{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Gallego I"],"funding":["MINECO | Instituto de Salud Carlos III","NIAID NIH HHS","Comunidad Autónoma de Madrid","HHS | NIH | National Institute of Allergy and Infectious Diseases","Ministerio de Economía y Competitividad"],"pagination":["3786-93"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4879421"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["60(6)"],"pubmed_abstract":["Sofosbuvir displays a high phenotypic barrier to resistance, and it is a component of several combination therapies for hepatitis C virus (HCV) infections. HCV fitness can be a determinant of decreased sensitivity to direct-acting antiviral agents such as telaprevir or daclatasvir, but fitness-dependent decreased drug sensitivity has not been established for drugs with a high phenotypic barrier to resistance. Low- and high-fitness HCV populations and biological clones derived from them were used to infect Huh-7.5 hepatoma cells. Sofosbuvir efficacy was analyzed by measuring virus progeny production during several passages and by selection of possible sofosbuvir resistance mutations determined by sequencing the NS5B-coding region of the resulting populations. Sofosbuvir exhibited reduced efficacy against high-fitness HCV populations, without the acquisition of sofosbuvir-specific resistance mutations. A reduced sofosbuvir efficacy, similar to that observed with the parental populations, was seen for high-fitness individual biological clones. In independently derived high-fitness HCV populations or clones passaged in the presence of sofosbuvir, M289L was selected as the only substitution in the viral polymerase NS5B. In no case was the sofosbuvir-specific resistance substitution S282T observed. High HCV fitness can lead to decreased sensitivity to sofosbuvir, without the acquisition of specific sofosbuvir resistance mutations. Thus, fitness-dependent drug sensitivity can operate with HCV inhibitors that display a high barrier to resistance. This mechanism may underlie treatment failures not associated with selection of sofosbuvir-specific resistance mutations, linked to in vivo fitness of pretreatment viral populations."],"journal":["Antimicrobial agents and chemotherapy"],"pubmed_title":["Barrier-Independent, Fitness-Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus."],"pmcid":["PMC4879421"],"funding_grant_id":["PI15/00829","PI13/00456","R01 AI099284","BFU-2011-23604","SAF2014-52400-R","S2013/ABI-2906"],"pubmed_authors":["Sheldon J","Moreno E","Quer J","Gallego I","Esteban JI","Domingo E","Gregori J","Rice CM","Perales C"],"additional_accession":[]},"is_claimable":false,"name":"Barrier-Independent, Fitness-Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus.","description":"Sofosbuvir displays a high phenotypic barrier to resistance, and it is a component of several combination therapies for hepatitis C virus (HCV) infections. HCV fitness can be a determinant of decreased sensitivity to direct-acting antiviral agents such as telaprevir or daclatasvir, but fitness-dependent decreased drug sensitivity has not been established for drugs with a high phenotypic barrier to resistance. Low- and high-fitness HCV populations and biological clones derived from them were used to infect Huh-7.5 hepatoma cells. Sofosbuvir efficacy was analyzed by measuring virus progeny production during several passages and by selection of possible sofosbuvir resistance mutations determined by sequencing the NS5B-coding region of the resulting populations. Sofosbuvir exhibited reduced efficacy against high-fitness HCV populations, without the acquisition of sofosbuvir-specific resistance mutations. A reduced sofosbuvir efficacy, similar to that observed with the parental populations, was seen for high-fitness individual biological clones. In independently derived high-fitness HCV populations or clones passaged in the presence of sofosbuvir, M289L was selected as the only substitution in the viral polymerase NS5B. In no case was the sofosbuvir-specific resistance substitution S282T observed. High HCV fitness can lead to decreased sensitivity to sofosbuvir, without the acquisition of specific sofosbuvir resistance mutations. Thus, fitness-dependent drug sensitivity can operate with HCV inhibitors that display a high barrier to resistance. This mechanism may underlie treatment failures not associated with selection of sofosbuvir-specific resistance mutations, linked to in vivo fitness of pretreatment viral populations.","dates":{"release":"2016-01-01T00:00:00Z","publication":"2016 Jun","modification":"2025-04-05T14:58:59.374Z","creation":"2025-04-05T14:58:59.374Z"},"accession":"S-EPMC4879421","cross_references":{"pubmed":["27067341"],"doi":["10.1128/aac.00581-16","10.1128/AAC.00581-16"]}}