Recurrent independent emergence and transmission of SARS-CoV-2 Spike amino acid H69/V70 deletions

Abstract

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 deletion in the S gene, which results in loss of two amino acids: H69 and V70. Of particular note this deletion, 𝚫H69/V70, often co-occurs with the receptor binding motif amino acid replacements N501Y, N439K and Y453F. One of the 𝚫H69/V70+ N501Y lineages, B.1.1.7, is comprised of over 4000 SARS-CoV-2 genome sequences from the UK and includes eight other S gene mutations: RBD (N501Y and A570D), S1 (𝚫H69/V70 and 𝚫144/145) and S2 (P681H, T716I, S982A and D1118H). Some of these mutations have presumably arisen as a result of the virus evolving from immune selection pressure in infected individuals and at least one, lineage B.1.1.7, potentially from a chronic infection. Given our recent evidence that 𝚫H69/V70 enhances viral infectivity (Kemp et al. 2020), its effect on virus fitness appears to be independent to the RBD changes. Enhanced surveillance for the 𝚫H69/V70 deletion with and without RBD mutations should be considered as a priority. Permissive mutations such as 𝚫H69/V70 have the potential to enhance the ability of SARS-CoV-2 to generate new variants, including vaccine escape variants, that would have otherwise significantly reduced viral fitness.

A Comprehensive Molecular Epidemiological Analysis of SARS-CoV-2 Infection in Cyprus from April 2020 to January 2021: Evidence of a Highly Polyphyletic and Evolving Epidemic

“…These three countries were identified as "sources" and "sinks" within our dataset for the B.1.258 lineage (Table 2, Figure 9). The B.1.258 lineage is characterized by ∆H69/V70 deletions in the S protein (Figures 2 and 3), and interestingly, these deletions have recurrently emerged in a number of lineages, including B.1.1.7 and B.1.351 [73][74][75]. ∆H69/V70 deletions in the S protein (specifically the N-terminal domain (NTD)) have been linked to increased infectivity and evasion of the host immune system.…”

“…∆H69/V70 deletions in the S protein (specifically the N-terminal domain (NTD)) have been linked to increased infectivity and evasion of the host immune system. These two deletions are suspected to compensate for mutations such as N501Y that reduce infectivity [73][74][75]. Moreover, ∆H69/V70 has been reported to be responsible for the failure of certain commercial testing kits to detect the S protein [62].…”

Inferring selection effects in SARS-CoV-2 with Bayesian Viral Allele Selection

“…Mechanisms of epistasis are likely pleiotropic, but some interactions likely arise from a need to a) incorporate mutations that confer immune escape against the current landscape of circulating variants while b) maintaining protein structure and function. This behavior has been demonstrated for the recurrent S:69-70 deletion (Gupta et al, 2021). Because the space of possible combinations of alleles is very large, most studies have characterized mutations either individually or in the combinations present in common lineages.…”

Design of Specific Primer Sets for the Detection of SARS-CoV-2 Variants of Concern B.1.1.7, B.1.351, P.1, B.1.617.2 using Artificial Intelligence

“…Researchers believe that the S-gene target failure occurs due to the failure of one of the RT-PCR probes to bind, as a result of the 69-70 deletion in the SARS-CoV-2 spike protein, present in B.1.1.7 3 . This 69-70 deletion, which affects its N-terminal domain, has been occurring in several different SARS-CoV-2 variants around the world 10,99 and has been associated with other spike protein receptor binding domain changes 9 . Due to the likeliness of mutations in the S-gene, assays relying solely on its detection are not recommended, and a multiplex approach is required 86,87,100 .…”