{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T15:30:43Z","timestamp":1789659043788,"version":"4.0.1"},"reference-count":40,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"University of Mississippi Medical Center","id":[{"id":"https:\/\/ror.org\/044pcn091","id-type":"ROR","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/044pcn091","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Programmed necrotic cell death (necroptosis) is a key antiviral defense pathway, yet its regulation during human cytomegalovirus (HCMV) infection remains incompletely defined in physiologically relevant cell types. The M45 protein of murine cytomegalovirus, a homologue of UL45, inhibits necroptosis and contributes to MCMV dissemination, providing a rationale for examining UL45 in HCMV. Previous studies of UL45 have largely relied only on fibroblasts or immortalized cell lines, which lack the necroptotic machinery necessary to reveal viral anti-necroptotic functions. To investigate the role of the HCMV UL45 protein, we generated a UL45 stop-frameshift mutant (UL45st) in the TB40E strain and compared its phenotype to that of the wild-type virus in primary human fibroblasts and monocyte-derived macrophages. In parallel, transfection-based assays in RIPK3-competent HT29 cells were used to assess the intrinsic cell-death-inhibitory activity of UL45. UL45st-infected primary macrophages exhibited significantly reduced numbers of viable cells and showed morphological features suggesting necroptotic death compared to wild-type-infected cells, whereas infected fibroblasts showed only modest defects. Expression of UL45 alone in HT29 cells partially protected cells from both apoptotic and RIPK3-dependent necroptotic stimuli, indicating a direct anti-death function of the protein. These findings demonstrate that HCMV UL45 promotes cellular survival in primary human macrophages and reveal that this function is likely associated with RIPK3-associated cell death. Collectively, this work identifies a never-before-shown function of HCMV UL45 as a key determinant of viral survival in myeloid compartment cells and underscores the importance of using physiologically relevant models to uncover cell-type-specific viral immune evasion mechanisms.<\/jats:p>","DOI":"10.3390\/v18091033","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T08:03:17Z","timestamp":1789632197000},"page":"1033","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["UL45 of Human Cytomegalovirus Promotes Macrophage Survival and Modulates RIPK3-Associated Cell Death"],"prefix":"10.3390","volume":"18","author":[{"given":"Christian S.","family":"Yu","sequence":"first","affiliation":[{"name":"Center for Immunology and Microbial Research, Jackson, MS 39216, USA"},{"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Komal","family":"Beeton","sequence":"additional","affiliation":[{"name":"Center for Immunology and Microbial Research, Jackson, MS 39216, USA"},{"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa P.","family":"Daley-Bauer","sequence":"additional","affiliation":[{"name":"Pathology Advanced Translational Research Unit, Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5166-8284","authenticated-orcid":false,"given":"Stephen J.","family":"Stray","sequence":"additional","affiliation":[{"name":"Center for Immunology and Microbial Research, Jackson, MS 39216, USA"},{"name":"Department of Cell and Molecular Biology, University of Mississippi Medical Center, Jackson, MS 39216, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1089\/vim.2022.0010","article-title":"Pathway of cell death and its role in virus infection","volume":"35","author":"Chen","year":"2022","journal-title":"Viral Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1152\/physrev.00002.2021","article-title":"The evolution of regulated cell death pathways in animals and their evasion by pathogens","volume":"102","author":"Tummers","year":"2022","journal-title":"Physiol. 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