Published online before print October 9, 2008

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(American Journal of Pathology. 2008;173:1369-1378.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071186

CD34⁺ Cord Blood Cell-Transplanted Rag2^–/– _c^–/– Mice as a Model for Epstein-Barr Virus Infection

Mario Cocco^*, Cristiana Bellan^*, Roxane Tussiwand, Davide Corti, Elisabetta Traggiai, Stefano Lazzi^*, Susanna Mannucci^*, Lucio Bronz, Nazzareno Palummo^*, Chiara Ginanneschi^*, Piero Tosi^*, Antonio Lanzavecchia, Markus G. Manz and Lorenzo Leoncini^*

From the Department of Human Pathology and Oncology,^* Division of Pathological Anatomy, University of Siena, Siena, Italy; the Institute for Research in Biomedicine, Bellinzona, Switzerland; and Ospedale San Giovanni, Bellinzona, Switzerland

Recent studies suggest that Epstein-Barr virus (EBV) can infect naïve B cells, driving them to differentiate into resting memory B cells via the germinal center reaction. This hypothesis has been inferred from parallels with the biology of normal B cells but has never been proven experimentally. Rag2^–/– _c^–/– mice that were transplanted with human CD34⁺ cord blood cells as newborns were recently shown to develop human B, T, and dendritic cells, constituting lymphoid organs in situ. Here we used this model to better define the strategy of EBV infection of human B cells in vivo and to compare this model system with different conditions of EBV infection in humans. Our results support the model of EBV persistence in vivo in cases that were characterized by follicular hyperplasia and a relatively normal CD4⁺ and CD8⁺ T-cell distribution. Intriguingly, in cases that were characterized by nodular and diffuse proliferation with a preponderance of CD8⁺ T cells, similar to infectious mononucleosis, EBV still infects naïve B cells but also induces clonal expansion and ongoing somatic mutations without germinal center reactions. Our results reveal different strategies of EBV infection in B cells that possibly result from variations in the host immune response. Future experiments might allow understanding of the mechanisms responsible for persistent EBV infection and provide targets for more highly tailored therapeutic interventions.

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