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Kaposi\u2019s Sarcoma-Associated Herpesvirus (KSHV) genomes associate with the viral encoded Latency-Associated Nuclear Antigen (LANA) to form stable nuclear bodies (NBs) during latent infection. Here, we show that LANA-NB formation and KSHV genome conformation involves LLPS. Using LLPS disrupting solvents, we show that LANA-NBs are partially disrupted, while DAXX and PML foci are highly resistant. LLPS disruption altered the LANA-dependent KSHV chromosome conformation but did not stimulate lytic reactivation. We found that LANA-NBs undergo major morphological transformation during KSHV lytic reactivation to form LANA-associated replication compartments encompassing KSHV DNA. DAXX colocalizes with the LANA-NBs during latency but is evicted from the LANA-associated lytic replication compartments. These findings indicate the LANA-NBs are dynamic super-molecular nuclear structures that partly depend on LLPS and undergo morphological transitions corresponding to the different modes of viral replication.<\/jats:p>","DOI":"10.1371\/journal.ppat.1009231","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T14:41:35Z","timestamp":1611153695000},"page":"e1009231","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":51,"title":["Phase separation and DAXX redistribution contribute to LANA nuclear body and KSHV genome dynamics during latency and reactivation"],"prefix":"10.1371","volume":"17","author":[{"given":"Olga","family":"Vladimirova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"De Leo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1153-7896","authenticated-orcid":true,"given":"Andreas","family":"Wiedmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5491-2975","authenticated-orcid":true,"given":"James","family":"Hayden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3935-9921","authenticated-orcid":true,"given":"Paul M.","family":"Lieberman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,1,20]]},"reference":[{"issue":"1","key":"ppat.1009231.ref001","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/s41572-019-0060-9","article-title":"Kaposi sarcoma","volume":"5","author":"E Cesarman","year":"2019","journal-title":"Nat Rev Dis Primers"},{"issue":"11","key":"ppat.1009231.ref002","doi-asserted-by":"crossref","first-page":"4258","DOI":"10.3390\/v6114258","article-title":"Twenty years of KSHV","volume":"6","author":"Y Chang","year":"2014","journal-title":"Viruses"},{"issue":"2","key":"ppat.1009231.ref003","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.tim.2019.09.002","article-title":"Control of Viral Latency by Episome Maintenance Proteins","volume":"28","author":"A De Leo","year":"2020","journal-title":"Trends 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