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We found that preformed US28 was rapidly delivered to monocytes by HCMV viral particles, whereas the de novo synthesis of 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 infection able to produce progeny virus. Infection with US28\u0394 HCMV resulted in the phosphorylation of the serine and threonine kinase Akt at Ser\n            <jats:sup>473<\/jats:sup>\n            and Thr\n            <jats:sup>308<\/jats:sup>\n            , in contrast with the phosphorylation of Akt only at Ser\n            <jats:sup>473<\/jats:sup>\n            after WT viral infection. Inhibiting the dual phosphorylation of Akt prevented the lytic replication of US28\u0394, and ectopic expression of a constitutively phosphorylated Akt variant triggered lytic replication of wild-type HCMV. Mechanistically, we found that US28 was necessary and sufficient to attenuate epidermal growth factor receptor (EGFR) signaling induced during the entry of WT virus, which led to the site-specific phosphorylation of Akt at Ser\n            <jats:sup>473<\/jats:sup>\n            . Thus, particle-delivered US28 fine-tunes Akt activity by limiting HCMV-induced EGFR activation during viral entry, enabling quiescent infection in monocytes.\n          <\/jats:p>","DOI":"10.1126\/scisignal.adn8727","type":"journal-article","created":{"date-parts":[[2024,8,27]],"date-time":"2024-08-27T17:58:40Z","timestamp":1724781520000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":10,"title":["Delivery of US28 by incoming HCMV particles rapidly attenuates Akt activity to suppress HCMV lytic replication in monocytes"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3091-2046","authenticated-orcid":true,"given":"Jamil","family":"Mahmud","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2032-5323","authenticated-orcid":true,"given":"Brittany W.","family":"Geiler","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juthi","family":"Biswas","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6523-8974","authenticated-orcid":true,"given":"Michael J.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5371-8361","authenticated-orcid":true,"given":"Julia E.","family":"Myers","sequence":"additional","affiliation":[{"name":"Infection Biology, Lerner Research Institute, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Cleveland Clinic, Cleveland, OH 44195, USA."},{"name":"Case Comprehensive Cancer Center, Cleveland, OH 44106, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8968-225X","authenticated-orcid":true,"given":"Stephen M.","family":"Matthews","sequence":"additional","affiliation":[{"name":"Infection Biology, Lerner Research Institute, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Cleveland Clinic, Cleveland, OH 44195, USA."},{"name":"Case Comprehensive Cancer Center, Cleveland, OH 44106, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7712-6259","authenticated-orcid":true,"given":"Amanda B.","family":"Wass","sequence":"additional","affiliation":[{"name":"Infection Biology, Lerner Research Institute, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Cleveland Clinic, Cleveland, OH 44195, USA."},{"name":"Case Comprehensive Cancer Center, Cleveland, OH 44106, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4943-3774","authenticated-orcid":true,"given":"Christine M.","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Infection Biology, Lerner Research Institute, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Cleveland Clinic, Cleveland, OH 44195, USA."},{"name":"Case Comprehensive Cancer Center, Cleveland, OH 44106, USA."},{"name":"Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8209-9777","authenticated-orcid":true,"given":"Gary C.","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse, NY 13210, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1002\/rmv.655"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2012.04.002"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1086\/508173"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0191482"},{"key":"e_1_3_2_6_2","doi-asserted-by":"crossref","first-page":"e0176160","DOI":"10.1371\/journal.pone.0176160","article-title":"Human cytomegalovirus glycoprotein polymorphisms and increasing viral load in AIDS patients","volume":"12","author":"Jiang X. 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