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      Barrier-Independent, Fitness-Associated Differences in Sofosbuvir Efficacy against Hepatitis C Virus

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          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.

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          Author and article information

          Journal
          Antimicrob Agents Chemother
          Antimicrob. Agents Chemother
          aac
          aac
          AAC
          Antimicrobial Agents and Chemotherapy
          American Society for Microbiology (1752 N St., N.W., Washington, DC )
          0066-4804
          1098-6596
          11 April 2016
          23 May 2016
          June 2016
          : 60
          : 6
          : 3786-3793
          Affiliations
          [a ]Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Consejo Superior de Investigaciones Científicas, Campus de Cantoblanco, Madrid, Spain
          [b ]Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Barcelona, Spain
          [c ]Liver Unit, Internal Medicine, Laboratory of Malalties Hepàtiques, Vall d'Hebron Institut de Recerca-Hospital Universitari Vall d′Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
          [d ]Roche Diagnostics, S.L., Sant Cugat del Vallés, Spain
          [e ]Universitat Autónoma de Barcelona, Barcelona, Spain
          [f ]Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, New York, USA
          Author notes
          Address correspondence to Celia Perales, cperales@ 123456cbm.csic.es .

          Citation Gallego I, Sheldon J, Moreno E, Gregori J, Quer J, Esteban JI, Rice CM, Domingo E, Perales C. 2016. Barrier-independent, fitness-associated differences in sofosbuvir efficacy against hepatitis C virus. Antimicrob Agents Chemother 60:3786–3793. doi: 10.1128/AAC.00581-16.

          Article
          PMC4879421 PMC4879421 4879421 00581-16
          10.1128/AAC.00581-16
          4879421
          27067341
          37d7d2af-7ed2-4124-b871-7e0daf403531
          Copyright © 2016, American Society for Microbiology. All Rights Reserved.
          History
          : 14 March 2016
          : 1 April 2016
          : 5 April 2016
          Page count
          Figures: 5, Tables: 0, Equations: 0, References: 50, Pages: 8, Words: 7574
          Funding
          Funded by: HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID) http://dx.doi.org/10.13039/100000060
          Award ID: R01 AI099284
          Award Recipient : Charles Rice
          Funded by: MINECO | Instituto de Salud Carlos III (ISCIII) http://dx.doi.org/10.13039/501100004587
          Award ID: PI13/00456
          Award Recipient : Juan Ignacio Esteban
          Funded by: MINECO | Instituto de Salud Carlos III (ISCIII) http://dx.doi.org/10.13039/501100004587
          Award ID: PI15/00829
          Award Recipient : Rafael Esteban
          Funded by: Ministerio de Economía y Competitividad (MINECO) http://dx.doi.org/10.13039/501100003329
          Award ID: BFU-2011-23604
          Award Recipient : Esteban Domingo
          Funded by: Ministerio de Economía y Competitividad (MINECO) http://dx.doi.org/10.13039/501100003329
          Award ID: SAF2014-52400-R
          Award Recipient : Esteban Domingo
          Funded by: Comunidad Autónoma de Madrid
          Award ID: S2013/ABI-2906
          Award Recipient : Esteban Domingo
          The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
          Categories
          Antiviral Agents

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