RT Journal Article
SR Electronic
T1 Recurrent emergence and transmission of a SARS-CoV-2 Spike deletion H69/V70
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.14.422555
DO 10.1101/2020.12.14.422555
A1 SA Kemp
A1 B Meng
A1 IATM Ferriera
A1 RP Datir
A1 WT Harvey
A1 DA Collier
A1 S Lytras
A1 G Papa
A1 The COVID-19 Genomics UK (COG-UK) Consortium
A1 AM Carabelli
A1 J Kenyon
A1 AML Lever
A1 LC James
A1 DL Robertson
A1 RK Gupta
YR 2021
UL http://biorxiv.org/content/early/2021/02/09/2020.12.14.422555.abstract
AB SARS-CoV-2 Spike amino acid replacements in the receptor binding domain (RBD) occur relatively frequently and some have a consequence for immune recognition. Here we report recurrent emergence and significant onward transmission of a six-nucleotide out of frame deletion in the S gene, which results in loss of two amino acids: H69 and V70. We show that ΔH69/V70 and other common NTD deletions occur at loop structures in RNA where polymerase activity is often compromised. In addition, the same two amino acid deletion is also observed in a set of closely related pangolin sarbecoviruses, but not in the bat sarbecovirus RaTG13. We report that in human infections ΔH69/V70 often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F, and in the latter two cases has followed the RBD mutation suggesting an epistatic interaction. One of the ΔH69/V70+ N501Y lineages, B.1.1.7, has undergone rapid expansion and includes eight other S gene mutations: RBD (N501Y and A570D), S1 (ΔH69/V70 and Δ144/145) and S2 (P681H, T716I, S982A and D1118H). In vitro, we show that ΔH69/V70 does not impact serum neutralisation across multiple convalescent sera. However, the ΔH69/V70 does increase infectivity of Spike and is able to compensate for infectivity defects induced by RBD mutations N501Y, N439K and Y453F. In addition replacement of H69 and V70 in B.1.1.7 Spike substantially reduces its infectivity. Mechanistically, we demonstrate that ΔH69/V70 is associated with two fold increased Spike incorporation into virions, though it does not increase cell-cell fusion. Based on our data ΔH69/V70 increases Spike infectivity, likely acting as a permissive mutation that allows acquisition of otherwise deleterious immune escape mutations. Enhanced surveillance for the ΔH69/V70 deletion with and without RBD mutations should be considered as a global priority not only as a marker for the B.1.1.7 variant, but potentially also for other emerging variants of concern.Competing Interest StatementRKG has received consulting fees from UMOVIS lab, Gilead Sciences and ViiV Healthcare, and a research grant from InvisiSmart Technologies.