Naturally occurring SARS-CoV-2 gene deletions close to the spike S1/S2 cleavage site in the viral quasispecies of COVID19 patients

Andres, Cristina; Garcia-Cehic, Damir; Gregori, Josep; Piñana, Maria; Rodriguez-Frias, Francisco; Guerrero-Murillo, Mercedes; Esperalba, Juliana; Rando, Ariadna; Goterris, Lidia; Codina, Maria Gema; Quer, Susanna; Martín, Maria Carmen; Campins, Magda; Ferrer, Ricard; Almirante, Benito; Esteban, Juan Ignacio; Pumarola, Tomás; Antón, Andrés; Quer, Josep

The SARS-CoV-2 spike (S) protein, the viral mediator for binding and entry into the host cell, has sparked great interest as a target for vaccine development and treatments with neutralizing antibodies. Initial data suggest that the virus has low mutation rates, but its large genome could facilitate recombination, insertions, and deletions, as has been described in other coronaviruses. Here, we deep-sequenced the complete SARS-CoV-2 S gene from 18 patients (10 with mild and 8 with severe COVID-19), and found that the virus accumulates deletions upstream and very close to the S1/S2 cleavage site, generating a frameshift with appearance of a stop codon. These deletions were found in a small percentage of the viral quasispecies (2.2%) in samples from all the mild and only half the severe COVID-19 patients. Our results suggest that the virus may generate free S1 protein released to the circulation. We propose that natural selection has favored a “Don’t burn down the house” strategy, in which free S1 protein may compete with viral particles for the ACE2 receptor, thus reducing the severity of the infection and tissue damage without losing transmission capability.