmeyer
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  4. Dinesh Adhikary
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  5. Andreas Moosmann
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  6. Nina Körber
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  7. Tanja Bauer
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  8. Klaus Witter
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  9. Henri-Jacques Delecluse
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  10. Uta Behrends
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  11. Josef Mautner
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Contributions

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.

Corresponding author

Correspondence to Josef Mautner.

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Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

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.

Additional information

Josef Mautner and Uta Behrends are joint senior authors.

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Cirac, A., Stützle, S., Dieckmeyer, M. et al. Epstein–Barr virus strain heterogeneity impairs human T-cell immunity. Cancer Immunol Immunother 67, 663–674 (2018). https://doi.org/10.1007/s00262-018-2118-z

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