{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:30:36Z","timestamp":1791221436993,"version":"4.1.0"},"reference-count":84,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007378","name":"Italian Multiple Sclerosis Foundation","doi-asserted-by":"publisher","award":["2022\/R-Single\/006"],"award-info":[{"award-number":["2022\/R-Single\/006"]}],"id":[{"id":"10.13039\/100007378","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Union\u2019s Horizon Europe Research and Innovation Actions","doi-asserted-by":"publisher","award":["101137235"],"award-info":[{"award-number":["101137235"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Epstein-Barr virus (EBV) infection shows the strongest causative association with multiple sclerosis (MS), but its contribution to disease progression and the mechanisms allowing for viral persistence in the MS brain are still elusive. Studies in post-mortem MS brain tissue indicate an ongoing yet ineffective antiviral immune reaction in advanced stages of the disease. EBV has evolved strategies to evade immune recognition and clearance by the host immune system during both the latency and lytic phase of its life cycle. Recent evidence demonstrates that cells expressing EBV latent membrane protein (LMP) 2A exploit the PD-1\/PDL1 inhibitory immune checkpoint to escape immune surveillance and maintain a persistent latent infection in the MS brain. This study investigated whether the virus also utilizes this inhibitory mechanism during other phases of the viral life cycle. By using multiple immunostainings on highly inflamed MS brain tissues containing meningeal tertiary lymphoid structures (TLSs), we analyzed PD-L1 expression on EBV-infected cells expressing EBNA2, five EBV lytic gene products, BZLF1, BHRF1, BMRF1, BALF2, and gp350\/220, as well as on follicular dendritic cells within the TLSs. This is the first study describing in secondary progressive MS brain tissue the expression and the cellular and tissue distribution of PD-L1 on EBV-infected cells being in different stages of the viral life cycle, and confirms the meningeal TLSs as immune-permissive habitats favoring the maintenance of an intracerebral EBV reservoir.<\/jats:p>","DOI":"10.3390\/ijms27010437","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T16:08:00Z","timestamp":1767197280000},"page":"437","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["EBV Early Lytic Antigens, EBNA2 and PDL-1, in Progressive Multiple Sclerosis Brain: A Coordinated Contribution to Viral Immune Evasion"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-8482-8334","authenticated-orcid":false,"given":"Lucia","family":"Benincasa","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9945-1527","authenticated-orcid":false,"given":"Barbara","family":"Rosicarelli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9897-080X","authenticated-orcid":false,"given":"Chiara","family":"Meloni","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6853-1161","authenticated-orcid":false,"given":"Barbara","family":"Serafini","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Istituto Superiore di Sanit\u00e0, Viale Regina Elena 299, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1111\/j.1750-3639.2004.tb00049.x","article-title":"Detection of ectopic B cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis","volume":"14","author":"Serafini","year":"2004","journal-title":"Brain Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1089","DOI":"10.1093\/brain\/awm038","article-title":"Meningeal B cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology","volume":"130","author":"Magliozzi","year":"2007","journal-title":"Brain"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2066","DOI":"10.1093\/brain\/awy151","article-title":"The compartmentalized inflammatory response in the multiple sclerosis brain is composed of tissue-resident CD8+ T lymphocytes and B cells","volume":"141","author":"Saji","year":"2018","journal-title":"Brain"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"578314","DOI":"10.1016\/j.jneuroim.2024.578314","article-title":"EBV infected cells in the multiple sclerosis brain express PD-L1: How the virus and its niche may escape immune surveillance","volume":"389","author":"Serafini","year":"2024","journal-title":"J. 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