Evolution of the Influenza A Virus Genome during Development of Oseltamivir ResistanceIn Vitro

• DOI: 10.1128/jvi.01067-13
• Publication Date: 2013-10-24T01:51:50Z
• Authors: Nicholas Renzette; Daniel R. Caffrey; Konstantin B. Zel...; Ping Liu; Glen R. Gallagher; Daniel Aiello; Alyssa J. Porter; Evelyn A. Kurt-Jones; Daniel N. Bolon; Yu-Ping Poh; Jeffrey D. Jensen; Celia A. Schiffer; Timothy F. Kowalik; Robert W. Finberg; Jennifer P. Wang
• Keywords: Oseltamivir; Neuraminidase inhibitor; Resistance mutation

ABSTRACT Influenza A virus (IAV) is a major cause of morbidity and mortality throughout the world. Current antiviral therapies include oseltamivir, neuraminidase inhibitor that prevents release nascent viral particles from infected cells. However, IAV genome can evolve rapidly, oseltamivir resistance mutations have been detected in numerous clinical samples. Using an vitro evolution platform whole-genome population sequencing, we investigated genomics during development resistance. Strain A/Brisbane/59/2007 (H1N1) was grown Madin-Darby canine kidney cells with or without escalating concentrations over serial passages. Following drug treatment, H274Y mutation fixed reproducibly within population. The presence population, at either low high frequency, led to measurable changes inhibition assay. Surprisingly, fixation not accompanied by alterations diversity differentiation, did alter selective environment. While neighboring K248E also target positive selection prior fixation, primary beneficial In addition, once evolved, persisted after withdrawal drug, even when populations. We conclude only required for deleterious absence drug. These collective results could offer explanation recent reproducible rise seasonal H1N1 strains humans.