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To propagate within the host organism, HSV-1 has evolved several strategies to subvert the host immune response. Due to the pivotal role of dendritic cells (DCs), bridging innate and adaptive immunity and activating na\u00efve T cells, they represent an attractive target for HSV-1-triggered immune regulation. Here, we report a novel HSV-1-mediated mechanism of signal transducer and activator of transcription 3 (STAT3) dysregulation in human monocyte-derived mature DCs (mDCs). Due to STAT3\u2019s antiviral activity, STAT3 was shown to be modulated by viruses to efficiently replicate in several different cell types, however, not in DCs. We show that HSV-1 infection of mDCs leads to diminished total STAT3 expression and STAT3 phosphorylation (pSTAT3), as well as downregulation of\n                    <jats:italic>STAT3<\/jats:italic>\n                    mRNA very early upon infection. Protein downregulation of STAT3 could be verified by label-free mass spectrometric analysis of HSV-1- and HSV-2-infected mDCs. We found that two viral proteins, the tegument protein virion host shutoff (vhs) and the immediate-early protein ICP27, contribute to STAT3 protein downregulation upon HSV-1 infection. However, HSV-1 \u0394vhs and \u0394ICP27 deletion strains still inhibited pSTAT3 in infected mDCs, suggesting that different viral proteins impair STAT3 phosphorylation and total STAT3. Moreover, STAT3 protein levels were degraded in a proteasome-dependent but apoptosis-independent manner. Taken together, we demonstrate that HSV-1 downregulates STAT3 in HSV-1-infected human mDCs at the transcript, protein and phosphorylation levels. Downregulation of STAT3 protein depended on vhs and the proteasome, very likely to shape DC function for immune evasion and modulation.\n                  <\/jats:p>","DOI":"10.1099\/jgv.0.002280","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T16:15:31Z","timestamp":1786551331000},"source":"Crossref","is-referenced-by-count":0,"title":["Herpes simplex virus type 1 interferes with signal transducer and activator of transcription 3 expression in infected mature dendritic cells"],"prefix":"10.1099","volume":"107","author":[{"given":"Alexandra","family":"Birzer","sequence":"first","affiliation":[{"name":"Harald zur Hausen Institute of Virology, Uniklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU), Erlangen, Germany"},{"name":"Department of Immune Modulation, Uniklinikum Erlangen, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg (FAU), Erlangen, 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