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However, the antiviral defense evolved as a transient, acute phase response and the effects of persistently ongoing stimulation onto cellular homeostasis are not well understood. To study the consequences of long-term innate immune activation, we expressed the NS5B polymerase of Hepatitis C virus (HCV), which in absence of viral genomes continuously produces immune-stimulatory RNAs. Surprisingly, within 3 weeks, NS5B expression declined and the innate immune response ceased. Proteomics and functional analyses indicated a reduced proliferation of those cells most strongly stimulated, which was independent of interferon signaling but required mitochondrial antiviral signaling protein (MAVS) and interferon regulatory factor 3 (IRF3). Depletion of MAVS or IRF3, or overexpression of the MAVS-inactivating HCV NS3\/4A protease not only blocked interferon responses but also restored cell growth in NS5B expressing cells. However, pan-caspase inhibition could not rescue the NS5B-induced cytostasis. Our results underline an active counter selection of cells with prolonged innate immune activation, which likely constitutes a cellular strategy to prevent persistent virus infections.<\/jats:p>","DOI":"10.3390\/v12060635","type":"journal-article","created":{"date-parts":[[2020,6,12]],"date-time":"2020-06-12T05:02:24Z","timestamp":1591938144000},"page":"635","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Persistent Innate Immune Stimulation Results in IRF3-Mediated but Caspase-Independent Cytostasis"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4080-2468","authenticated-orcid":false,"given":"Christian","family":"Urban","sequence":"first","affiliation":[{"name":"Institute of Virology, School of Medicine, Technical University of Munich, 81675 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hendrik","family":"Welsch","sequence":"additional","affiliation":[{"name":"Research Group \u201cDynamics of Early Viral Infection and the Innate Antiviral Response\u201d, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Faculty of Biosciences, Heidelberg University, 69117 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1940-7727","authenticated-orcid":false,"given":"Katharina","family":"Heine","sequence":"additional","affiliation":[{"name":"Research Group \u201cDynamics of Early Viral Infection and the Innate Antiviral Response\u201d, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"W\u00fcst","sequence":"additional","affiliation":[{"name":"Research Group \u201cDynamics of Early Viral Infection and the Innate Antiviral Response\u201d, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5543-4875","authenticated-orcid":false,"given":"Darya A.","family":"Haas","sequence":"additional","affiliation":[{"name":"Institute of Virology, School of Medicine, Technical University of Munich, 81675 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6441-3099","authenticated-orcid":false,"given":"Christopher","family":"D\u00e4chert","sequence":"additional","affiliation":[{"name":"Research Group \u201cDynamics of Early Viral Infection and the Innate Antiviral Response\u201d, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"},{"name":"Faculty of Biosciences, Heidelberg University, 69117 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aparna","family":"Pandey","sequence":"additional","affiliation":[{"name":"Research Group \u201cDynamics of Early Viral Infection and the Innate Antiviral Response\u201d, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0166-1367","authenticated-orcid":false,"given":"Andreas","family":"Pichlmair","sequence":"additional","affiliation":[{"name":"Institute of Virology, School of Medicine, Technical University of Munich, 81675 Munich, Germany"},{"name":"German Center for Infection Research (DZIF), Munich Partner Site, 81675 Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco","family":"Binder","sequence":"additional","affiliation":[{"name":"Research Group \u201cDynamics of Early Viral Infection and the Innate Antiviral Response\u201d, Division Virus-Associated Carcinogenesis (F170), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/nri3581","article-title":"Regulation of type I interferon responses","volume":"14","author":"Ivashkiv","year":"2013","journal-title":"Nat. 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