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Sensors of double-stranded RNA (dsRNA) are known to detect replication intermediates of RNA viruses. It has long been suggested that annealing of mRNA from symmetrical transcription of both top and bottom strands of DNA virus genomes can produce dsRNA during infection. Supporting this hypothesis, nearly all DNA viruses encode inhibitors of dsRNA-recognition pathways. However, direct evidence that DNA viruses produce dsRNA is lacking. Contrary to dogma, we show that the nuclear-replicating DNA virus adenovirus (AdV) does not produce detectable levels of dsRNA during infection. In contrast, abundant dsRNA is detected within the nucleus of cells infected with AdV mutants defective for viral RNA processing. In the presence of nuclear dsRNA, the cytoplasmic dsRNA sensor PKR is relocalized and activated within the nucleus. Accumulation of viral dsRNA occurs in the late phase of infection, when unspliced viral transcripts form intron\/exon base pairs between top and bottom strand transcripts. We propose that DNA viruses actively limit dsRNA formation by promoting efficient splicing and mRNA processing, thus avoiding detection and restriction by host innate immune sensors of pathogenic nucleic acids.<\/jats:p>","DOI":"10.1093\/nar\/gkab896","type":"journal-article","created":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T21:22:36Z","timestamp":1633728156000},"page":"1201-1220","source":"Crossref","is-referenced-by-count":26,"title":["Adenovirus prevents dsRNA formation by promoting efficient splicing of viral RNA"],"prefix":"10.1093","volume":"50","author":[{"given":"Alexander M","family":"Price","sequence":"first","affiliation":[{"name":"Division of Protective Immunity, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert T","family":"Steinbock","sequence":"additional","affiliation":[{"name":"Division of Protective Immunity, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA"},{"name":"Cell & Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Di","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1463-3111","authenticated-orcid":false,"given":"Katharina\u00a0E","family":"Hayer","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yize","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christin","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Division of Protective Immunity, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA"},{"name":"Cell & Molecular Biology Graduate Group, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas\u00a0A","family":"Parenti","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jillian\u00a0N","family":"Whelan","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan\u00a0R","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9713-167X","authenticated-orcid":false,"given":"Matthew\u00a0D","family":"Weitzman","sequence":"additional","affiliation":[{"name":"Division of Protective Immunity, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA"},{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,10,21]]},"reference":[{"key":"2022022200005142600_B1","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/nrmicro.2016.45","article-title":"Viral evasion of intracellular DNA and RNA sensing","volume":"14","author":"Chan","year":"2016","journal-title":"Nat. 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