{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T17:26:17Z","timestamp":1787851577652,"version":"build-2784847793"},"reference-count":52,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,12,16]],"date-time":"2023-12-16T00:00:00Z","timestamp":1702684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Baloxavir marboxil (baloxavir) is an FDA-approved inhibitor of the influenza virus polymerase acidic (PA) protein. Here, we used next-generation sequencing to compare the genomic mutational profiles of IAV H1N1 and H3N2, and IBV wild type (WT) and mutants (MUT) viruses carrying baloxavir resistance-associated substitutions (H1N1\u2014PA I38L, I38T, and E199D; H3N2\u2014PA I38T; and IBV\u2014PA I38T) during passaging in normal human bronchial epithelial (NHBE) cells. We determined the ratio of nonsynonymous to synonymous nucleotide mutations (dN\/dS) and identified the location and type of amino acid (AA) substitutions that occurred at a frequency of \u226530%. We observed that IAV H1N1 WT and MUT viruses remained relatively stable during passaging. While the mutational profiles for IAV H1N1 I38L, I38T, and E199D, and IBV I38T MUTs were relatively similar after each passage compared to the respective WTs, the mutational profile of the IAV H3N2 I38T MUT was significantly different for most genes compared to H3N2 WT. Our work provides insight into how baloxavir resistance-associated substitutions may impact influenza virus evolution in natural settings. Further characterization of the potentially adaptive mutations identified in this study is needed.<\/jats:p>","DOI":"10.3390\/v15122446","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T05:41:35Z","timestamp":1702878095000},"page":"2446","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Genomic Analysis of Influenza A and B Viruses Carrying Baloxavir Resistance-Associated Substitutions Serially Passaged in Human Epithelial Cells"],"prefix":"10.3390","volume":"15","author":[{"given":"Brady T.","family":"Hickerson","sequence":"first","affiliation":[{"name":"Division of Biotechnology Review and Research II, Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce K.","family":"Huang","sequence":"additional","affiliation":[{"name":"Division of Biotechnology Review and Research II, Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana N.","family":"Petrovskaya","sequence":"additional","affiliation":[{"name":"Division of Biotechnology Review and Research III, Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia A.","family":"Ilyushina","sequence":"additional","affiliation":[{"name":"Division of Biotechnology Review and Research II, Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41572-018-0002-y","article-title":"Influenza","volume":"4","author":"Krammer","year":"2018","journal-title":"Nat. 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