In vitro evolution of Remdesivir resistance reveals genome plasticity of SARS-CoV-2

Szemiel, A. M.; Merits, A.; Orton, R. J.; MacLean, O.; Wickenhagen, A.; Lieber, G.; Pinto, R. M.; Turnbull, M. L.; Wang, S.; Mair, D.; da Silva Filipe, A.; Willett, B. J.; Wilson, S. J.; Patel, A. H.; Thomson, E. C.; Palmarini, M.; Kohl, A.; Stewart, M. E.

doi:10.1101/2021.02.01.429199

bioRxiv · 10.1101/2021.02.01.429199

In vitro evolution of Remdesivir resistance reveals genome plasticity of SARS-CoV-2

Szemiel, A. M.·Merits, A.·Orton, R. J.·MacLean, O.·Wickenhagen, A.·Lieber, G.·Pinto, R. M.·Turnbull, M. L.·Wang, S.·Mair, D.·da Silva Filipe, A.·Willett, B. J.·Wilson, S. J.·Patel, A. H.·Thomson, E. C.·Palmarini, M.·Kohl, A.·Stewart, M. E.

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Abstract

Remdesivir (RDV) is used widely for COVID-19 patients despite varying results in recent clinical trials. Here, we show how serially passaging SARS-CoV-2 in vitro in the presence of RDV selected for drug-resistant viral populations. We determined that the E802D mutation in the RNA-dependent RNA polymerase was sufficient to confer decreased RDV sensitivity without affecting viral fitness. Analysis of more than 200,000 sequences of globally circulating SARS-CoV-2 variants show no evidence of widespread transmission of RDV-resistant mutants. Surprisingly, we also observed changes in the Spike (i.e., H69 E484, N501, H655) corresponding to mutations identified in emerging SARS-CoV-2 variants indicating that they can arise in vitro in the absence of immune selection. This study illustrates SARS-CoV-2 genome plasticity and offers new perspectives on surveillance of viral variants. One Sentence SummarySARS-CoV-2 drug resistance & genome plasticity

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Szemiel, A. M., Merits, A., Orton, R. J., MacLean, O., Wickenhagen, A., Lieber, G., Pinto, R. M., Turnbull, M. L., Wang, S., Mair, D., da Silva Filipe, A., Willett, B. J., Wilson, S. J., Patel, A. H., Thomson, E. C., Palmarini, M., Kohl, A., Stewart, M. E.. 2021-02-10. In vitro evolution of Remdesivir resistance reveals genome plasticity of SARS-CoV-2. https://doi.org/10.1101/2021.02.01.429199

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