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Longitudinal data show that EBV seroconversion precedes MS onset, while mechanistic studies identify molecular mimicry between EBV antigens and central nervous system proteins. Yet, MS treatments remain largely immunosuppressive, potentially impairing antiviral surveillance required to control EBV latency. Therapies that deplete T cells or impair lymphocyte trafficking have been linked to EBV-driven lymphoproliferative complications, potentially leading to EBV reactivation and exacerbation of MS. In contrast, B-cell\u2013depleting therapies may reduce EBV reservoirs by targeting infected memory B cells and thus be more suited to treating EBV-associated MS. In this Review, we examine the paradox of treating an EBV-associated disease with immunosuppression, highlight data suggesting EBV reactivation under certain MS therapies, and propose that future MS management may require integration of EBV-targeted strategies, including vaccines and virus-directed immunotherapies, to address the underlying viral etiology.<\/jats:p>","DOI":"10.1093\/ofid\/ofag097","type":"journal-article","created":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T12:38:04Z","timestamp":1771936684000},"source":"Crossref","is-referenced-by-count":1,"title":["The Immunosuppression Paradox in Multiple Sclerosis: Are We Fueling the Fire by Suppressing Immunity in an Epstein\u2013Barr Virus\u2013Linked Disease?"],"prefix":"10.1093","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3380-7356","authenticated-orcid":false,"given":"Anna","family":"Onisiforou","sequence":"first","affiliation":[{"name":"Department of Psychology, University of Cyprus , Nicosia ,","place":["Cyprus"]},{"name":"Psychoneuroendocrinology Laboratory, Department of Psychology, University of Wisconsin Milwaukee , Milwaukee, Wisconsin ,","place":["USA"]},{"name":"Center of Applied Neuroscience , Nicosia ,","place":["Cyprus"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"2026030607065325100_ofag097-B1","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1177\/1352458520970841","article-title":"Rising prevalence of multiple sclerosis worldwide: insights from the Atlas of MS, third edition","volume":"26","author":"Walton","year":"2020","journal-title":"Mult Scler J"},{"key":"2026030607065325100_ofag097-B2","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0140-6736(23)01473-3","article-title":"Multiple 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