Thread by @TimothyChase

(1/n) #B1617 #variants (dropping the dots for the hashtag) "... the B.1.617.2 variant has mutations called 452R and 478K, which Tang says are both linked to increased transmissibility. Both mutations alter the spike protein...."
nature.com/articles/d4158…

(2/n) [L]452R is believed to result in the spike binding more closely to the ACE2 receptor and may simultaneously result in a degree of Immune escape. From analysis of B.1.429 which has the same mutation...

(3/n) "This replacement is predicted to create a much stronger attachment of the virus to the human cells and also might allow it to avoid the neutralizing antibodies that try to interfere with this attachment." (2021 Feb 26)

newsroom.uw.edu/news/single-mu…

(4/n) [T]478K apparently changes the charge in the receptor binding domain from neutral to positive which both results in it's binding more tightly and some immune escape similar to E484K. Please see the "Discussion" in:

onlinelibrary.wiley.com/doi/10.1002/jm…

(5/n) This then would seem to be the same story as L452R as L is neutral to and R is basic, meaning positive, and that part of the receptor binding domain it binds to has a negative electrostatic charge.

Please see: ...

(6/n) "L452R substitution can cause a gain of  electrostatics complementarity (Selzer et al., 2000) (Figure 2F). Because the residue 452 is located close proximity to the negatively charged patch of ACE2...

rapidreviewscovid19.mitpress.mit.edu/pub/jcavas70/r…

(7/n) L452R also decreases the ability of T-cells, macrophages and other cells to mount a cellular immune response through the production of interferon gamma (type II interferon - an inflammatory cytokine) that is distinct from from the humoral, antibody-based immune system.

(8/n) Please see for example:

"Here we demonstrated the L452R and Y453F mutations can contribute to escaping from an HLA-restricted cellular immunity."

Ibid.

Note that they are specifically looking at these mutations in the context of the B.1.427 and B.1.429 variants...

(9/n) Nevertheless, these mutations and other mutations keep occurring independently and bring selected for as they increase the fitness of those lineages. For example, the E484K mutation both promotes replaces a negative charge with a positive one, decreasing the...

(10/n) ... antibodies to attach to the spike protein, and consequently, although originally discovered in B.1.351 it appeared independently at least 3 different times against the background of the B.1.1.7 background in Bristol, England, in India and in Oregon.

(11/n) Interestingly, , B.1.617.1 has in addition to T478K and L452R a spike mutation similar to E484K, but instead of replacing E with K it replaces E with Q. E is negatively charged, K positively charged but Q is neutral. This it is not surprising that Q affords some immune...

(12/n) escape but not to the same extent as the K substitution.

The Nature article states:

"But B.1.617.1 also carries a different mutation called 484Q, which is more strongly associated with vaccine escape. This mutation isn’t found in B.1.617.2."

nature.com/articles/d4158…

(13/n) But is the E484Q actually that strong in immune escape, more potent that either of the two other mutations?

B.1.617.1 is the ancestral lineage, B.1.617.2 a descendant. If E484Q is that potent wouldn't there be strong selection for it?

(14/n) L452R falls within 448-456, and:

"A bioinformatic study has suggested that the 9-mer peptide in the RBM, NYNYLYRLF (we designate this peptide "NF9"), which spans 448-456 in the S protein, can be the potential epitope presented by HLA-A24..."

biorxiv.org/content/10.110…

(15/n) T478K? Perhaps increased fitness is escape + binding:

"We found that the T478K mutation in Mexico variant (B.1.1.222) has the most significant high value of predicted [Binding Free Energy] changes and is one of the potential vaccine-escape [5]"

biorxiv.org/content/10.110…

(16/n). Oftentimes a mutation may involve tradeoffs. One notable example is D614G which happened early on in the pandemic then became so widespread among the lineages that at one point someone remarked it has become the pandemic. Both D and G are neutral and it does not exist...

(17/n) in the binding region itself. Instead it serves to stabilize the spikes that bind to the ACE2 receptor. In it's absence the spikes tend to break off and the virion is said to "shed spikes". Thus the mutation increases transmissibility.

Please see:

science.sciencemag.org/content/372/65…

(18/n) However, this mutation improves transmission at the price of making the virion more susceptible to neutralization by antibodies. But this isn't the result of something so simple as substituting a negative electrostatic charge for a positive one.

(19/n) It increases the exposed surface area:

"Structural studies suggest that the mutation stabilizes a conformation of the receptor-binding domain (RBD) which increases its exposure on the surface of the virus."

immunology.ox.ac.uk/covid-19/covid…

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