SARS-CoV-2 genome signature leads to replicative advantage in presence of Remdesivir

By Dr. Tomislav Meštrović, MD, Ph.D.Sep 22 2021

A new study by researchers from the United Kingdom indicates that low-level resistance of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to remdesivir is not widespread and dissimilar to other RNA viruses revealing evolutionary predictability of this pandemic virus.

Study: In vitro selection of Remdesivir resistance suggests evolutionary predictability of SARS-CoV-2. Image Credit: Bernard Chantal/ Shutterstock

Background

The emergence of SARS-CoV-2 and consequent coronavirus disease (COVID-19) pandemic has resulted in substantial disease burden and mortality. Although vaccine development and subsequent distribution have been conducted at an unprecedented rate, there is still a lack of efficacious drugs.

A global effort to repurpose antiviral inhibitors quickly identified remdesivir (a broadly acting nucleoside analog) as a candidate for treating patients hospitalized due to SARS-CoV-2, following its swift emergency approval by the U.S. Food and Drug Administration (FDA).

Treatment with remdesivir is still prescribed to hospitalized SARS-CoV-2 patients in certain parts of the world; one notable example was its wide usage during the second COVID-19 wave in India.

It is known that viruses frequently mutate and adapt to become resistant to antiviral treatment, affecting patient and disease management. Thus far, no reports have identified SARS-CoV-2 resistance to remdesivir in patients or animal models.

In a recent paper published in the journal PLOS Pathogens, a research group led by Dr. Angieszka M. Szemiel from the MRC-University of Glasgow Centre for Virus Research in Glasgow (United Kingdom) aimed to appraise the potential of the virus for developing resistance to the aforementioned drug.

From viral passages to big data

In this study, the researchers have selected drug-resistant viral populations by passaging SARS-CoV-2 in vitro in the presence of remdesivir. In addition, viruses serving as controls were passaged in parallel to monitor for mutations that can arise due to cell culture adaptation unrelated to remdesivir resistance.

Furthermore, the change in the half-maximal effective concentration (EC50) and replication kinetics of remdesivir have been appraised in a subset of such passaged virus populations, as these variables may indicate the rise of viral resistance.

Finally, this paper has also evaluated available SARS-CoV-2 genome sequences in the GISAID database (i.e., a repository where phylogenetic clades and lineages to genetic sequences of this pandemic virus can be found) to determine its replacement frequency.

Mutation with a cost to viral fitness

The researchers have pinpointed a mutation in the SARS-CoV-2 polymerase responsible for decreased sensitivity to remdesivir. Although a change at this conserved site was not predicted, the mutation did not result in a replication advantage or sensitivity change to another antiviral drug.

An important 'big data' finding was that this change was present at a very low frequency on a global level. Moreover, the passage of SARS-CoV-2 resulted in an accumulation of mutations in spike glycoprotein at analogous sites but to different residues when compared to emerging variants of concern.

"Our data demonstrates that selection of remdesivir resistance in SARS-CoV-2 can occur but there is no evidence of global spread of remdesivir-resistant strains as the remdesivir resistance mutation identified in our study provides a cost to viral fitness", explain study authors.

Study implications

In short, this in vitro evolution study found a genome signature in SARS-CoV-2, leading to replicative advantage in the presence of the drug remdesivir. This is something to have in mind in non-responding patients, as thus far, the leading hypothesis was a drug tolerance by synchronization.

"In addition, we have also shown that key amino acid residues that have been identified in emerging variants of concerns in three different continents can occur in vitro in the absence of immune pressure," say study authors.

Overall, this study provides a new perspective for the surveillance of SARS-CoV-2 variants and the clinical management of patients treated with remdesivir. The results may be used to inform these types of studies when new drugs come on the market, as the problem of antiviral resistance is always looming.