Nasopharyngeal specific selection and emergence of SARS-CoV-2 spike fusion peptide mutation P812S during chronic infection

Abstract

Persistent SARS-CoV-2 infections are a likely source of new variants of concern. In a fatal infection in an immunocompromised patient, we find association between viral load and diversity, and abrupt diversification between contemporaneous nasopharyngeal and endotracheal aspirate samples following remdesivir and convalescent plasma treatment. Shared high proportion of G>T mutations suggests spread of viruses from the lower to the upper tract as the patient deteriorated. We identified the S:P812S spike mutation adjacent to the fusion peptide unique to the nasopharyngeal sample site. We find P812S reduced S1/S2 cleavage and decreased entry efficiency in cell lines with a range of ACE2 and TMPRSS2 expression levels. This reduction of infectivity contrasted with reduced susceptibility to neutralising antibodies in sera from vaccinated individuals conferred by P812S at both 37°C and 32°C (simulating upper tract). Thus, S:P812S is a specific adaptation during SARS-CoV-2 intrahost evolution, allowing immune evasion at lower temperatures observed in the upper respiratory tract at the expense of target cell entry efficiency.