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Epstein–Barr Virus Infection in Humanized Mice

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Abstract

Epstein–Barr virus (EBV) is a lymphotropic herpes virus associated with a variety of diseases including infectious mononucleosis, lymphoproliferative diseases, and malignant diseases such as Burkitt lymphoma and Hodgkin lymphoma. EBV is also implicated in various autoimmune diseases. Humans are the only natural host of EBV and small animal models of EBV infection have not been available, although a few new-world monkeys can be infected with the virus experimentally. Humanized mice harboring functioning human lymphocytes can be readily infected with EBV and have reproduced cardinal features associated with human EBV infection, including lymphoproliferative disease, hemophagocytic lymphohistiocytosis, erosive arthritis resembling rheumatoid arthritis, and asymptomatic persistent infection. EBV-specific T-cell responses are induced in humanized mice that protect them from uncontrolled proliferation of EBV-infected cells. Chronic active EBV infection, an EBV-associated T/NK lymphoproliferative disease, that could not be reproduced in humanized mice, has been recapitulated by xenogeneic transplantation of patient’s peripheral blood mononuclear cells to NOG mice. This chapter summarizes features of human EBV infection that were reproduced in humanized mouse models and mouse xenograft models, and shows how they have been utilized to analyze EBV pathogenesis and normal and aberrant human immune responses to the virus.

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Abbreviations

EBV:

Epstein–Barr virus

IM:

Infectious mononucleosis

LPD:

Lymphoproliferative disease

RA:

Rheumatoid arthritis

LCL:

Lymphoblastoid cell line

CTL:

Cytotoxic T lymphocyte

EBNA:

EBV nuclear antigen

LMP:

Latent membrane protein

EBER:

EBV-encoded small RNA

BART:

BamHI-A rightward transcript

CAEBV:

Chronic active EBV infection

PBMC:

Peripheral blood mononuclear cells

HSC:

Hematopoietic stem cell

HLH:

Hemophagocytic lymphohistiocytosis

XLP:

X-linked lymphoproliferative disease

HA:

Hemagglutinin

NOG:

NOD/Shi-scid Il2rg null

BRG:

Balb/c Rag2 -/- Il2rg -/-

NSG:

NOD/LtSz-scid Il2rg -/-

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Acknowledgments

This study was supported by grants from the Ministry of Health, Labour and Welfare of Japan (H24-Nanchi-046 and H22-AIDS-I-002), the Grant of National Center for Child Health and Development (25-9), a grant for the Research on Publicly Essential Drugs and Medical Devices from The Japan Health Sciences Foundation (KHD1221), and the Grant-in-Aid for Scientific Research (C) (H22-22590430).

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Authors and Affiliations

  1. Department of Infectious Diseases, National Research Institute for Child Health and Development, 157-8535, Tokyo, Japan

    Shigeyoshi Fujiwara, Go Matsuda & Ken-Ichi Imadome

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  1. Shigeyoshi Fujiwara
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  2. Go Matsuda
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  3. Ken-Ichi Imadome
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Correspondence to Shigeyoshi Fujiwara .

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Editors and Affiliations

  1. Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA

    Larisa Y. Poluektova

  2. Center for AIDS Research, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

    J. Victor Garcia

  3. Research Center for AIDS Laboratory of Viral Pathogenesis, Kyoto University Institute for Virus Research, Sakyo-ku, Japan

    Yoshio Koyanagi

  4. Division of Hematology, University Hospital Zürich, Zürich, Switzerland

    Markus G. Manz

  5. Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA

    Andrew M. Tager

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Fujiwara, S., Matsuda, G., Imadome, KI. (2014). Epstein–Barr Virus Infection in Humanized Mice. In: Poluektova, L., Garcia, J., Koyanagi, Y., Manz, M., Tager, A. (eds) Humanized Mice for HIV Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1655-9_39

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