In vitro selection of Remdesivir resistance suggests evolutionary predictability of SARS-CoV-2

Szemiel, A. M. et al. (2021) In vitro selection of Remdesivir resistance suggests evolutionary predictability of SARS-CoV-2. PLoS Pathogens, 17(9), e1009929. (doi: 10.1371/journal.ppat.1009929) (PMID:34534263) (PMCID:PMC8496873)

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Abstract

Remdesivir (RDV), a broadly acting nucleoside analogue, is the only FDA approved small molecule antiviral for the treatment of COVID-19 patients. To date, there are no reports identifying SARS-CoV-2 RDV resistance in patients, animal models or in vitro. Here, we selected drug-resistant viral populations by serially passaging SARS-CoV-2 in vitro in the presence of RDV. Using high throughput sequencing, we identified a single mutation in RNA-dependent RNA polymerase (NSP12) at a residue conserved among all coronaviruses in two independently evolved populations displaying decreased RDV sensitivity. Introduction of the NSP12 E802D mutation into our SARS-CoV-2 reverse genetics backbone confirmed its role in decreasing RDV sensitivity in vitro. Substitution of E802 did not affect viral replication or activity of an alternate nucleoside analogue (EIDD2801) but did affect virus fitness in a competition assay. Analysis of the globally circulating SARS-CoV-2 variants (>800,000 sequences) showed no evidence of widespread transmission of RDV-resistant mutants. Surprisingly, we observed an excess of substitutions in spike at corresponding sites identified in the emerging SARS-CoV-2 variants of concern (i.e., H69, E484, N501, H655) indicating that they can arise in vitro in the absence of immune selection. The identification and characterisation of a drug resistant signature within the SARS-CoV-2 genome has implications for clinical management and virus surveillance.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Furnon, Dr Wilhelm and Suarez, Dr Nicolas and Turnbull, Dr Matthew and Willett, Professor Brian and Wilson, Professor Sam and Wickenhagen, Mr Arthur and Palmarini, Professor Massimo and Thomson, Professor Emma and Mair, Mr Daniel and Szemiel, Dr Agnieszka and Orton, Dr Richard and MacLean, Dr Oscar and Da Silva Filipe, Dr Ana and Stewart, Dr Meredith and Lieber, Mr Gauthier and Patel, Professor Arvind and Kohl, Professor Alain and Pinto, Dr Rute
Creator Roles:
Szemiel, A. M.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing – original draft, Writing – review and editing
Orton, R. J.Data curation, Investigation, Visualization, Writing – review and editing
MacLean, O. A.Data curation, Investigation, Methodology, Validation, Visualization, Writing – review and editing
Pinto, R. M.Methodology, Writing – review and editing
Wickenhagen, A.Resources, Writing – review and editing
Lieber, G.Investigation, Writing – review and editing
Turnbull, M. L.Investigation, Writing – review and editing
Furnon, W.Methodology
Suarez, N. M.Methodology
Mair, D.Investigation
da Silva Filipe, A.Funding acquisition, Methodology, Resources
Willett, B. J.Funding acquisition, Writing – original draft, Writing – review and editing
Wilson, S. J.Funding acquisition, Methodology, Resources
Patel, A. H.Funding acquisition, Methodology, Resources
Thomson, E. C.Conceptualization, Resources, Writing – review and editing
Palmarini, M.Conceptualization, Funding acquisition, Resources, Writing – original draft, Writing – review and editing
Kohl, A.Conceptualization, Funding acquisition, Project administration, Resources, Writing – original draft, Writing – review and editing
Stewart, M. E.Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing – original draft, Writing – review and editing
Authors: Szemiel, A. M., Merits, A., Orton, R. J., MacLean, O. A., Pinto, R. M., Wickenhagen, A., Lieber, G., Turnbull, M. L., Wang, S., Furnon, W., Suarez, N. M., Mair, D., da Silva Filipe, A., Willett, B. J., Wilson, S. J., Patel, A. H., Thomson, E. C., Palmarini, M., Kohl, A., and Stewart, M. E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Published Online:17 September 2021
Copyright Holders:Copyright © 2021 Szemiel et al.
First Published:First published in PLoS Pathogens 17(9): e1009929
Publisher Policy:Reproduced under a Creative Commons License
Data DOI:10.5525/gla.researchdata.1184

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
656551Arbovirus interactions with arthropod hostsAlain KohlMedical Research Council (MRC)MC_UU_12014/8MVLS III - CENTRE FOR VIRUS RESEARCH
656491Basis of the host range and tissue tropism for hepatitis C virusArvind PatelMedical Research Council (MRC)MC_UU_12014/2MVLS III - CENTRE FOR VIRUS RESEARCH
Viral Genomics and BioinformaticsAndrew DavisonMedical Research Council (MRC)MC_UU_12014/12III-MRC-GU Centre for Virus Research
302172A One Health approach to pan-valent morbillivirus vaccinesBrian WillettBiotechnology and Biological Sciences Research Council (BBSRC)BB/R019843/1III - Centre for Virus Research