Slack / Private Message Drop — page 341

[2020-12-23 04:04:37] [Robert Garry] Several different changes in SC2 to enable replication in mink. All involve changing the contact residues in RBD to enable better interaction with mink ACE2. One of the changes is N501T. I don't think mink NEED to change Q493 because their contact residues K33/Y34 are similar to human K33/H34. [2020-12-23 04:08:31] [Robert Garry] 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. [2020-12-23 04:14:36] [Robert Garry] 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 in a cryo structure from Andrew Ward. [2020-12-23 04:15:50] [Robert Garry] In Andrew's virological post you see the selection of 501Y - it goes from partial (a quasi-species) to a fixed variant. [2020-12-23 04:20:17] [Robert Garry] 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. [2020-12-23 04:22:34] [Robert Garry] 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. [2020-12-23 04:35:58] [Robert Garry] 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 enabled species 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. [2020-12-23 04:40:29] [Robert Garry] Finally to end my rant - let's not give Baric or Fouchier the idea of making SC1 N493Q + T487Y. That to me would be scary with the possibility of SC2 transmissibility and SC1 CFR. [2020-12-23 04:46:04] [Andrew Rambaut] 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? [2020-12-23 05:05:52]