High fusion and cytopathy of SARS-CoV-2 variant B.1.640.1

Author:

Bolland William12ORCID,Michel Vincent3,Planas Delphine14,Hubert Mathieu1,Staropoli Isabelle1,Guivel-Benhassine Florence1,Porrot Françoise1,N'Debi Mélissa56,Rodriguez Christophe56,Fourati Slim56ORCID,Prot Matthieu7,Planchais Cyril8,Hocqueloux Laurent9,Simon-Lorière Etienne7,Mouquet Hugo8,Prazuck Thierry9,Pawlotsky Jean-Michel56ORCID,Bruel Timothée14,Schwartz Olivier14ORCID,Buchrieser Julian1ORCID

Affiliation:

1. Virus and Immunity Unit, Institut Pasteur, Université Paris Cité, CNRS UMR3569, Paris, France

2. Université Paris Cité, Paris, France

3. Pathogenesis of Vascular Infections Unit, Institut Pasteur, INSERM, Paris, France

4. Vaccine Research Institute, Créteil, France

5. Department of Virology, Hôpital Henri Mondor (AP-HP), Université Paris-Est, Créteil, France

6. Institut Mondor de Recherche Biomédicale, INSERM U955, Créteil, France

7. Evolutionary Genomics of RNA Viruses, Institut Pasteur, Université Paris Cité, Paris, France

8. Humoral Immunology Unit, Institut Pasteur, Université Paris Cité, INSERM U1222, Paris, France

9. CHR d’Orléans, Infectious Diseases Service, Orléans, France

Abstract

ABSTRACT SARS-CoV-2 variants with undetermined properties have emerged intermittently throughout the COVID-19 pandemic. Some variants possess unique phenotypes and mutations which allow further characterization of viral evolution and Spike functions. Around 1,100 cases of the B.1.640.1 variant were reported in Africa and Europe between 2021 and 2022, before the expansion of Omicron. Here, we analyzed the biological properties of a B.1.640.1 isolate and its Spike. Compared to the ancestral Spike, B.1.640.1 carried 14 amino acid substitutions and deletions. B.1.640.1 escaped binding by some anti-N-terminal domain and anti-receptor-binding domain monoclonal antibodies, and neutralization by sera from convalescent and vaccinated individuals. In cell lines, infection generated large syncytia and a high cytopathic effect. In primary airway cells, B.1.640.1 replicated less than Omicron BA.1 and triggered more syncytia and cell death than other variants. The B.1.640.1 Spike was highly fusogenic when expressed alone. This was mediated by two poorly characterized and infrequent mutations located in the Spike S2 domain, T859N and D936H. Altogether, our results highlight the cytopathy of a hyper-fusogenic SARS-CoV-2 variant, supplanted upon the emergence of Omicron BA.1. (This study has been registered at ClinicalTrials.gov under registration no. NCT04750720.) IMPORTANCE Our results highlight the plasticity of SARS-CoV-2 Spike to generate highly fusogenic and cytopathic strains with the causative mutations being uncharacterized in previous variants. We describe mechanisms regulating the formation of syncytia and the subsequent consequences in a primary culture model, which are poorly understood.

Funder

Pasteur-Paris University International Doctoral Program

Institut Pasteur

Vaccine Research Institute

INCEPTION

NIH PICREID

Fondation pour la Recherche Médicale

Labex IBEID

ANR / FRM Flash Covid PROTEO-SARS-CoV-2

ANR Coronamito

HERA European funding

Sanofi US | Sanofi Pasteur

IDISCOVR

Publisher

American Society for Microbiology

Subject

Virology,Insect Science,Immunology,Microbiology

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