Modeling EBV infection and pathogenesis in new-generation humanized mice

The development of highly immunodeficient mouse strains has allowed the reconstitution of functional human immune system components in mice. New-generation humanized mice generated in this manner have been extensively used for modeling viral infections that are exclusively human tropic. Epstein–Barr virus (EBV)-infected humanized mice reproduce cardinal features of EBV-associated B-cell lymphoproliferative disease and EBV-associated hemophagocytic lymphohistiocytosis (HLH). Erosive arthritis morphologically resembling rheumatoid arthritis (RA) has also been recapitulated in these mice. Low-dose EBV infection of humanized mice results in asymptomatic, persistent infection. Innate immune responses involving natural killer cells, EBV-specific adaptive T-cell responses restricted by human major histocompatibility and EBV-specific antibody responses are also elicited in humanized mice. EBV-associated T-/natural killer cell lymphoproliferative disease, by contrast, can be reproduced in a distinct mouse xenograft model. In this review, recent findings on the recapitulation of human EBV infection and pathogenesis in these mouse models, as well as their application to preclinical studies of experimental anti-EBV therapies, are described. Infections with Epstein–Barr virus (EBV) can be initiated in mice by adding components of the human immune system. EBV usually only infects humans, causing massive proliferation of some blood cells and a range of conditions including arthritis. Modeling infection in small animals such as mice would provide researchers with a tool for understanding how the virus affects the immune system and for devising ways to prevent or treat EBV infection. Shigeyoshi Fujiwara from the National Research Institute for Child Health and Development in Tokyo and colleagues review how introduction of components of the human immune system into mice results in the mice exhibiting many features of human EBV infection, including immune cell activation, blood cell abnormalities and arthritis. These advances could pave the way for therapies for EBV infection.