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Latency is observed in most tumor cells of the 200,000 EBV-associated cancers\/year. EBV reactivation is increasingly implicated in autoimmune diseases, including multiple sclerosis. However, mechanisms that regulate EBV reactivation have remained incompletely understood. Here, we leveraged multi-omic approaches to reveal the existence of pro-latency and a pro-lytic viral long noncoding RNAs (lncRNAs) that counter-regulate the lytic switch. Known reactivation triggers rapidly induced expression of the pro-lytic lncRNA, which encodes an RNA G-quadruplex that mediated its interaction with CTCF. The pro-lytic lncRNA occupies viral origin of lytic replication enhancers and promotes their looping to the immediate early lytic promoter to trigger reactivation. The pro-latency lncRNA duplexes with the pro-lytic RNA to impede its interactions with CTCF. These studies lay a foundation for therapeutic approaches to manipulate the EBV lytic switch.<\/jats:p>","DOI":"10.1101\/2025.10.29.685446","type":"posted-content","created":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T02:45:20Z","timestamp":1761878720000},"source":"Crossref","is-referenced-by-count":2,"title":["Epstein-Barr Virus Encoded lncRNAs Control the Viral Lytic 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