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While in patients with late stage of Kaposi\u2019s sarcoma the majority of spindle cells are KSHV-infected, viral copies are rapidly lost in vitro, both upon culture of tumor-derived cells or from newly infected endothelial cells. We addressed this discrepancy by investigating a KSHV-infected endothelial cell line in various culture conditions and in tumors of xenografted mice. We show that, in contrast to two-dimensional endothelial cell cultures, KSHV genomes are maintained under 3D cell culture conditions and in vivo. Additionally, an increased rate of newly infected cells was detected in 3D cell culture. Furthermore, we show that the PI3K\/Akt\/mTOR and ATM\/\u03b3H2AX pathways are modulated and support an improved KSHV persistence in 3D cell culture. These mechanisms may contribute to the persistence of KSHV in tumor tissue in vivo and provide a novel target for KS specific therapeutic interventions.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Key messages<\/jats:title>\n                <jats:p><jats:list list-type=\"bullet\">\n                  <jats:list-item>\n                    <jats:p>In vivo maintenance of episomal KSHV can be mimicked in 3D spheroid cultures<\/jats:p>\n                  <\/jats:list-item>\n                  <jats:list-item>\n                    <jats:p>3D maintenance of KSHV is associated with an increased de novo infection frequency<\/jats:p>\n                  <\/jats:list-item>\n                  <jats:list-item>\n                    <jats:p>PI3K\/Akt\/mTOR and ATM\/ \u03b3H2AX pathways contribute to viral maintenance<\/jats:p>\n                  <\/jats:list-item>\n                <\/jats:list><\/jats:p>\n              <\/jats:sec>","DOI":"10.1007\/s00109-020-02020-8","type":"journal-article","created":{"date-parts":[[2021,1,23]],"date-time":"2021-01-23T07:03:23Z","timestamp":1611385403000},"page":"425-438","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["3D culture conditions support Kaposi\u2019s sarcoma herpesvirus (KSHV) maintenance and viral spread in endothelial cells"],"prefix":"10.1007","volume":"99","author":[{"given":"Tatyana","family":"Dubich","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Dittrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristine","family":"Bousset","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Geffers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guntram","family":"B\u00fcsche","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"K\u00f6ster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hansj\u00f6rg","family":"Hauser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas F.","family":"Schulz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2541-6251","authenticated-orcid":false,"given":"Dagmar","family":"Wirth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,23]]},"reference":[{"key":"2020_CR1","first-page":"6","volume":"3","author":"S Chakraborty","year":"2012","unstructured":"Chakraborty S, Veettil MV, Chandran B (2012) Kaposi\u2019s sarcoma associated herpesvirus entry into target cells. 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Dagmar Wirth and Hansj\u00f6rg Hauser (together with Tobias May) have filed a patent concerning the technology for establishment of conditionally immortalized cell lines (PCT\/EP2009\/004854).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Animal experiments were performed in accordance with the ethical laws. A written approval was provided by the local authorities (LAVES - Nieders\u00e4chsisches Landesamt f\u00fcr Verbraucherschutz und Lebenssicherheit, permission number 33.19-42502-04-17\/2480).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}