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Current treatment for people with this type of infection is generally limited to supportive care. To address the need for reliable antivirals, we utilized a strategy of lethal mutagenesis to limit virus replication. We evaluated ribavirin (RBV), favipiravir (FAV) and <jats:italic>N<\/jats:italic><jats:sup>4<\/jats:sup>-hydroxycytidine (NHC) against La Crosse virus (LACV), which is one of the most common causes of pediatric arboviral encephalitis cases in North America and serves as a model for viral CNS invasion during acute infection. NHC was approximately 3 to 170 times more potent than RBV or FAV in neuronal cells. Oral administration of molnupiravir (MOV), the prodrug of NHC, decreased neurological disease development (assessed as limb paralysis, ataxia and weakness, repeated seizures, or death) by 31% (4 mice survived out of 13) when treatment was started on the day of infection. MOV also reduced disease by 23% when virus was administered intranasally (IN). NHC and MOV produced less fit viruses by incorporating predominantly G to A or C to U mutations. Furthermore, NHC also inhibited virus production of two other orthobunyaviruses, Jamestown Canyon virus and Cache Valley virus. Collectively, these studies indicate that NHC\/MOV has therapeutic potential to inhibit viral replication and subsequent neurological disease caused by orthobunyaviruses and potentially as a generalizable strategy for treating acute viral encephalitis.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012574","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T17:37:38Z","timestamp":1727717858000},"page":"e1012574","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["N4-Hydroxycytidine\/molnupiravir inhibits RNA virus-induced encephalitis by producing less fit mutated viruses"],"prefix":"10.1371","volume":"20","author":[{"given":"Durbadal","family":"Ojha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Collin S.","family":"Hill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuntai","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa","family":"Evans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline M.","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A.","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franck","family":"Amblard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyson A.","family":"Woods","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond F.","family":"Schinazi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph S.","family":"Baric","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin E.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7777-0773","authenticated-orcid":true,"given":"Ronald","family":"Swanstrom","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,9,30]]},"reference":[{"key":"ppat.1012574.ref001","doi-asserted-by":"crossref","first-page":"e642","DOI":"10.1542\/peds.2014-0498","article-title":"Neuroinvasive arboviral disease in the United States: 2003 to 2012","volume":"134","author":"JT Gaensbauer","year":"2014","journal-title":"Pediatrics"},{"key":"ppat.1012574.ref002","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.idc.2017.10.007","article-title":"Encephalitis in US Children","volume":"32","author":"K Messacar","year":"2018","journal-title":"Infect Dis Clin North Am"},{"key":"ppat.1012574.ref003","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1056\/NEJM199804303381808","article-title":"HIV-protease inhibitors","volume":"338","author":"C. 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