Private channel session 716
18 messages over 1h 59m, 2020-12-23 – 2020-12-23.
A “conversation” here is an activity session — a run of messages with under 60 minutes of silence inside it. The channel had no native conversation boundaries.
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Cliff Notes version:
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Two RBD residues (residues 479 and 487) had to mutate to enable civet SC1 (the 99+% virus) to jump to humans. These changes allow interaction with contact residues on human ACE2. JVI paper sums it nicely. This happened more than once with SC1.
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The two SC1 residues are equivalent in how they interact with ACE2 to to SC2 RBD residues Q493 and N501.
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Two interspecies transfers of SC2 have occurred. Human to mouse in the lab. Human to mink and back on the fur farms. Residues Q493 and N501 are also involved. N501Y enables replication of SC2 in mice; Q493H makes the mouse adapted SC2 pathogenic prob by increasing replication. A SC2 Q493K change can increase both replication and pathogenesis in mice.
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Several different changes in SC2 to enable replication in mink. All involve changing the contact residues in RBD toenable better interaction with mink ACE2. One of the changes is N501T. I don't think mink NEED to change Q493because their contact residues K33/Y34 are similar to human K33/H34.
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Kristian asked why the change in SC1 was so fast - I think the answer is that civets are probably already sampling the mutational space of SC1 RBD residues 479 and 487 because these are important epitopes. If there are the right quasispecies with immune escape mutants in the civet that you picked for dinner these would be selected on your human ACE2.
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This brings us to Nelly and her cousins. Humans with long term infections are also generating SC2 immune escape mutants. N501Y is likely one of those. It also has the selective advantage that it increases binding to ACE2. I think this is a strong aromatic:aromatic interaction between Spike 501Y and ACE2 41Y, but yeah would like to see that ina cryo structure from Andrew Ward.
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In Andrew's virological post you see the selection of 501Y - it goes from partial (a quasi-species) to a fixed variant.
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There are other mutations in the elephants that also involve RBD residues, including a Q493K mutant on the Mass patient SC2 that may be due to the fact that he was treated with Regeneron Mabs. Th other RBD residues are either immune escape/enhanced ACE2 binders or both.
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The other elephant mutations outside RBD including the dels in the NTD and the P681H near the FCS could indeed be enabling, enhancing replication in their own right or perhaps they are also immune escapes.
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I think this is all relevant to PO2 - it's pretty clear that the changes in SC2 493 and 501 or SC1 479 and 487 enabledspecies jumps - per PO1 there are bat sarbecovs that have an SC2 N501 and we know these infect human cells.We know enough about the epitopes and MAb binding and escape to back up Andrew's point on virological that immune escape is driving the changes in the elephants - the problem happens when immune escape creates variants that are more transmissible or heaven forbid are vaccine resistant.
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Finally to end my rant - let's not give Baric or Fouchier the idea of making SC1 N493Q + T487Y. That to me wouldbe scary with the possibility of SC2 transmissibility and SC1 CFR.
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One more intersting observation: Some of the South African variant viruses (possibly all of them - it seems their bioinformatics pipeline doesn't call deletions very well) have a deletion at sites 11288-11296 (amino acid 3675-3677 in ORF1ab - thus the in nsp6). Exactly the same deletion is seen in the UK B.1.1.7 lineage. I don't know the significance of this. Any thoughts?
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195303/ From this modeling NSP6 looks like a viroporin to me - would have to look at the exact deletion, but most viroporins are involved in virion entry and cytopathogenesis.Same wheelhouse as the RBD and FCS mutations.
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Covs have other viroporins (E protein) that are virion associated, but NSP6 is likely remodeling cell membranes insome way to benefit virus replication.
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Mmm. So definitely could be associated with a change in virus behaviour. Cool
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I'll map the deletion on the model, which is prob pretty accurate, when I get to the office after dropping off the dog. Ifit's in one of the loops would likely affect regulation and yes change virus behavior.
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Seems to crop up with a small bunch in Australia with spike S477N, and a few others here and there.