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We previously reported that TRIM5\u03b1 derived from humans and rhesus macaques inhibits replication of orthoflaviviruses belonging to the tick-borne encephalitis virus (TBEV) serocomplex, including TBEV, Kyasanur forest disease virus and Langat virus (LGTV), but interestingly not the tick-borne Powassan virus (POWV). To further characterize the primate TRIM5\u03b1 and orthoflavivirus interface, we screened TRIM5\u03b1 variants from representative old- and new-world primates for restriction capacity. TRIM5\u03b1 from old-world African green monkey, De Brazza\u2019s monkey and chimpanzee demonstrated virus-specific restriction of tick-borne orthoflaviviruses. Efforts to determine why TRIM5\u03b1 fails to inhibit POWV revealed that our lab stock had acquired a non-synonymous mutation in NS3 that, when introduced into a POWV molecular clone, facilitated virus replication in the presence of all inhibitory primate TRIM5\u03b1 proteins. Infection of human dendritic cells with TRIM5\u03b1-resistant POWV resulted in high early replication and strong induction of interferon responses that limited replication compared with the wild-type virus. Thus, primate TRIM5\u03b1 functions as a potent cellular barrier to infection with tick-borne orthoflaviviruses that restrains replication to a level that may help avoid early innate immune recognition.<\/jats:p>","DOI":"10.1038\/s42003-026-10613-1","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T02:29:38Z","timestamp":1783391378000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Restraint of Powassan virus replication by TRIM5\u03b1 facilitates viral avoidance of antiviral immunity"],"prefix":"10.1038","volume":"9","author":[{"given":"Rebecca M.","family":"Broeckel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily A.","family":"Fitzmeyer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8860-2994","authenticated-orcid":false,"given":"Eva","family":"Chebishev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4211-4308","authenticated-orcid":false,"given":"Jeffrey G.","family":"Shannon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byron","family":"Shue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7668-892X","authenticated-orcid":false,"given":"Adam","family":"Hage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Spada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Efrosini","family":"Artikis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhilash I.","family":"Chiramel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin L.","family":"McNally","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles L.","family":"Larson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maarit","family":"von Kutzleben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shelly J.","family":"Robertson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0736-1664","authenticated-orcid":false,"given":"Danielle K.","family":"Offerdahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilary A.","family":"Lakin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7003-2313","authenticated-orcid":false,"given":"Marshall E.","family":"Bloom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skyler","family":"Kuhn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinod","family":"Nair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5424-7573","authenticated-orcid":false,"given":"Nicholas S.","family":"Eyre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Beard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3465-3782","authenticated-orcid":false,"given":"Michael E.","family":"Grigg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fadila","family":"Bouamr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0206-297X","authenticated-orcid":false,"given":"Sonja M.","family":"Best","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"10613_CR1","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1038\/s41564-020-0714-0","volume":"5","author":"TC Pierson","year":"2020","unstructured":"Pierson, T. 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