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Defective Epstein–Barr virus in chronic active infection and haematological malignancy

Nature Microbiology volume 4, pages 404–413 (2019)Cite this article

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A Publisher Correction to this article was published on 30 January 2019

Abstract

Epstein–Barr virus (EBV) infection is highly prevalent in humans and is implicated in various diseases, including cancer1,2. Chronic active EBV infection (CAEBV) is an intractable disease classified as a lymphoproliferative disorder in the 2016 World Health Organization lymphoma classification1,2. CAEBV is characterized by EBV-infected T/natural killer (NK) cells and recurrent/persistent infectious mononucleosis-like symptoms3. Here, we show that CAEBV originates from an EBV-infected lymphoid progenitor that acquires DDX3X and other mutations, causing clonal evolution comprising multiple cell lineages. Conspicuously, the EBV genome in CAEBV patients harboured frequent intragenic deletions (27/77) that were also common in various EBV-associated neoplastic disorders (28/61), including extranodal NK/T-cell lymphoma and EBV-positive diffuse large B-cell lymphoma, but were not detected in infectious mononucleosis or post-transplant lymphoproliferative disorders (0/47), which suggests a unique role of these mutations in neoplastic proliferation of EBV-infected cells. These deletions frequently affected BamHI A rightward transcript microRNA clusters (31 cases) and several genes that are essential for producing viral particles (20 cases). The deletions observed in our study are thought to reactivate the lytic cycle by upregulating the expression of two immediate early genes, BZLF1 and BRLF14,5,6,7, while averting viral production and subsequent cell lysis. In fact, the deletion of one of the essential genes, BALF5, resulted in upregulation of the lytic cycle and the promotion of lymphomagenesis in a xenograft model. Our findings highlight a pathogenic link between intragenic EBV deletions and EBV-associated neoplastic proliferations.

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Fig. 1: Mutational analysis of CAEBV.
Fig. 2: Clonal evolution of CAEBV.
Fig. 3: Cell origin of CAEBV.
Fig. 4: Mutational analysis of the EBV genome.
Fig. 5: Lymphomagenesis of LCLs carrying EBV with an essential gene deletion.

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Code availability

Custom codes used for the simulation of EBV deletions are available from GitHub repository (https://github.com/yusukeokuno/ebvsimulation) with no restriction on access.

Data availability

Sequence data has been deposited at the European Genome-phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001003159. Further information about EGA can be found on https://ega-archive.org and ref. 49. We also registered assembled sequences of the EBV genomes in DNA Data Bank of Japan (DDBJ; https://www.ddbj.nig.ac.jp/) under BioProject accession number PRJDB7503. The sequences can be individually via getentry (http://getentry.ddbj.nig.ac.jp/) using the accession numbers AP019012–AP019188.

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Acknowledgements

The authors would like to thank all of the subjects and families for participating in this study. The authors would like to thank N. Yoshida, M. Okada, H. Moriuchi, K. Yamamoto, S. Kamimura, Y. Horikoshi and T. Kinoshita for providing samples. The authors would also like to thank Y. Miura, Y. Imanishi, F. Ando, S. Kumagai, T. Kunogi, H. Matsuda, H.M.A. Masud and H. Namizaki for their valuable assistance. The authors acknowledge M. Nakatochi for valuable comments. The authors acknowledge the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine for technical support of cell sorting and next-generation sequencing. The authors acknowledge the Human Genome Center, the Institute of Medical Science, the University of Tokyo (http://sc.hgc.jp/shirokane.html) for providing super-computing resources. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to H.K. (grant nos 25293109 and 17H04081), grants from Japan Agency for Medical Research and Development to H.K. (grant no. JP17ek0109286) and T.M. (grant no. JP17fm0208016), a grant from the Hori Sciences and Arts Foundation and from the Ministry of Health, Labor, and Welfare of Japan to H.K. (grant no. H29-Nanchi-016).

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Author notes

  1. These authors contributed equally: Seishi Ogawa, Hiroshi Kimura.

Authors and Affiliations

  1. Center for Advanced Medicine and Clinical Research, Nagoya University Hospital, Nagoya, Japan

    Yusuke Okuno

  2. Department of Virology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Takayuki Murata, Yoshitaka Sato, Takahiro Watanabe, Yohei Narita, Masahiro Yoshida, Fumi Goshima & Hiroshi Kimura

  3. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Hideki Muramatsu, Yoshinori Ito, Tatsuya Okuno, Norihiro Murakami, Jun-ichi Kawada, Yoshiyuki Takahashi & Seiji Kojima

  4. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kenichi Yoshida & Seishi Ogawa

  5. Department of Hematology/Oncology, Osaka Women’s and Children’s Hospital, Osaka, Japan

    Akihisa Sawada, Masami Inoue & Keisei Kawa

  6. Department of Pathology, Kurume University School of Medicine, Kurume, Japan

    Masao Seto & Koichi Ohshima

  7. Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka & Satoru Miyano

  8. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Tetsuya Nishida & Hitoshi Kiyoi

  9. Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan

    Seiichi Kato & Shigeo Nakamura

  10. Division of Endocrinology, Diabetes and Metabolism, Hematology, Rheumatology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan

    Satoko Morishima

  11. Department of Pediatrics, Fujita Health University School of Medicine, Toyoake, Japan

    Tetsushi Yoshikawa

  12. Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan

    Shigeyoshi Fujiwara

  13. Center for Stem Cell and Regenerative Medicine, Division of Advanced Biomedical Engineering Research, Institute of Research, Tokyo Medical and Dental University, Tokyo, Japan

    Norio Shimizu

  14. Division of Hematology and Oncology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan

    Yasushi Isobe

  15. Department of Hematology, Juntendo University Urayasu Hospital, Urayasu, Japan

    Masaaki Noguchi

  16. Department of Pediatric Oncology, Fukushima Medical University School of Medicine, Fukushima, Japan

    Atsushi Kikuta

  17. Department of Dermatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Keiji Iwatsuki

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  1. Yusuke Okuno
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Contributions

Y.O., T.M., Y.Sato and H.M. designed and performed the research, analysed the data and wrote the paper. T.O., N.M., K.Y., Y.Shiraishi, K.C., H.T. and S.Miyano performed bioinformatics analyses of the sequencing data. Y.N., M.Y., T.W. and F.G. performed the research and analysed the data. Y.Ito, A.S., M.I., K.K., M.S., K.O., J.K., T.N., H.Kiyoi, S.Kato, S.N., S.Morishima, T.Y., S.F., N.S., Y.Isobe, M.N., A.K., K.I. and Y.T. collected specimens and clinical data. S.Kojima, S.O. and H.Kimura led the entire project and wrote the paper. All authors critically reviewed the manuscript for its content.

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Correspondence to Hiroshi Kimura.

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S.Kojima was supported by a grant from Sanofi K.K. All other authors declare no competing interests.

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Okuno, Y., Murata, T., Sato, Y. et al. Defective Epstein–Barr virus in chronic active infection and haematological malignancy. Nat Microbiol 4, 404–413 (2019). https://doi.org/10.1038/s41564-018-0334-0

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