TY - JOUR
T1 - SARS-CoV-2 evolution during treatment of chronic infection
AU - Royal Papworth Hospital ICU
AU - Addenbrooke’s Hospital ICU
AU - Cambridge & Peterborough Foundation Trust
AU - ANPC & Centre for Molecular Medicine & Innovative Therapeutics
AU - NIHR BioResource
AU - The COVID-19 Genomics UK (COG-UK) Consortium
AU - The CITIID-NIHR BioResource COVID-19 Collaboration
AU - Principal investigators
AU - CRF & volunteer research nurses
AU - Sample logistics
AU - Sample processing & data acquisition
AU - Clinical data collection
AU - Kemp, Steven A.
AU - Collier, Dami A.
AU - Datir, Rawlings P.
AU - Ferreira, Isabella A.T.M.
AU - Gayed, Salma
AU - Jahun, Aminu
AU - Hosmillo, Myra
AU - Rees-Spear, Chloe
AU - Mlcochova, Petra
AU - Lumb, Ines Ushiro
AU - Roberts, David J.
AU - Chandra, Anita
AU - Temperton, Nigel
AU - Baker, Stephen
AU - Dougan, Gordon
AU - Hess, Christoph
AU - Kingston, Nathalie
AU - Lehner, Paul J.
AU - Lyons, Paul A.
AU - Matheson, Nicholas J.
AU - Owehand, Willem H.
AU - Saunders, Caroline
AU - Summers, Charlotte
AU - Thaventhiran, James E.D.
AU - Toshner, Mark
AU - Weekes, Michael P.
AU - Bucke, Ashlea
AU - Calder, Jo
AU - Canna, Laura
AU - Domingo, Jason
AU - Elmer, Anne
AU - Fuller, Stewart
AU - Harris, Julie
AU - Hewitt, Sarah
AU - Kennet, Jane
AU - Jose, Sherly
AU - Kourampa, Jenny
AU - Meadows, Anne
AU - O’Brien, Criona
AU - Price, Jane
AU - Publico, Cherry
AU - Rastall, Rebecca
AU - Ribeiro, Carla
AU - Rowlands, Jane
AU - Ruffolo, Valentina
AU - Tordesillas, Hugo
AU - Bullman, Ben
AU - Dunmore, Benjamin J.
AU - Fawke, Stuart
AU - Gräf, Stefan
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/4/8
Y1 - 2021/4/8
N2 - The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.
AB - The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical for virus infection through the engagement of the human ACE2 protein1 and is a major antibody target. Here we show that chronic infection with SARS-CoV-2 leads to viral evolution and reduced sensitivity to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma, by generating whole-genome ultra-deep sequences for 23 time points that span 101 days and using in vitro techniques to characterize the mutations revealed by sequencing. There was little change in the overall structure of the viral population after two courses of remdesivir during the first 57 days. However, after convalescent plasma therapy, we observed large, dynamic shifts in the viral population, with the emergence of a dominant viral strain that contained a substitution (D796H) in the S2 subunit and a deletion (ΔH69/ΔV70) in the S1 N-terminal domain of the spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype were reduced in frequency, before returning during a final, unsuccessful course of convalescent plasma treatment. In vitro, the spike double mutant bearing both ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, while maintaining infectivity levels that were similar to the wild-type virus.The spike substitution mutant D796H appeared to be the main contributor to the decreased susceptibility to neutralizing antibodies, but this mutation resulted in an infectivity defect. The spike deletion mutant ΔH69/ΔV70 had a twofold higher level of infectivity than wild-type SARS-CoV-2, possibly compensating for the reduced infectivity of the D796H mutation. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.
UR - https://www.scopus.com/pages/publications/85100656245
U2 - 10.1038/s41586-021-03291-y
DO - 10.1038/s41586-021-03291-y
M3 - Artículo
C2 - 33545711
AN - SCOPUS:85100656245
SN - 0028-0836
VL - 592
SP - 277
EP - 282
JO - Nature
JF - Nature
IS - 7853
ER -