SARS-CoV-2 evolution during treatment of chronic infection

Kemp, Steven A., Collier, Dami A., Datir, Rawlings P., Ferreira, Isabella A. T. M., Gayed, Salma, Jahun, Aminu, Hosmillo, Myra, Rees-Spear, Chloe, Mlcochova, Petra, Ushiro Lumb, Ines, Roberts, David J., Chandra, Anita, Temperton, Nigel, Sharrocks, Katherine, Blane, Elizabeth, Modis, Yorgo, Leigh, Kendra E., Briggs, John A. G., van Gils, Marit J., Smith, Kenneth G. C., Bradley, John R., Smith, Chris, Doffinger, Rainer, Ceron-Gutierrez, Lourdes, Barcenas-Morales, Gabriela, Pollock, David D., Goldstein, Richard A., Smielewska, Anna, Skittrall, Jordan P., Gouliouris, Theodore, Goodfellow, Ian G., Gkrania-Klotsas, Effrossyni, Illingworth, Christopher J. R., McCoy, Laura E. and Gupta, Ravindra K. and The CITIID-NIHR BioResource COVID-19 Collaboration, The COVID-19 Genomics UK (COG-UK) Consortium (2021) SARS-CoV-2 evolution during treatment of chronic infection. Nature, 592 (7853). pp. 277-282. ISSN 0028-0836

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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.

Item Type: Article
Additional Information: Funding Information: Acknowledgements We are grateful to the patient and his family. We thank the staff at CUH and the NIHR Cambridge Clinical Research Facility; R. Kugathasan and W. Barclay for discussions; M. Curran, W. Hamilton and D. Sparkes, A. Floto and F. Gallagher; J. Voss for the gift of HeLa cells stably expressing ACE2; and J. Nathan for the RBD protein and L. James for the nucleocapsid protein. COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute. R.K.G. is supported by a Wellcome Trust Senior Fellowship in Clinical Science (WT108082AIA). L.E.M. is supported by a Medical Research Council Career Development Award (MR/ R008698/1). S.A.K. is supported by the Bill and Melinda Gates Foundation via PANGEA grant (OPP1175094). D.A.C. is supported by a Wellcome Trust Clinical PhD Research Fellowship. C.J.R.I. acknowledges MRC funding (MC_UU_00002/11). This research was supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, the Cambridge Clinical Trials Unit (CCTU) and by the UCL Coronavirus Response Fund and made possible through generous donations from UCL’s supporters, alumni, and friends (to L.E.M.). J.A.G.B. is supported by the Medical Research Council (MC_UP_1201/16). I.G.G. is a Wellcome Senior Fellow and supported by the Wellcome Trust (207498/Z/17/Z). D.D.P. is supported by NIH GM083127. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer Nature Limited.
Uncontrolled Keywords: general ,/dk/atira/pure/subjectarea/asjc/1000
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
UEA Research Groups: Faculty of Medicine and Health Sciences > Research Groups > Nutrition and Preventive Medicine
Faculty of Medicine and Health Sciences > Research Centres > Norwich Institute for Healthy Aging
Faculty of Medicine and Health Sciences > Research Centres > Lifespan Health
Faculty of Medicine and Health Sciences > Research Groups > Musculoskeletal Medicine
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Depositing User: LivePure Connector
Date Deposited: 21 Sep 2022 09:30
Last Modified: 22 Nov 2023 04:35
DOI: 10.1038/s41586-021-03291-y


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