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In vitro selection of Remdesivir resistance suggests evolutionary predictability of SARS-CoV-2.
Szemiel, Agnieszka M; Merits, Andres; Orton, Richard J; MacLean, Oscar A; Pinto, Rute Maria; Wickenhagen, Arthur; Lieber, Gauthier; Turnbull, Matthew L; Wang, Sainan; Furnon, Wilhelm; Suarez, Nicolas M; Mair, Daniel; da Silva Filipe, Ana; Willett, Brian J; Wilson, Sam J; Patel, Arvind H; Thomson, Emma C; Palmarini, Massimo; Kohl, Alain; Stewart, Meredith E.
  • Szemiel AM; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Merits A; Institute of Technology, University of Tartu, Tartu, Estonia.
  • Orton RJ; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • MacLean OA; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Pinto RM; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Wickenhagen A; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Lieber G; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Turnbull ML; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Wang S; Institute of Technology, University of Tartu, Tartu, Estonia.
  • Furnon W; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Suarez NM; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Mair D; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • da Silva Filipe A; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Willett BJ; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Wilson SJ; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Patel AH; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Thomson EC; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Palmarini M; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Kohl A; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
  • Stewart ME; MRC-University of Glasgow Centre for Virus Research, Glasgow, United Kingdom.
PLoS Pathog ; 17(9): e1009929, 2021 09.
Article in English | MEDLINE | ID: covidwho-1430555
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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Drug Resistance, Microbial / Adenosine Monophosphate / Alanine / Coronavirus RNA-Dependent RNA Polymerase / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: PLoS Pathog Year: 2021 Document Type: Article Affiliation country: Journal.ppat.1009929

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Drug Resistance, Microbial / Adenosine Monophosphate / Alanine / Coronavirus RNA-Dependent RNA Polymerase / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: PLoS Pathog Year: 2021 Document Type: Article Affiliation country: Journal.ppat.1009929