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. 2023 Dec 19;12(1):2.
doi: 10.3390/microorganisms12010002.

Assessing Genomic Mutations in SARS-CoV-2: Potential Resistance to Antiviral Drugs in Viral Populations from Untreated COVID-19 Patients

Daniele Lombardo  1 , Cristina Musolino  2 , Valeria Chines  1 , Giuseppe Caminiti  1 , Claudia Palermo  1 , Irene Cacciola  1 , Giuseppina Raffa  1 , Teresa Pollicino  1
Affiliations

Assessing Genomic Mutations in SARS-CoV-2: Potential Resistance to Antiviral Drugs in Viral Populations from Untreated COVID-19 Patients

Daniele Lombardo et al. Microorganisms. .

Abstract

Naturally occurring SARS-CoV-2 variants mutated in genomic regions targeted by antiviral drugs have not been extensively studied. This study investigated the potential of the RNA-dependent RNA polymerase (RdRp) complex subunits and non-structural protein (Nsp)5 of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) to accumulate natural mutations that could affect the efficacy of antiviral drugs. To this aim, SARS-CoV-2 genomic sequences isolated from 4155 drug-naive individuals from southern Italy were analyzed using the Illumina MiSeq platform. Sequencing of the 4155 samples showed the following viral variant distribution: 71.2% Delta, 22.2% Omicron, and 6.4% Alpha. In the Nsp12 sequences, we found 84 amino acid substitutions. The most common one was P323L, detected in 3777/4155 (91%) samples, with 2906/3777 (69.9%) also showing the G671S substitution in combination. Additionally, we identified 28, 14, and 24 different amino acid substitutions in the Nsp5, Nsp7, and Nsp8 genomic regions, respectively. Of note, the V186F and A191V substitutions, affecting residues adjacent to the active site of Nsp5 (the target of the antiviral drug Paxlovid), were found in 157/4155 (3.8%) and 3/4155 (0.07%) samples, respectively. In conclusion, the RdRp complex subunits and the Nsp5 genomic region exhibit susceptibility to accumulating natural mutations. This susceptibility poses a potential risk to the efficacy of antiviral drugs, as these mutations may compromise the drug ability to inhibit viral replication.

Keywords: COVID-19; SARS-CoV-2; antiviral drug resistance; antiviral drugs; antiviral therapy; coronaviruses; natural variants; new generation sequencing; viral genomic mutation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of SARS-CoV-2 lineages prevalence in 4155 samples from subjects with a first positive SARS-CoV-2 PCR test analyzed at the Molecular Diagnostic Laboratory of the Unit of Advanced Diagnostic Laboratories, University Hospital of Messina, Italy, from April 2021 to October 2022.
Figure 2
Figure 2
Representation of prevalence expressed in percentage (%) of SARS-CoV-2 variants prevalence between April 2021 and October 2022. * B.1.617.2 and parent lineages; ° B.1.1.529 and parent lineages.
Figure 3
Figure 3
Schematic representation of the most frequent amino acid substitutions identified in Nsp12, 5, 7, and 8 in the samples analyzed. I, II, III represent the three domains of NSP5 protein. # B.1.1.7; * B.1.617.2 and parent lineages.
Figure 4
Figure 4
Phylogenetic tree of Nsp12 (a), Nsp7 (b), Nsp8 (c), and Nsp5 (d) showing evolutionary relationship between the samples analyzed and the reference sequence. The evolutionary history was inferred by using the Maximum Likelihood method and the Tamura–Nei model. The presence of single nucleotide mutations caused the further subdivision of the clades in different subgroups.
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