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We have integrated time-series analysis, molecular phylogenetics, and structural biology to understand how H5N1 is circulating in North America and adapting to new hosts. Our time-series analysis reveals that the circulation of H5N1 follows a distinct seasonal pattern, with cases in the United States increasing November to April. We also document an increase in the number of cases reported since 2021. We show that H5N1 spreads in North America as 2 distinct lineages. These viral lineages have achieved a vast host range by efficiently binding the viral surface protein hemagglutinin to both mammalian and avian cell surface receptors. This novel host-range promiscuity is concomitant with the strengthening of the viral polymerase basic 2 protein binding for mammalian and avian immune proteins. Once bound, the immune proteins have diminished ability to fight the virus, thus allowing for efficient replication. Our analyses predict that while most antivirals remain effective, a fatal human isolate showed reduced binding to multiple drugs from different classes. The H5N1 virus is causing an animal pandemic through promiscuity of host range and strengthening ability to evade the innate immune systems of both mammalian and avian cells.<\/jats:p>","DOI":"10.34133\/csbj.0066","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T07:31:08Z","timestamp":1775028668000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark_01","source":"Crossref","is-referenced-by-count":0,"title":["Computational Structural Analysis Predicts Host-Range Promiscuity and Antiviral Resistance in North American H5N1 Lineages"],"prefix":"10.34133","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1472-2261","authenticated-orcid":true,"given":"Sayal","family":"Guirales-Medrano","sequence":"first","affiliation":[{"name":"Center for Computational Intelligence to Predict Health and Environmental Risks (CIPHER), \rUniversity of North Carolina at Charlotte, Charlotte, NC, USA."},{"name":"Department of Bioinformatics and Genomics, \rUniversity of North Carolina at Charlotte, Charlotte, NC, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2151-7418","authenticated-orcid":false,"given":"Kary","family":"Oca\u00f1a","sequence":"additional","affiliation":[{"name":"National Laboratory of Scientific Computing","place":["Brazil"]},{"name":"Department of Biological Sciences, \rUniversity of North Carolina at Charlotte, Charlotte, NC, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khaled","family":"Obeid","sequence":"additional","affiliation":[{"name":"Center for Computational Intelligence to Predict Health and Environmental Risks (CIPHER), \rUniversity of North Carolina at Charlotte, Charlotte, NC, USA."},{"name":"Department of Bioinformatics and Genomics, \rUniversity of North Carolina at Charlotte, Charlotte, NC, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7681-2190","authenticated-orcid":false,"given":"Rachel","family":"Alexander","sequence":"additional","affiliation":[{"name":"Center for Computational Intelligence to Predict Health and Environmental Risks (CIPHER), \rUniversity of North Carolina at Charlotte, Charlotte, NC, USA."},{"name":"Department of Bioinformatics and Genomics, \rUniversity of North Carolina at Charlotte, Charlotte, NC, USA."},{"name":"School of Data Science, \rUniversity of North Carolina at Charlotte, Charlotte, NC, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7859-3622","authenticated-orcid":false,"given":"Colby T.","family":"Ford","sequence":"additional","affiliation":[{"name":"Center for Computational Intelligence to Predict Health and Environmental Risks (CIPHER), \rUniversity of North Carolina at Charlotte, Charlotte, NC, USA."},{"name":"Department of Bioinformatics and Genomics, \rUniversity of North Carolina at Charlotte, Charlotte, NC, USA."},{"name":"School of Data Science, \rUniversity of North Carolina at Charlotte, Charlotte, NC, USA."},{"name":"Tuple LLC","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7890-9906","authenticated-orcid":true,"given":"Daniel","family":"Janies","sequence":"additional","affiliation":[{"name":"Center for Computational Intelligence to Predict Health and Environmental Risks (CIPHER), \rUniversity of North Carolina at Charlotte, Charlotte, NC, USA."},{"name":"Department of Bioinformatics and Genomics, \rUniversity of North Carolina at Charlotte, Charlotte, NC, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"221","published-online":{"date-parts":[[2026,5,8]]},"reference":[{"key":"e_1_3_4_2_2","article-title":"Influenza A viruses: An ecology review","volume":"1","author":"Wahlgren J","year":"2011","unstructured":"Wahlgren J. 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