Difference between revisions of "Time Course"

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==Previously Confirmed Mutations ==
 
==Previously Confirmed Mutations ==
 
<big>In the last 6 months, 3 new members of the omicron (B.1.1.529) lineage have emerged, and subsequently been recognized as variants of interest (VOI) by the World Health Organization (WHO), which are the BA.2.75, XBB, and BQ.1 subvariants that rose to prominence in July, August and October 2022 respectively. Each of these VOIs has brought along an array of novel mutable sites crucial for refining the viral fitness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Leading mutations identified by our deLemus analysis that emerged within the aforementioned timeframe are listed as follows:<br /></big>
 
<big>In the last 6 months, 3 new members of the omicron (B.1.1.529) lineage have emerged, and subsequently been recognized as variants of interest (VOI) by the World Health Organization (WHO), which are the BA.2.75, XBB, and BQ.1 subvariants that rose to prominence in July, August and October 2022 respectively. Each of these VOIs has brought along an array of novel mutable sites crucial for refining the viral fitness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Leading mutations identified by our deLemus analysis that emerged within the aforementioned timeframe are listed as follows:<br /></big>
 +
 +
=== S939F ===
 +
<big>Amino acid site 939, which corresponds to the S939F mutation, has been detected be mutationally active since December 2022, based on our deLemus analysis. This S2 mutation is lately possessed by one of the top accelerating variants, BQ1.1. The position of this mutation within the heptad repeat 1 responsible for facilitating virus-cell membrane fusion has been revealed to potentially destabilize both the pre-fusion and post-fusion S2 conformations, as indicated by the substitution of a solvent-accessible polar serine residue to a bulky phenylaniline residue.<ref name="Olivie" /> Despite the lowered S2 stability, when combined with the highly prevalent D614G mutation, experimental and computational studies have respectively shown that S939F is capable of enhancing the infectivity of and modulating the T-cell immune response against SARS-CoV-2.<ref name="LiImpactCell" /><ref>Donzelli, S. ''et al.'' Evidence of a SARS-CoV-2 double spike mutation D614G/S939F potentially affecting immune response of infected subjects. ''Comput Struct Biotechnol J'' '''20,''' 733–744 (2022).</ref></big>
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===E583D ===
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<big>Amino acid site 583, which corresponds to the E583D mutation, has been outlined to bear a strong mutational signal since December 2022, based on our deLemus analysis. This CTD mutation has emerged in one of the top accelerating variants, BQ.1.1. The glutamic acid-to-aspartic acid substitution allows the site to retain its negative charge, and further investigations would be required to confirm the possible viral functions this mutation may confer.</big>
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 +
===Q613H ===
 +
<big>Amino acid site 613, corresponding to the Q613H mutation, has been detected to be mutationally active since December 2022, based on our deLemus analysis. This particular mutation is currently harbored by one of the top accelerating variants, BQ.1.1. While current studies have yet to elucidate its potential functions, its close proximity to the crucial D614G mutation carried by all existing variants has led researchers to speculate that it may pose similar effects in enhancing the replicative fitness and transmissibility of SARS-CoV-2.<ref name=":0">Harvey, W. T. ''et al.'' SARS-CoV-2 variants, Spike mutations and immune escape. ''Nat Rev Microbiol'' '''19,''' 409–424 (2021).</ref><ref>Bugembe, D. L. ''et al.'' Emergence and spread of a SARS-COV-2 lineage a variant (A.23.1) with altered Spike Protein in Uganda. ''Nat Microbiol'' '''6,''' 1094–1101 (2021).</ref></big>
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===F486P/I ===
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<big>Amino acid site 486 has been exhibiting a strong mutational signal since November 2022, based on our deLemus analysis. Mutation at this site in the form of F486P is carried by the currently proliferating XBB.1.5 variant, rendering this variant with an enhanced hACE2-binding affinity when compared to its ancestor, XBB.1.<ref name="XBB.1.5" /> It is likely that the tighter receptor attachment confers quicker transmissibility for the XBB.1.5 strain, as demonstrated by its looming dominance in the US.<ref name="CNBC XBB.1.5" /> Additionally, we have noticed another leading mutation located at the same site, F486I, which may also alter the viral fitness of SARS-CoV-2.</big>
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===K356T ===
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<big>Amino acid site 356, which corresponds to the K356T mutation, initially piqued our interest due to its persistent mutational signal since April 2022, based on our deLemus analysis. The importance of this mutation would subsequently be affirmed, as it is carried by one of the top accelerating variants, BN.1.4, according to the EV data retrieved from GISAID. In fact, a recent study has revealed that this particular mutation promotes immune evasion.<ref>Cao, Y. ''et al.'' Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution. ''Nature'' (2022). doi:10.1038/s41586-022-05644-7</ref></big> <big>Moreover, it has come to our attention that this lysine-to-threonine mutation gives rise to an NXT sequon (<sub>354</sub>NRT<sub>356</sub>), which may potentially enable the generation of a novel ''N''-glycosylation site.<br /></big>
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===N460K===
 
===N460K===
 
<big>Amino acid site 460, which corresponds to the N460K mutation, has been exhibiting a persistently strong mutational signal since February 2022, based on our deLemus analysis. Mutation at this site was first reported in the BA.2.75 strain, and was subsequently retained in the XBB and BQ.1 subvariants. The asparagine-to-lysine substitution introduces a cationic residue in the receptor binding motif (RBM) of the receptor binding domain (RBD), which increases the ACE2-binding affinity of the spike glycoprotein by enabling the formation of a new hydrogen bond with the electrostatically complementary ACE2 surface.<ref>Zahradník, J. ''et al.'' SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution. ''Nat Microbiol'' '''6,''' 1188–1198 (2021).</ref><ref>Makowski, E. K., Schardt, J. S., Smith, M. D. & Tessier, P. M. Mutational analysis of SARS-CoV-2 variants of concern reveals key tradeoffs between receptor affinity and antibody escape. ''PLOS Comput Biol'' '''18,''' (2022).</ref><ref name=":0">Qu, P. ''et al.'' Evasion of neutralizing antibody responses by the SARS-CoV-2 BA.2.75 variant. ''Cell Host Microbe'' '''30,''' (2022).</ref> Moreover, this mutation grants the virus with enhanced immune evasive capability and fusogenicity for better syncytia formation.<ref name=":0" /></big>
 
<big>Amino acid site 460, which corresponds to the N460K mutation, has been exhibiting a persistently strong mutational signal since February 2022, based on our deLemus analysis. Mutation at this site was first reported in the BA.2.75 strain, and was subsequently retained in the XBB and BQ.1 subvariants. The asparagine-to-lysine substitution introduces a cationic residue in the receptor binding motif (RBM) of the receptor binding domain (RBD), which increases the ACE2-binding affinity of the spike glycoprotein by enabling the formation of a new hydrogen bond with the electrostatically complementary ACE2 surface.<ref>Zahradník, J. ''et al.'' SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution. ''Nat Microbiol'' '''6,''' 1188–1198 (2021).</ref><ref>Makowski, E. K., Schardt, J. S., Smith, M. D. & Tessier, P. M. Mutational analysis of SARS-CoV-2 variants of concern reveals key tradeoffs between receptor affinity and antibody escape. ''PLOS Comput Biol'' '''18,''' (2022).</ref><ref name=":0">Qu, P. ''et al.'' Evasion of neutralizing antibody responses by the SARS-CoV-2 BA.2.75 variant. ''Cell Host Microbe'' '''30,''' (2022).</ref> Moreover, this mutation grants the virus with enhanced immune evasive capability and fusogenicity for better syncytia formation.<ref name=":0" /></big>

Revision as of 18:47, 3 February 2023

Previously Confirmed Mutations

In the last 6 months, 3 new members of the omicron (B.1.1.529) lineage have emerged, and subsequently been recognized as variants of interest (VOI) by the World Health Organization (WHO), which are the BA.2.75, XBB, and BQ.1 subvariants that rose to prominence in July, August and October 2022 respectively. Each of these VOIs has brought along an array of novel mutable sites crucial for refining the viral fitness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Leading mutations identified by our deLemus analysis that emerged within the aforementioned timeframe are listed as follows:

S939F

Amino acid site 939, which corresponds to the S939F mutation, has been detected be mutationally active since December 2022, based on our deLemus analysis. This S2 mutation is lately possessed by one of the top accelerating variants, BQ1.1. The position of this mutation within the heptad repeat 1 responsible for facilitating virus-cell membrane fusion has been revealed to potentially destabilize both the pre-fusion and post-fusion S2 conformations, as indicated by the substitution of a solvent-accessible polar serine residue to a bulky phenylaniline residue.[1] Despite the lowered S2 stability, when combined with the highly prevalent D614G mutation, experimental and computational studies have respectively shown that S939F is capable of enhancing the infectivity of and modulating the T-cell immune response against SARS-CoV-2.[2][3]

E583D

Amino acid site 583, which corresponds to the E583D mutation, has been outlined to bear a strong mutational signal since December 2022, based on our deLemus analysis. This CTD mutation has emerged in one of the top accelerating variants, BQ.1.1. The glutamic acid-to-aspartic acid substitution allows the site to retain its negative charge, and further investigations would be required to confirm the possible viral functions this mutation may confer.

Q613H

Amino acid site 613, corresponding to the Q613H mutation, has been detected to be mutationally active since December 2022, based on our deLemus analysis. This particular mutation is currently harbored by one of the top accelerating variants, BQ.1.1. While current studies have yet to elucidate its potential functions, its close proximity to the crucial D614G mutation carried by all existing variants has led researchers to speculate that it may pose similar effects in enhancing the replicative fitness and transmissibility of SARS-CoV-2.[4][5]

F486P/I

Amino acid site 486 has been exhibiting a strong mutational signal since November 2022, based on our deLemus analysis. Mutation at this site in the form of F486P is carried by the currently proliferating XBB.1.5 variant, rendering this variant with an enhanced hACE2-binding affinity when compared to its ancestor, XBB.1.[6] It is likely that the tighter receptor attachment confers quicker transmissibility for the XBB.1.5 strain, as demonstrated by its looming dominance in the US.[7] Additionally, we have noticed another leading mutation located at the same site, F486I, which may also alter the viral fitness of SARS-CoV-2.

K356T

Amino acid site 356, which corresponds to the K356T mutation, initially piqued our interest due to its persistent mutational signal since April 2022, based on our deLemus analysis. The importance of this mutation would subsequently be affirmed, as it is carried by one of the top accelerating variants, BN.1.4, according to the EV data retrieved from GISAID. In fact, a recent study has revealed that this particular mutation promotes immune evasion.[8] Moreover, it has come to our attention that this lysine-to-threonine mutation gives rise to an NXT sequon (354NRT356), which may potentially enable the generation of a novel N-glycosylation site.

N460K

Amino acid site 460, which corresponds to the N460K mutation, has been exhibiting a persistently strong mutational signal since February 2022, based on our deLemus analysis. Mutation at this site was first reported in the BA.2.75 strain, and was subsequently retained in the XBB and BQ.1 subvariants. The asparagine-to-lysine substitution introduces a cationic residue in the receptor binding motif (RBM) of the receptor binding domain (RBD), which increases the ACE2-binding affinity of the spike glycoprotein by enabling the formation of a new hydrogen bond with the electrostatically complementary ACE2 surface.[9][10][4] Moreover, this mutation grants the virus with enhanced immune evasive capability and fusogenicity for better syncytia formation.[4]

R346T, L368I, and V445P

Amino acid sites 346, 368, and 445 have been exhibiting strong mutational signals since the end of 2021, May 2022, and April 2022 respectively, based on our deLemus analysis. Out of these 3 sites, only the R346 residue displays significant polymorphism, as seen from how 2 different substitutions have arisen from this site, being the R346K of mu (B.1.621) and R346T of XBB; the other 2 mutations are specific to XBB. All these RBD mutations are experimentally found to confer immune evasion capabilities when carried by the spike glycoprotein,[11][12] of which the R346T mutation particularly impairs the binding of class 3 antibodies.[13] While the immunologically effects of these mutations are not well elucidated mechanistically, structural analysis has revealed that the bulky phenylaniline residue introduced by the V445P mutation is what contributed to the weakened spike-antibody interactions.[13] In addition to these immune escape functions, L368I has been characterized to increase the ACE2-binding affinity of the SARS-CoV-2 spike.[11]

K444T and F486V/S

Amino acid sites 444 and 486 have been exhibiting strong mutational signals since the end of 2021 and March 2022 respectively, based on our deLemus analysis. Mutation at the former site, K444T, is specific to the BQ.1 subvariant, which has been reported to hinder the binding of class 3 antibodies by abrogating its hydrogen bond and salt bridge formation with the spike glycoprotein.[14] Residue at the latter location, on the other hand, has been identified to be polymorphic, as indicated by the fact that 2 major substitutions exist in this site, which are the F486V of BA.4, BA.5, and BQ.1, and F486S of XBB. The crucial role of this phenylaniline residue as both an ACE2 and antibody binding site implicates that spike glycoproteins carrying the F486V/S mutations would possess enhanced immune evasion capabilities against certain class 1 and 2 antibodies at the cost of having lowered ACE2-binding affinities.[14][15][16]

References

  1. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Olivie
  2. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named LiImpactCell
  3. ↑ Donzelli, S. et al. Evidence of a SARS-CoV-2 double spike mutation D614G/S939F potentially affecting immune response of infected subjects. Comput Struct Biotechnol J 20, 733–744 (2022).
  4. ↑ 4.0 4.1 4.2 Harvey, W. T. et al. SARS-CoV-2 variants, Spike mutations and immune escape. Nat Rev Microbiol 19, 409–424 (2021). Cite error: Invalid <ref> tag; name ":0" defined multiple times with different content
  5. ↑ Bugembe, D. L. et al. Emergence and spread of a SARS-COV-2 lineage a variant (A.23.1) with altered Spike Protein in Uganda. Nat Microbiol 6, 1094–1101 (2021).
  6. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named XBB.1.5
  7. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named CNBC XBB.1.5
  8. ↑ Cao, Y. et al. Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution. Nature (2022). doi:10.1038/s41586-022-05644-7
  9. ↑ Zahradník, J. et al. SARS-CoV-2 variant prediction and antiviral drug design are enabled by RBD in vitro evolution. Nat Microbiol 6, 1188–1198 (2021).
  10. ↑ Makowski, E. K., Schardt, J. S., Smith, M. D. & Tessier, P. M. Mutational analysis of SARS-CoV-2 variants of concern reveals key tradeoffs between receptor affinity and antibody escape. PLOS Comput Biol 18, (2022).
  11. ↑ 11.0 11.1 Tamura, T. et al. Virological characteristics of the SARS-CoV-2 XBB variant derived from recombination of two omicron subvariants. Preprint at https://www.biorxiv.org/content/10.1101/2022.12.27.521986v1 (2022).
  12. ↑ Cao, Y. et al. Imprinted SARS-CoV-2 humoral immunity induces convergent Omicron RBD evolution. Nature (2022). doi:10.1038/s41586-022-05644-7
  13. ↑ 13.0 13.1 Wang, Q. et al. Alarming antibody evasion properties of rising SARS-CoV-2 BQ and XBB subvariants. Cell 186, (2023).
  14. ↑ 14.0 14.1 Qu, P. et al. Enhanced neutralization resistance of SARS-CoV-2 omicron subvariants BQ.1, BQ.1.1, BA.4.6, BF.7, and BA.2.75.2. Cell Host Microbe 31, (2023).
  15. ↑ Tuekprakhon, A. et al. Antibody escape of SARS-CoV-2 omicron BA.4 and BA.5 from Vaccine and BA.1 Serum. Cell 185, (2022).
  16. ↑ Wang, Q. et al. Antibody evasion by SARS-CoV-2 omicron subvariants BA.2.12.1, BA.4 and BA.5. Nature 608, 603–608 (2022).
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