{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T19:25:29Z","timestamp":1771356329339,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013941","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T00:00:00Z","timestamp":1771286400000}}],"reference-count":59,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T00:00:00Z","timestamp":1770595200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI153209"],"award-info":[{"award-number":["R01AI153209"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AI095366-10"],"award-info":[{"award-number":["R01AI095366-10"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH","award":["UC7AI180311"],"award-info":[{"award-number":["UC7AI180311"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Encephalitogenic alphaviruses are mosquito-borne viruses that can cause fatal disease in humans and equines. Currently, there are no licensed vaccines or antiviral treatments for these infections. Western equine encephalitis virus (WEEV) is a member of this group that had not produced a human infection in over a decade. However, an outbreak of WEEV encephalitis in humans and equines was reported recently in South America, indicating a need for additional countermeasures. Blind passage approaches to generation of RNA virus live attenuated vaccines (LAVs) frequently result in acquisition of positively charged amino acid mutations that confer heparan sulfate (HS) binding and that are attenuating factors in resultant LAVs. To develop an informed approach for creation of alphavirus LAVs, we have utilized the WEEV McMillan (McM) strain as an HS weak\/non-binding platform into which we have placed positively charged amino acid substitution mutations at positions in the E2 glycoprotein previously shown to confer HS-dependent infection upon other alphaviruses. This approach yielded four mutants with high efficiency HS binding and avirulence in mice, which were further subjected to yield optimization by\n                    <jats:italic>in vitro<\/jats:italic>\n                    selection of second-site mutations. Interestingly, the original mutations concomitantly increased HS interactions and reduced infection promoted by VLDLR and PCDH10 protein receptors, while the second site mutations improved infectivity mediated by VLDLR. Further, we report a newly generated 4.1\u00c5 cryo-EM reconstruction of WEEV McM strain into which we have mapped the mutations to provide an E2 glycoprotein domain-based representation of receptor binding site location.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013941","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T18:50:22Z","timestamp":1770663022000},"page":"e1013941","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Informed mutation of western equine encephalitis virus to heparan sulfate binding: Implications for rational design of alphavirus live attenuated vaccines"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4939-9222","authenticated-orcid":true,"given":"Tetyana","family":"Lukash","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shishir","family":"Poudyal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Theron C.","family":"Gilliland","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Klose","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengqun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shauna N.","family":"Vasilatos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jessica L.","family":"Farren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Long Kwan Metthew","family":"Lam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard J.","family":"Kuhn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4506-7842","authenticated-orcid":true,"given":"William B.","family":"Klimstra","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,2,9]]},"reference":[{"issue":"16","key":"ppat.1013941.ref001","doi-asserted-by":"crossref","first-page":"5997","DOI":"10.1073\/pnas.85.16.5997","article-title":"Western equine encephalitis virus is a recombinant virus","volume":"85","author":"CS Hahn","year":"1988","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"ppat.1013941.ref002","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1128\/jvi.71.1.613-623.1997","article-title":"Recombinational history and molecular evolution of western equine encephalomyelitis complex alphaviruses","volume":"71","author":"SC Weaver","year":"1997","journal-title":"J Virol"},{"issue":"9","key":"ppat.1013941.ref003","doi-asserted-by":"crossref","first-page":"1834","DOI":"10.3201\/eid3009.240530","article-title":"Molecular Epidemiology of Western Equine Encephalitis Virus, South America, 2023-2024","volume":"30","author":"AS Campos","year":"2024","journal-title":"Emerg Infect Dis"},{"key":"ppat.1013941.ref004","unstructured":"Public health risk assessment related to Western Equine Encephalitis (WEE) virus in the Region of the Americas. 2024. 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