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SARS-CoV-2 Remdesivir Exposure Leads to Different Evolutionary Pathways That Converge in Moderate Levels of Drug Resistance

Fernandez-Antunez et al., Viruses, doi:10.3390/v17081055, Jul 2025
https://c19early.org/fernandezantunez.html
In Vitro and hamster study showing that SARS-CoV-2 can develop resistance to remdesivir through multiple evolutionary pathways.
Gérard, Zhou, Wu, Kamo, Choi, Kim show increased risk of acute kidney injury, Leo, Briciu, Muntean, Petrov show increased risk of liver injury, and Negru show increased risk of cardiac disorders with remdesivir.
Fernandez-Antunez et al., 29 Jul 2025, peer-reviewed, 11 authors. Contact: santseharayra@sund.ku.dk (corresponding author), carlota.fernandez.antunez@regionh.dk, line.ryberg@sund.ku.dk, kuan.wang@regionh.dk, pham@sund.ku.dk, lotte.scheibelein.mikkelsen@regionh.dk, ulrik@sund.ku.dk, kholmbeck@sund.ku.dk, jbukh@sund.ku.dk, katoh@sund.ku.dk, elvang@sund.ku.dk.
SARS-CoV-2 Remdesivir Exposure Leads to Different Evolutionary Pathways That Converge in Moderate Levels of Drug Resistance
Carlota Fernandez-Antunez, Line A Ryberg, Kuan Wang, Long V Pham, Lotte S Mikkelsen, Ulrik Fahnøe, Katrine T Hartmann, Henrik E Jensen, Kenn Holmbeck, Jens Bukh, Santseharay Ramirez
Viruses, doi:10.3390/v17081055
Various SARS-CoV-2 remdesivir resistance-associated substitutions (RAS) have been reported, but a comprehensive comparison of their resistance levels is lacking. We identified novel RAS and performed head-to-head comparisons with known RAS in Vero E6 cells. A remdesivir escape polyclonal virus exhibited a 3.6-fold increase in remdesivir EC 50 and mutations throughout the genome, including substitutions in nsp12 (E796D) and nsp14 (A255S). However, in reverse-genetics infectious assays, viruses harboring both these substitutions exhibited only a slight decrease in remdesivir susceptibility (1.3-fold increase in EC 50 ). The nsp12-E796D substitution did not impair viral fitness (Vero E6 cells or Syrian hamsters) and was reported in a remdesivir-treated COVID-19 patient. In replication assays, a subgenomic replicon containing nsp12-E796D+nsp14-A255S led to a 16.1-fold increase in replication under remdesivir treatment. A comparison with known RAS showed that S759A, located in the active site of nsp12, conferred the highest remdesivir resistance (106.1fold increase in replication). Nsp12-RAS V166A/L, V792I, E796D or C799F, all adjacent to the active site, caused intermediate resistance (2.0-to 11.5-fold), whereas N198S, D484Y, or E802D, located farther from the active site, showed no resistance (≤2.0-fold). In conclusion, our classification system, correlating replication under remdesivir treatment with RAS location in nsp12, shows that most nsp12-RAS cause moderate resistance.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/v17081055/s1 , Supporting Methods; Figure S1 : Antiviral activity of remdesivir, GS-441524, obeldesivir, and molnupiravir; Figure S2 : Competitive fitness of original and RDV escape viruses; Figure S3 : Neutralizing curves of hamster plasma samples; Figure S4 : Principal component analysis of nsp12-motif D in a nsp7-nsp8-nsp12 molecular dynamics simulation; Table S1 : Genotypic characterization of remdesivir resistance selection experiment-derived viruses; Table S2 : Genotypic characterization of mutant viruses; Table S3 : Histopathological analysis of animal lungs. Conflicts of Interest: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.
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DOI record: { "DOI": "10.3390/v17081055", "ISSN": [ "1999-4915" ], "URL": "http://dx.doi.org/10.3390/v17081055", "abstract": "<jats:p>Various SARS-CoV-2 remdesivir resistance-associated substitutions (RAS) have been reported, but a comprehensive comparison of their resistance levels is lacking. We identified novel RAS and performed head-to-head comparisons with known RAS in Vero E6 cells. A remdesivir escape polyclonal virus exhibited a 3.6-fold increase in remdesivir EC50 and mutations throughout the genome, including substitutions in nsp12 (E796D) and nsp14 (A255S). However, in reverse-genetics infectious assays, viruses harboring both these substitutions exhibited only a slight decrease in remdesivir susceptibility (1.3-fold increase in EC50). The nsp12-E796D substitution did not impair viral fitness (Vero E6 cells or Syrian hamsters) and was reported in a remdesivir-treated COVID-19 patient. In replication assays, a subgenomic replicon containing nsp12-E796D+nsp14-A255S led to a 16.1-fold increase in replication under remdesivir treatment. A comparison with known RAS showed that S759A, located in the active site of nsp12, conferred the highest remdesivir resistance (106.1-fold increase in replication). Nsp12-RAS V166A/L, V792I, E796D or C799F, all adjacent to the active site, caused intermediate resistance (2.0- to 11.5-fold), whereas N198S, D484Y, or E802D, located farther from the active site, showed no resistance (≤2.0-fold). In conclusion, our classification system, correlating replication under remdesivir treatment with RAS location in nsp12, shows that most nsp12-RAS cause moderate resistance.</jats:p>", "alternative-id": [ "v17081055" ], "author": [ { "ORCID": "https://orcid.org/0000-0002-3505-4733", "affiliation": [ { "name": "Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark" } ], "authenticated-orcid": false, "family": "Fernandez-Antunez", "given": "Carlota", "sequence": "first" }, { "affiliation": [ { "name": "Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark" } ], "family": "Ryberg", "given": "Line A.", "sequence": "additional" }, { "affiliation": [ { "name": "Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark" } ], "family": "Wang", "given": "Kuan", "sequence": "additional" }, { "affiliation": [ { "name": "Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark" } ], "family": "Pham", "given": "Long V.", "sequence": "additional" }, { "affiliation": [ { "name": "Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital, 2650 Hvidovre and Department of Immunology and Microbiology, Faculty of Health and Medical 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