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In order to gain insights into this synergy, we investigated HLA\u2010DR15 positive human immune compartments after reconstitution in immune\u2010compromised mice (humanized mice) with and without EBV infection. We detected elevated activation of both CD4\n                    <jats:sup>+<\/jats:sup>\n                    and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in HLA\u2010DR15 donor\u2010reconstituted humanized mice at steady state, even when compared to immune compartments carrying HLA\u2010DRB1*04:01 (HLA\u2010DR4), which is associated with other autoimmune diseases. Increased CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell expansion and activation was also observed in HLA\u2010DR15 donor\u2010reconstituted humanized mice after EBV infection. Despite this higher immune activation, EBV viral loads were less well controlled in the context of HLA\u2010DR15. Indeed, HLA\u2010DR15\u2010restricted CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell clones recognized EBV\u2010transformed B cell lines less efficiently and demonstrated cross\u2010reactivity toward allogeneic target cells and one MS autoantigen. These findings suggest that EBV as one of the main environmental risk factors and HLA\u2010DR15 as the main genetic risk factor for MS synergize by priming hyperreactive T\u2010cell compartments, which then control the viral infection less efficiently and contain cross\u2010reactive CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell clones.\n                  <\/jats:p>","DOI":"10.1002\/eji.202048655","type":"journal-article","created":{"date-parts":[[2020,9,19]],"date-time":"2020-09-19T13:49:36Z","timestamp":1600523376000},"page":"64-75","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":110,"title":["Attenuated immune control of Epstein\u2013Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA\u2010DR15"],"prefix":"10.1002","volume":"51","author":[{"given":"Hana","family":"Zdimerova","sequence":"first","affiliation":[{"name":"Viral Immunobiology Institute of 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G.Martino  Messina Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccarda","family":"Capaul","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology University of Z\u00fcrich  Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Zbinden","sequence":"additional","affiliation":[{"name":"Institute of Medical Virology University of Z\u00fcrich  Z\u00fcrich Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3874-8554","authenticated-orcid":false,"given":"Guido","family":"Ferlazzo","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology and Biotherapy Department of Human Pathology University of Messina  Messina Italy"},{"name":"Cell Factory Center University of Messina  Messina Italy"},{"name":"Cell Therapy Program University Hospital Policlinico G.Martino  Messina Italy"},{"name":"Division of Clinical Pathology 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