Recurrent emergence of SARS-CoV-2 spike deletion H69/V70 and its role in the Alpha variant B.1.1.7

The COVID-19 Genomics UK (COG-UK) Consortium, Bo Meng, Steven A. Kemp, Guido Papa, Rawlings Datir, Isabella A.T.M. Ferreira, Sara Marelli, William T. Harvey, Spyros Lytras, Ahmed Mohamed, Giulia Gallo, Nazia Thakur, Dami A. Collier, Petra Mlcochova, Lidia M. Duncan, Alessandro M. Carabelli, Julia C. Kenyon, Andrew M. Lever, Anna De Marco, Christian SalibaKatja Culap, Elisabetta Cameroni, Nicholas J. Matheson, Luca Piccoli, Davide Corti, Leo C. James, David L. Robertson, Dalan Bailey, Ravindra K. Gupta

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Abstract

We report severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike ΔH69/V70 in multiple independent lineages, often occurring after acquisition of receptor binding motif replacements such as N439K and Y453F, known to increase binding affinity to the ACE2 receptor and confer antibody escape. In vitro, we show that, although ΔH69/V70 itself is not an antibody evasion mechanism, it increases infectivity associated with enhanced incorporation of cleaved spike into virions. ΔH69/V70 is able to partially rescue infectivity of spike proteins that have acquired N439K and Y453F escape mutations by increased spike incorporation. In addition, replacement of the H69 and V70 residues in the Alpha variant B.1.1.7 spike (where ΔH69/V70 occurs naturally) impairs spike incorporation and entry efficiency of the B.1.1.7 spike pseudotyped virus. Alpha variant B.1.1.7 spike mediates faster kinetics of cell-cell fusion than wild-type Wuhan-1 D614G, dependent on ΔH69/V70. Therefore, as ΔH69/V70 compensates for immune escape mutations that impair infectivity, continued surveillance for deletions with functional effects is warranted.

Original languageEnglish
Article number109292
Number of pages24
JournalCell Reports
Volume35
Issue number13
Early online date8 Jun 2021
DOIs
Publication statusPublished - 29 Jun 2021

Bibliographical note

Funding Information:
R.K.G. is supported by a Wellcome Trust Senior Fellowship in Clinical Science (WT108082AIA). I.A.T.M.F. is funded by the Sub-Saharan African Network for TB/HIV Research Excellence fellowship (SANTHE, a DELTAS Africa Initiative; DEL-15?006). 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. This study was supported by the Cambridge NIHRB Biomedical Research Centre. S.A.K. is supported by the Bill and Melinda Gates Foundation via PANGEA grant OPP1175094. D.L.R. is funded by the MRC (MC UU 1201412). W.H. is funded by the MRC (MR/R024758/1). We thank James Voss for the kind gift of HeLa cells stably expressing ACE2, Paul Lehner for Calu-3 cells, and Simon Cook for H1299 cells. N.J.M. is funded by the MRC (CSF ref. MR/P008801/1), NHSBT (grant ref. WPA15-02), and the Addenbrooke's Charitable Trust, Cambridge University Hospitals (grant ref. 900239). We thank Wendy Barclay and Thomas Peacock for helpful discussions and the Geno2pheno UK Consortium. S.L. is funded by Medical Research Council MC_UU_12014/12. This study was also partly funded by the Rosetrees Trust. A.M.L. is funded by the Cambridge NIHRB Biomedical Research Centre. R.K.G. B.M. R.D. I.A.T.M.F. D.L.R. L.C.J. D.B. L.P. A.D.M. N.J.M. and D.A.C. designed the study and experiments. W.T.H. and A.M.C. designed and performed structural analyses. S.A.K. B.M. S.M. L.M.D. A.D.M. C.S. E.C. and K.C. performed experiments. L.P. A.D.M. D.A.C. B.M. R.K.G. D.L.R. D.B. R.D. I.A.T.M.F. and S.A.K. interpreted data. L.P. D.A.C. R.D. I.A.T.M.F. R.K.G. B.M. S.A.K. and D.L.R. performed data analysis and manuscript preparation. A.D.M. C.S. K.C. E.C. L.P. and D.A.C. are employees of Vir Biotechnology and may hold shares in Vir Biotechnology. R.K.G. has received consulting fees from UMOVIS lab, Gilead Sciences, and ViiV Healthcare and a research grant from InvisiSmart Technologies.

Publisher Copyright:
© 2021 The Author(s)

Keywords

  • Alpha variant
  • antibody escape
  • B.1.1.7
  • COVID-19
  • deletion
  • infectivity
  • neutralizing antibodies
  • resistance
  • SARS-CoV-2
  • spike mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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