Influenza A virus resistance to 4'-fluorouridine coincides with viral attenuation in vitro and in vivo.

"raw reads are available in ncbi bioproject prjna1028360 ( s1 to s4 data ). whole genome sequencing of 4'-flu-experienced virus populations at study end and selected intermediate passages identified in each lineage at least one and up to three point mutations in rdrp subunits that had become allele-dominant but were absent in the vehicle-treated virus populations ( fig 1d ; s1 table ; s1 data ).; relative allele frequencies of mutations in lineages #1 #2 and #3 plummeted rapidly indicating a fitness penalty compared to the parent virus ( fig 2f and s2 data ).; relative allele frequency of all mutations but pb1 m290v was near 100% in virus populations isolated from lung tissue 5 to 10 days after infection ( s3 data ) when individual animals reached endpoints10 1371/journal ppat 1011993 g004 fig 4 a) schematic of the pathogenicity study.; whole genome sequencing of the different virus populations extracted from animal lungs at study endpoints revealed genetic stability of recca09 lin #4 through the course of the study in both source and after successful transmission from vehicle-treated animals contact ferrets ( fig 5h ; s4 data ).; raw reads are available in ncbi bioproject prjna1028360 ( s1 to s4 data ).; source data and statistical analysis are shown in the s5 data and s6 data files respectively.; symbols represent individual animals lines connect data means; n = 3 (tif) click here for additional data file s1 data data can be found at https://github com/greninger-lab/lieber_iav_4fiu_supplemental_data_1-4/tree/main/s1_data/adaptation_rava_plots (zip) click here for additional data file s2 data data can be found at https://github com/greninger-lab/lieber_iav_4fiu_supplemental_data_1-4/tree/main/s2_data/fitness_rava_plots (zip) click here for additional data file s3 data data can be found at https://github com/greninger-lab/lieber_iav_4fiu_supplemental_data_1-4/tree/main/s3_data/mouse_rava_plots (zip) click here for additional data file s4 data data can be found at https://github com/greninger-lab/lieber_iav_4fiu_supplemental_data_1-4/tree/main/s4_data/ferret_rava_plots (zip) click here for additional data file s5 data (xlsx) click here for additional data file s6 data (xlsx) click here for additional data file. zip) click here for additional data file s2"

"MGN is a coinventor on patent WO 2019/1736002 covering composition of matter and use of 4’-FlU (EIDD-2749) and its analogs as an antiviral treatment. This study could affect his personal financial status. RKP reports contract testing from Enanta Pharmaceuticals and Atea Pharmaceuticals, and research support from Gilead Sciences, outside of the described work. ALG reports contract testing from Abbott, Cepheid, Novavax, Pfizer, Janssen and Hologic, research support from Gilead, outside of the described work. All other authors declare that they have no competing interests."

"This study was supported, in part, by public health service grants AI141222 (to R.K.P.) and AI171403 project 1 (to R.K.P.) from the NIH/NIAID. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."