Atypical Mutational Spectrum of SARS-CoV-2 Replicating in the Presence of Ribavirin

Somovilla, Pilar; García-Crespo, Carlos; Martínez-González, Brenda; Soria, María Eugenia; Ávila, Ana Isabel de; Gallego, Isabel; Mínguez, Pablo; Durán-Pastor, Antoni; Ferrer-Orta, Cristina; Salar-Vidal, Llanos; Esteban-Muñoz, Mario; Zúñiga, Sonia; Sola, Isabel; Enjuanes, Luis; Esteban, Jaime; Fernández-Roblas, R.; Gadea, Ignacio; Gómez, Jordi; Verdaguer, N.; Domingo, Esteban; Perales, Celia

doi:10.1128/aac.01315-22

Cited by 6 publications

(16 citation statements)

References 92 publications

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“…However, the only bias that reached statistical significance was the presence of a G at the 5 0 side of A ! G transitions in populations treated with RBV, a preference that was previously reported (Somovilla et al, 2023). Mutational site biases appear to have played a minor role in the synergy between RDV and RBV for SARS-CoV-2.…”

Section: Increase Of Sars-cov-2 Mutational Load Upon Replication Of S...supporting

confidence: 73%

“…• Their synergistic activity can extinguish the virus. Beaucourt & Vignuzzi, 2014;Brady et al, 2022;Geraghty et al, 2021;Somovilla et al, 2023). As a step towards searching for repositioned drugs that could suppress SARS-CoV-2, we have explored whether the activity of RBV against SARS-CoV-2 could be reinforced by the inhibition exerted by remdesivir…”

Section: What Does This Study Addmentioning

confidence: 99%

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Synergism between remdesivir and ribavirin leads to SARS‐CoV‐2 extinction in cell culture

García‐Crespo,

de Ávila,

Gallego

et al. 2024

British J Pharmacology

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Background and PurposeThere is a need for effective anti‐COVID‐19 treatments, mainly for individuals at risk of severe disease such as the elderly and the immunosuppressed. Drug repositioning has proved effective in identifying drugs that can find a new application for the control of coronavirus disease, in particular COVID‐19. The purpose of the present study was to find synergistic antiviral combinations for COVID‐19 based on lethal mutagenesis.Experimental ApproachThe effect of combinations of remdesivir and ribavirin on the infectivity of SARS‐CoV‐2 in cell culture has been tested. Viral populations were monitored by ultra‐deep sequencing, and the decrease of infectivity as a result of the treatment was measured.Key ResultsRemdesivir and ribavirin exerted a synergistic inhibitory activity against SARS‐CoV‐2, quantified both by CompuSyn (Chou‐Talalay method) and Synergy Finder (ZIP‐score model). In serial passage experiments, virus extinction was readily achieved with remdesivir‐ribavirin combinations at concentrations well below their cytotoxic 50 value, but not with the drugs used individually. Deep sequencing of treated viral populations showed that remdesivir, ribavirin, and their combinations evoked significant increases of the number of viral mutations and haplotypes, as well as modification of diversity indices that characterize viral quasi‐species.Conclusion and ImplicationsSARS‐CoV‐2 extinction can be achieved by synergistic combination treatments based on lethal mutagenesis. In addition, the results offer prospects of triple drug treatments for effective SARS‐CoV‐2 suppression.

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Section: Increase Of Sars-cov-2 Mutational Load Upon Replication Of S...supporting

confidence: 73%

Section: What Does This Study Addmentioning

confidence: 99%

Synergism between remdesivir and ribavirin leads to SARS‐CoV‐2 extinction in cell culture

García‐Crespo,

de Ávila,

Gallego

et al. 2024

British J Pharmacology

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“…Several studies have shown that RBV inhibits the replication of SARS-CoV in vitro [ 25 , 26 , 27 ]. However, other studies have found that RBV does not exert any effect on virus replication in vivo [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Clinico-Virological Outcomes and Mutational Profile of SARS-CoV-2 in Adults Treated with Ribavirin Aerosol for COVID-19 Pneumonia

Morsica,

Messina,

Bagaglio

et al. 2024

Microorganisms

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The emergence of new SARS-CoV-2 variants can affect vaccine efficacy, laboratory diagnosis and the therapies already available, triggering interest in the search for antiviral agents for SARS-CoV-2 infections. Ribavirin (RBV) is a broad-spectrum antiviral with demonstrated in vitro activity against multiple viruses, including SARS-CoV-2. This retrospective study evaluated the dynamics and viral clearance of SARS-CoV-2 in hospitalised adult participants (PTs) with COVID-19 pneumonia who received an RBV aerosol within a compassionate use study. The impact of RBV on the clinical outcome and the mutational profile of SARS-CoV-2 was also assessed. The median RNA values measured in nine PTs included in this study decreased from baseline to discharge (at BL, threshold cycle (Ct) = 22.4, IQR 19.84–5.07; at discharge, Ct = 27.92, IQR 26.43–36.11), with a significant decline in the Ct value evaluated by Friedman rank ANOVA analysis, p = 0.032. Seven out of nine PTs experienced a clinical improvement, while two PTs deceased during hospitalisation. In PTs with a favourable outcome, the virus clearance rate at discharge was 28.6%. The cumulative clearance rate was 71.4% within 14 days from discharge. A mutational pattern after RBV was detected in three out of five PTs in whom whole-genome sequencing was available. Our findings suggest that RBV limits SARS-CoV-2 replication, possibly resulting in a favourable clinical outcome. Ribavirin may also contribute to the mutational spectrum of SARS-CoV-2.

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“…With this isolate, we have recently documented the synergistic antiviral activity exerted by the nucleoside analogs Rdv and Rib in cell culture (García-Crespo et al, 2024). Rib and, to a lesser extent, Rdv increased the mutation frequency of SARS-CoV-2 (Somovilla et al, 2023;García-Crespo et al, 2024). In that prior study, we reported the mutant spectrum composition of residues 22,872-23,645 (also with a mutation and deletion frequency cutoff of 0.1%) of 11 populations of USA-WA1/2020.…”

Section: Discordant Amino Acids and Deletions In Laboratory Preparati...mentioning

confidence: 99%

“…The laboratory populations analyzed resulted from infection of Vero E6 by SARS-CoV-2 USA-WA1/2020 (NCBI reference sequence NR-52281_70036318) (clade 19B) at a multiplicity of infection of 0.001 PFU/cell (monolayers of 2 × 10 5 -1 × 10 6 Vero E6 cells) as part of our ongoing project on lethal mutagenesis of SARS-CoV-2. The infections were carried out either in absence of drugs or in the presence of Rdv (5 μM or 10 μM) alone, Rib (100 μM or 150 μM) alone, or combinations of the two drugs (Rdv 2.5 μM or 5 μM; Rib 80 μM or 100 μM); the duration of the infection was 48 h. Drug concentrations were chosen according to their CC 50 and EC 50 values, to allow the presence of sufficient viral RNA for ultra-deep sequencing analysis (Somovilla et al, 2023;García-Crespo et al, 2024). All passage series in the absence and presence of drugs and all titrations for virus quantifications were carried out in triplicate (García-Crespo et al, 2024).…”

Section: Sars-cov-2 Patient Samples Laboratory Populations and Infect...mentioning

confidence: 99%

SARS-CoV-2 mutant spectra as variant of concern nurseries: endless variation?

Martínez-González,

Soria,

Mínguez

et al. 2024

Front. Microbiol.

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IntroductionSARS-CoV-2 isolates of a given clade may contain low frequency genomes that encode amino acids or deletions which are typical of a different clade.MethodsHere we use high resolution ultra-deep sequencing to analyze SARS-CoV-2 mutant spectra.ResultsIn 6 out of 11 SARS-CoV-2 isolates from COVID-19 patients, the mutant spectrum of the spike (S)-coding region included two or more amino acids or deletions, that correspond to discordant viral clades. A similar observation is reported for laboratory populations of SARS-CoV-2 USA-WA1/2020, following a cell culture infection in the presence of remdesivir, ribavirin or their combinations. Moreover, some of the clade-discordant genome residues are found in the same haplotype within an amplicon.DiscussionWe evaluate possible interpretations of these findings, and reviewed precedents for rapid selection of genomes with multiple mutations in RNA viruses. These considerations suggest that intra-host evolution may be sufficient to generate minority sequences which are closely related to sequences typical of other clades. The results provide a model for the origin of variants of concern during epidemic spread─in particular Omicron lineages─that does not require prolonged infection, involvement of immunocompromised individuals, or participation of intermediate, non-human hosts.

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Atypical Mutational Spectrum of SARS-CoV-2 Replicating in the Presence of Ribavirin

Cited by 6 publications

References 92 publications

Synergism between remdesivir and ribavirin leads to SARS‐CoV‐2 extinction in cell culture

Synergism between remdesivir and ribavirin leads to SARS‐CoV‐2 extinction in cell culture

Clinico-Virological Outcomes and Mutational Profile of SARS-CoV-2 in Adults Treated with Ribavirin Aerosol for COVID-19 Pneumonia

SARS-CoV-2 mutant spectra as variant of concern nurseries: endless variation?

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