Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections

Nooruzzaman, Mohammed; Johnson, Katherine E. E.; Rani, Ruchi; Finkelsztein, Eli J.; Caserta, Leonardo C.; Kodiyanplakkal, Rosy P.; Wang, Wei; Hsu, Jingmei; Salpietro, Maria T.; Banakis, Stephanie; Albert, Joshua; Westblade, Lars F.; Zanettini, Claudio; Marchionni, Luigi; Soave, Rosemary; Ghedin, Elodie; Diel, Diego G.; Salvatore, Mirella

doi:10.1038/s41467-024-51924-3

Cited by 3 publications

References 53 publications

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Naturally occurring N-terminal mutations in SARS-CoV-2 nsp1 impact innate immune modulation but do not affect virus virulence

Rani,

Nooruzzaman,

Caserta

et al. 2024

Preprint

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The non-structural protein 1 (nsp1) of SARS-CoV-2 plays a key role in host innate immune evasion. We identified two deletion variants (Δ82-85 and Δ83-86) in the N-terminal region of the nsp1 of a SARS-CoV-2 BA.5.2.1 variant recovered from a human patient. Analysis of the sequence databases revealed a frequency of 0.5% of these mutations amongst available SARS-CoV-2 sequences. Structural analysis of the deletion mutant nsp1Δ82-85 and nsp1Δ83-86 revealed a distortion in the protein pocket when compared to the wild-type nsp1 which may affect protein function. To evaluate the functional relevance of these mutations, we cloned the mutant BA.5.2.1 nsp1Δ82-85 and nsp1Δ83-86 and wild-type nsp1 proteins in expression plasmids and performed luciferase reporter-based assays to assess activation of the interferon and nuclear factor kappa B (NF-κB) signalling pathways. Both nsp1Δ82-85 and nsp1Δ83-86 mutants showed marked decreased ability to inhibit the interferon beta (IFN-β) and NF-κB pathway activation. To assess the relevance of these deletions in the context of SARS-CoV-2 infection, we generated recombinant viruses carrying the wild type BA.5.2.1 nsp1 or the BA.5.2.1 nsp1Δ82-85 and nsp1Δ83-86 deletions in the backbone of WA1 strain. In vitro characterization of the recombinant SARS-CoV-2 viruses revealed that the recombinant viruses containing the nsp1Δ82-85 and nsp1Δ83-86 deletions presented similar plaque size and morphology to those produced by the wild-type rWA1-BA.5.2.1-nsp1 virus, indicating a similar ability of the mutant viruses to spread from cell to cell. Importantly, pathogenesis studies revealed that these mutations did not affect virus virulence and pathogenesis in a hamster model of SARS-CoV-2 infection.

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Naturally occurring N-terminal mutations in SARS-CoV-2 nsp1 impact innate immune modulation but do not affect virus virulence

Rani,

Nooruzzaman,

Caserta

et al. 2024

Preprint

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Host-Directed Repurposed Diltiazem Enhances the Antiviral Activity of Classic Antivirals Against Influenza and Sars-Cov-2

Padey,

Droillard,

Dulière

et al. 2024

Preprint

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SARS-CoV-2 Evolution: Implications for Diagnosis, Treatment, Vaccine Effectiveness and Development

Angius,

Puxeddu,

Zaimi

et al. 2024

Vaccines

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The COVID-19 pandemic, driven by the rapid evolution of the SARS-CoV-2 virus, presents ongoing challenges to global public health. SARS-CoV-2 is characterized by rapidly evolving mutations, especially in (but not limited to) the spike protein, complicating predictions about its evolutionary trajectory. These mutations have significantly affected transmissibility, immune evasion, and vaccine efficacy, leading to multiple pandemic waves with over half a billion cases and seven million deaths globally. Despite several strategies, from rapid vaccine development and administration to the design and availability of antivirals, including monoclonal antibodies, already having been employed, the persistent circulation of the virus and the emergence of new variants continue to result in high case numbers and fatalities. In the past four years, immense research efforts have contributed much to our understanding of the viral pathogenesis mechanism, the COVID-19 syndrome, and the host–microbe interactions, leading to the development of effective vaccines, diagnostic tools, and treatments. The focus of this review is to provide a comprehensive analysis of the functional impact of mutations on diagnosis, treatments, and vaccine effectiveness. We further discuss vaccine safety in pregnancy and the implications of hybrid immunity on long-term protection against infection, as well as the latest developments on a pan-coronavirus vaccine and nasal formulations, emphasizing the need for continued surveillance, research, and adaptive public health strategies in response to the ongoing SARS-CoV-2 evolution race.

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Emergence of transmissible SARS-CoV-2 variants with decreased sensitivity to antivirals in immunocompromised patients with persistent infections

Cited by 3 publications

References 53 publications

Naturally occurring N-terminal mutations in SARS-CoV-2 nsp1 impact innate immune modulation but do not affect virus virulence

Naturally occurring N-terminal mutations in SARS-CoV-2 nsp1 impact innate immune modulation but do not affect virus virulence

Host-Directed Repurposed Diltiazem Enhances the Antiviral Activity of Classic Antivirals Against Influenza and Sars-Cov-2

SARS-CoV-2 Evolution: Implications for Diagnosis, Treatment, Vaccine Effectiveness and Development

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