{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T03:59:54Z","timestamp":1788235194761,"version":"build-2803163510"},"reference-count":47,"publisher":"American Society for Microbiology","issue":"9","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2025,9,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>Human cytomegalovirus (CMV) is a ubiquitous pathogen that establishes lifelong, latent infection in hematopoietic cells. Immune-competent individuals are usually asymptomatic for disease. However, immune dysregulation in latently infected individuals can result in viral reactivation, often causing further complications. Viral gene transcription during latency is restricted, although the CMV-encoded G protein-coupled receptor homologs, US28 and UL78, are expressed. We and others find US28 is critical for establishing and maintaining viral latency, in part, through regulating host cell signaling. How US28 switches from pro-latent to pro-lytic during reactivation, however, is unknown, though our findings herein reveal a role for UL78. Myeloid cells infected with a UL78 open reading frame deletion mutant maintain viral latency yet fail to efficiently reactivate. However, the UL78 G protein-coupling domain is not required for reactivation, suggesting UL78-mediated signaling is not critical for reactivation. Prior work revealed that UL78 and US28 interact, resulting in altered US28-mediated signaling. Additionally, we showed that US28 attenuates extracellular signal-regulated kinase (ERK) phosphorylation during latency, while ERK is phosphorylated upon reactivation; however, the mechanism underlying this switch is unknown. Thus, we hypothesized the UL78:US28 interaction is important for altering US28-mediated signaling upon viral reactivation. We find US28 and UL78 interact during lytic infection of fibroblasts and colocalize in myeloid cells upon their differentiation. Furthermore, reactivation in myeloid cells latently infected with wild-type virus results in upregulated ERK phosphorylation, while parallel cultures infected with the UL78-deficient virus fail to do so. Our data reveal the first function for UL78 in myeloid cells, where it influences cellular signaling during reactivation.<\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>Cytomegalovirus (CMV) is a ubiquitous human herpesvirus, infecting the majority of the population worldwide. As with all herpesviruses, once an individual is infected with CMV, the virus remains in the person\u2019s blood cells for life in a silenced state called latency, and this infection, for the most part, remains asymptomatic. When an infected individual\u2019s immune system fails to function properly, however, CMV can become active (termed viral reactivation), which allows the virus to replicate and cause downstream disease. Our understanding of the cellular and viral factors that dictate this switch from silenced to activated remains incomplete. Here, we show a viral protein, UL78, is required for this switch. We find that UL78 helps to reshape cellular signaling, changing the cell environment from one that favors latency to one that supports reactivation. This highlights a new avenue for therapeutic intervention to prevent CMV reactivation and downstream disease.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01057-25","type":"journal-article","created":{"date-parts":[[2025,8,27]],"date-time":"2025-08-27T13:00:31Z","timestamp":1756299631000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Human cytomegalovirus-encoded G protein-coupled receptor (GPCR) UL78 regulates viral reactivation"],"prefix":"10.1128","volume":"99","author":[{"given":"Samuel A.","family":"Osanyinlusi","sequence":"first","affiliation":[{"name":"Infection Biology, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Cleveland Clinic Research, Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2882-7785","authenticated-orcid":true,"given":"Vargab","family":"Baruah","sequence":"additional","affiliation":[{"name":"Infection Biology, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Cleveland Clinic Research, Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8882-6701","authenticated-orcid":true,"given":"Ian J.","family":"Groves","sequence":"additional","affiliation":[{"name":"Infection Biology, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Cleveland Clinic Research, Cleveland Clinic","place":["Cleveland, USA"]},{"id":[{"id":"https:\/\/ror.org\/00fpjq451","id-type":"ROR","asserted-by":"publisher"}],"name":"Case Comprehensive Cancer Center","place":["Cleveland, USA"]},{"id":[{"id":"https:\/\/ror.org\/02x4b0932","id-type":"ROR","asserted-by":"publisher"}],"name":"Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine H.","family":"Kulp","sequence":"additional","affiliation":[{"name":"Infection Biology, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Cleveland Clinic Research, Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin A.","family":"Krishna","sequence":"additional","affiliation":[{"name":"Infection Biology, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Cleveland Clinic Research, Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4943-3774","authenticated-orcid":true,"given":"Christine M.","family":"O'Connor","sequence":"additional","affiliation":[{"name":"Infection Biology, Sheikha Fatima bint Mubarak Global Center for Pathogen and Human Health Research, Cleveland Clinic Research, Cleveland Clinic","place":["Cleveland, USA"]},{"id":[{"id":"https:\/\/ror.org\/00fpjq451","id-type":"ROR","asserted-by":"publisher"}],"name":"Case Comprehensive Cancer Center","place":["Cleveland, USA"]},{"id":[{"id":"https:\/\/ror.org\/02x4b0932","id-type":"ROR","asserted-by":"publisher"}],"name":"Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic","place":["Cleveland, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2021.692226"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12889-022-13971-7"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-021-00582-z"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2023.1276912"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.aivir.2022.01.001"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00741-16"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1900783116"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2009420117"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1099\/jgv.0.001894"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens9110869"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1710522114"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.110653"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00013-18"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","unstructured":"Collins-McMillen D De Oliveira Pessoa D Zarrella K Parkins CJ Daily M Moorman NJ Kamil JP Caposio P Padi M Goodrum FD. 2024. 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