In vitro selection of Remdesivir resistance suggests evolutionary predictability of SARS-CoV-2.
Adenosine Monophosphate
/ analogs & derivatives
Alanine
/ analogs & derivatives
Animals
Antiviral Agents
/ pharmacology
Biological Evolution
Chlorocebus aethiops
Coronavirus RNA-Dependent RNA Polymerase
/ genetics
Drug Resistance, Microbial
/ genetics
Humans
Mutation
SARS-CoV-2
/ drug effects
Spike Glycoprotein, Coronavirus
/ metabolism
Vero Cells
COVID-19 Drug Treatment
Journal
PLoS pathogens
ISSN: 1553-7374
Titre abrégé: PLoS Pathog
Pays: United States
ID NLM: 101238921
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
02
04
2021
accepted:
30
08
2021
revised:
07
10
2021
pubmed:
18
9
2021
medline:
16
10
2021
entrez:
17
9
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34534263
doi: 10.1371/journal.ppat.1009929
pii: PPATHOGENS-D-21-00714
pmc: PMC8496873
doi:
Substances chimiques
Antiviral Agents
0
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
remdesivir
3QKI37EEHE
Adenosine Monophosphate
415SHH325A
Coronavirus RNA-Dependent RNA Polymerase
EC 2.7.7.48
NSP12 protein, SARS-CoV-2
EC 2.7.7.48
Alanine
OF5P57N2ZX
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1009929Subventions
Organisme : Medical Research Council
ID : MC_PC_19026
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12014/10
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12014/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_UU_12014/8
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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