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We found virion-associated US28 was rapidly delivered to monocytes, while\n                  <jats:italic>de novo<\/jats:italic>\n                  synthesized US28 was delayed for several days. A recombinant mutant virus lacking US28 (US28\u0394) was unable to establish a quiescent infection, resulting in a fully productive lytic replication cycle. Mechanistically, viral entry of US28\u0394 phosphorylated Akt at both serine 473 (S473) and threonine 308 (T308), which contrasted with the site-specific phosphorylation of Akt at S473 following WT infection. Preventing Akt bi-phosphorylation prevented lytic replication of US28\u0394, and ectopic expression of a constitutively phosphorylated Akt variant triggered lytic replication of WT infection. Our data demonstrate that virion-delivered US28 fine-tunes Akt activity to permit HCMV infection to enter a quiescent state following primary infection of monocytes.\n                <\/jats:p>","DOI":"10.1101\/2023.09.05.556359","type":"posted-content","created":{"date-parts":[[2023,9,6]],"date-time":"2023-09-06T00:00:33Z","timestamp":1693958433000},"source":"Crossref","is-referenced-by-count":2,"title":["Virion-associated US28 rapidly modulates Akt activity to suppress HCMV lytic replication in monocytes"],"prefix":"10.64898","author":[{"given":"Jamil","family":"Mahmud","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brittany W.","family":"Geiler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juthi","family":"Biswas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5371-8361","authenticated-orcid":false,"given":"Julia E.","family":"Myers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8968-225X","authenticated-orcid":false,"given":"Stephen M.","family":"Matthews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7712-6259","authenticated-orcid":false,"given":"Amanda B.","family":"Wass","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4943-3774","authenticated-orcid":false,"given":"Christine M.","family":"O\u2019Connor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8209-9777","authenticated-orcid":false,"given":"Gary C.","family":"Chan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023090807300955000_2023.09.05.556359v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.655"},{"key":"2023090807300955000_2023.09.05.556359v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2012.04.002"},{"key":"2023090807300955000_2023.09.05.556359v1.3","doi-asserted-by":"publisher","DOI":"10.1086\/508173"},{"key":"2023090807300955000_2023.09.05.556359v1.4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0191482"},{"key":"2023090807300955000_2023.09.05.556359v1.5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0176160"},{"key":"2023090807300955000_2023.09.05.556359v1.6","doi-asserted-by":"crossref","unstructured":"W. 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