A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes.

Sanderson, Theo ORCID: 0000-0003-4177-2851, Hisner, Ryan, Donovan-Banfield, I'ah ORCID: 0000-0002-5124-2427, Hartman, Hassan, Løchen, Alessandra, Peacock, Thomas P ORCID: 0000-0001-7077-2928 and Ruis, Christopher ORCID: 0000-0003-0977-5534 (2023) A molnupiravir-associated mutational signature in global SARS-CoV-2 genomes. Nature, 623 (7987). pp. 594-600.

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Official URL: http://dx.doi.org/10.1038/s41586-023-06649-6

Abstract

Molnupiravir, an antiviral medication widely used against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), acts by inducing mutations in the virus genome during replication. Most random mutations are likely to be deleterious to the virus and many will be lethal; thus, molnupiravir-induced elevated mutation rates reduce viral load<sup>1,2</sup>. However, if some patients treated with molnupiravir do not fully clear the SARS-CoV-2 infections, there could be the potential for onward transmission of molnupiravir-mutated viruses. Here we show that SARS-CoV-2 sequencing databases contain extensive evidence of molnupiravir mutagenesis. Using a systematic approach, we find that a specific class of long phylogenetic branches, distinguished by a high proportion of G-to-A and C-to-T mutations, are found almost exclusively in sequences from 2022, after the introduction of molnupiravir treatment, and in countries and age groups with widespread use of the drug. We identify a mutational spectrum, with preferred nucleotide contexts, from viruses in patients known to have been treated with molnupiravir and show that its signature matches that seen in these long branches, in some cases with onward transmission of molnupiravir-derived lineages. Finally, we analyse treatment records to confirm a direct association between these high G-to-A branches and the use of molnupiravir.

Item Type:	Article
Uncontrolled Keywords:	Humans, Hydroxylamines, Cytidine, Antiviral Agents, Viral Load, Evolution, Molecular, Phylogeny, Virus Replication, Mutagenesis, Mutation, Genome, Viral, COVID-19, SARS-CoV-2, COVID-19 Drug Treatment
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Infection, Veterinary and Ecological Sciences
Depositing User:	Symplectic Admin
Date Deposited:	29 Nov 2023 09:13
Last Modified:	08 Dec 2023 13:21
DOI:	10.1038/s41586-023-06649-6
Open Access URL:	https://www.nature.com/articles/s41586-023-06649-6
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3177046