Spike Protein NTD mutation G142D in SARS-CoV-2 Delta VOC lineages is associated with frequent back mutations, increased viral loads, and immune evasion

Abstract

The significantly greater infectivity of the SARS-CoV-2 Delta variants of concern (VOC) is hypothesized to be driven by key mutations that result in increased transmissibility, viral load and/or evasion of host immune response. We surveyed the mutational profiles of Delta VOC genomes between September 2020 and mid-August 2021 and identified a previously unreported mutation pattern at amino acid position 142 in the N-terminal domain (NTD) of the spike protein which demonstrated multiple rounds of mutation from G142 to D142 and back. This pattern of frequent back mutations was observed at multiple time points and across Delta VOC sub-lineages. The etiology for these recurrent mutations is unclear but raises the possibility of host-directed editing of the SARS-CoV-2 genome. Within Delta VOC this mutation is associated with higher viral load, further enhanced in the presence of another NTD mutation (T95I) which was also frequently observed in these cases. Protein modeling of both mutations predicts alterations of the surface topography of the NTD by G142D, specifically disturbance of the ′super site′ epitope that binds NTD-directed neutralizing antibodies (NAbs). The appearance of frequent and repeated G142D followed by D142G back mutations is previously unreported in SARS-CoV-2 and may represent viral adaptation to evolving host immunity characterized by increasing frequency of spike NAbs, from both prior infection and vaccine-based immunity. The emergence of alterations of the NTD in and around the main NAb epitope is a concerning development in the ongoing evolution of SARS-CoV-2 which may contribute to increased infectivity, immune evasion and ′breakthrough infections′ characteristic of Delta VOC. Future vaccine and therapy development may benefit by recognizing the emergence of these novel spike NTD mutations and considering their impact on antibody recognition, viral neutralization, infectivity, replication, and viral load.

SARS-CoV-2 Mutations and Their Impact on Diagnostics, Therapeutics and Vaccines

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Computational prediction of the effect of mutations in the receptor-binding domain on the interaction between SARS-CoV-2 and human ACE2

“…The increased frequency of spike (S) protein mutations, particularly those affecting the receptor-binding domain (RBD), raises awareness. This is because if the mutation continues, it will cause a significant change in the structure of the RBD, resulting in a dramatic increase in the rate of reinfection and immunity evasion [7]. The S protein is composed of two subunits: Subunit 1 (S1), which contains the ACE2 receptor-binding domain (RBD), and Subunit 2 (S2), which contributes to the fusion process [8][9][10] (Fig.…”

Interpretable and Predictive Deep Modeling of the SARS-CoV-2 Spike Protein Sequence

“…For example, at the third-highest position, protein structure analysis suggests that G142D, which is present in some Delta and Delta sub-lineage sequences, may be linked to higher infectivity and immune evasion. [156] In the GISAID data, sequences containing G142D are in fact generally associated with lower severity, although that is partly a function of its more recent emergence which would result in a lower apparent severity for the reasons discussed above. The highly ranked sites also include locations known to be significant for differentiating SARS-CoV-2 variants, such as positions 69 (corresponding to the 68-69 deletion), 501 (where the N501Y mutation occurs, which is characteristic of B.1.1.7/Alpha) and 681 (P681R and P681H) as shown in Fig.…”