Dangerous Deletions

Dangerous Deletions

Scientific studies reveal that the SARS-CoV-2 virus mutates at a comparatively slower rate. The virus accumulates 1-2 single-nucleotide mutations in its genome per month. This is ½ the rate of the influenza virus and ¼ the rate of HIV. One of the reasons for the ‘slow’ mutation is that coronaviruses have a novel exoribonuclease (ExoN) encoded in their genomes, unlike most RNA viruses.

ExoN corrects many of the errors that occur during replication, researchers suspect. Due to the genetic inactivation of this exonuclease in SARS-CoV and murine coronavirus (MHV), mutation rates in these viruses have increased by 15 to 20 fold, they found.

Nucleotide deletions, unlike substitutions, cannot be corrected by this proofreading mechanism, which is a factor that may accelerate adaptive evolution to some degree.

SARS-CoV-2’s spike (S) protein is 1273 amino acids long. It forms the main target of most of the current COVID-19 vaccines, as well as those in the pipeline.

This portion of its anatomy is very crucial for the virus as it recognises and binds to host cellular receptors and mediates viral entry. SARS-CoV-2 is unable to infect host cells without it.

Mutations in the S gene, particularly those that affect portions of the protein that are critical for pathogenesis and normal function (such as the receptor-binding domain (RBD) or furin cleavage site) or those that cause conformational changes to the S protein, are therefore critical to the virus’ life cycle. Depending on the specific mutation, addition or deletion occurs.

Mutations may be neutral, beneficial or harmful to an organism. These mutations may provide an avenue for the virus to evade the defenses set up against the original SARS-CoV-2 strain.

D614G, which constitutes the replacement of aspartate (D) with glycine (G) at the 614th amino acid of S protein, is a mutation which was found in nearly all SARS-CoV-2 samples worldwide by the end of June, 2020.

D614G enhances viral replication in human lung epithelial cells and primary human airway tissues by increasing the infectivity and stability of virions.

N-Terminus

Nucleotide deletions in the amino (N)-terminal domain (NTD) of the S protein may alter antigenicity. The B.1.1.7 variant, first found in the UK, has a deletion of amino acids 69 and 70. It is likely to cause a conformational change in the spike protein, say researchers at the Centers for Disease Control and Prevention (CDC).

Deletion of amino acid 144 in B.1.1.7 and amino acids 242-244 in B.1.351 isolated in South Africa have also been associated with a reduced binding capacity of certain neutralising antibodies.

The P.1 variant, found in Brazil, has a number of amino acid substitutions in the NTD that are of still unknown significance.

RBD

The receptor-binding domain (RBD) of the S protein is composed of amino acids 319-541. It binds directly to ACE2 receptors on human cells.

B.1.1.7, B.1.351 and P.1 all possess a mutation that replaces asparagine (N) with tyrosine (Y) at position 501 of the RBD. N501Y has been shown to increase the binding capacity of SARS-CoV-2 to human ACE2 receptors, disrupt antibody binding to RBD and has been implicated in reduced antibody production via weakened T and B cell cooperation.

B.1.351 and P.1 have 2 additional RBD mutations in common, K417N, a lysine to asparagine substitution at position 417, and E484K, glutamate to lysine substitution at position 484. E484K increases the affinity of RBD for ACE2, boosts resistance to SARS-CoV-2 neutralising antibodies, makes the virus less responsive to monoclonal antibody therapy and reduces neutralisation by convalescent plasma.

Furin Cleavage Site

The furin cleavage site of S protein subunits S1 and S2 is essential for membrane fusion of SARS-CoV-2. B.1.1.7 has a proline to histidine substitution at position 681 that is located near the furin cleavage site.

C-Terminus

B.1.1.7, B.1.351 and P.1 all have multiple mutations in the C-terminal domain of the S protein that are still of unknown significance.

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