Ryan Hisner Profile picture
Nov 25, 2021 9 tweets 5 min read Read on X
1/9 Something seemed familiar about the Q498R mutation. Then I remembered: @_b_meyer, examining in-vitro evolution of RBD mutations, predicted this mutation could emerge & lead to a variant with higher infectivity & immune evasion than any existing ones. nature.com/articles/s4156…
2/9 Q498R was not just one of many mutations they predicted: it was far & away their top candidate to become a major RBD mutation. It's the only novel mutation they mention in the abstract, noting that it requires the N501Y mutation to confer increased ACE2 binding affinity.
3/9 They used yeast to display human ACE2 receptors, then let various versions of SARS-CoV-2 S RBD compete against one another, with the highest binding-affinity RBDs advancing to the next round.
4/9 Random mutations were introduced in ways I'm not competent to explain, so I've included the relevant description in the screenshot below.
5/9 Mutations common in known VOCs quickly emerged, especially E484K and N501Y, which quickly became dominant. To me, this seems a good indication that their methods are valid & useful.
6/9 For library B5, they used ACE2 that required extremely high binding affinity, & this "resulted in the fixation of mutations E484K, Q498R and N501Y in all sequenced clones." Q498R was present in all the RBD variants with the highest binding affinity.
7/9 Figure 2f shows binding affinity on the x-axis and makes clear the ability of Q498R to increase ACE 2 binding affinity, hence their prediction that this mutation could emerge & spread.
8/9 Perhaps even more worrying, computer modeling by this team indicates that Q498R could confer a significant amount of immune evasion on any variant possessing it. No wonder this new SA variant is the first to worry @GuptaR_lab since the emergence of Delta.
9/9 I'm not an expert, so if I've made any errors or mischaracterized anything above, I welcome corrections from real experts. Besides @_b_meyer, the only other authors on the study on Twitter I could find were @Matthew_Gagne_ and @Nadav_Elad.

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More from @LongDesertTrain

Oct 13
There's a new BA.3.2.2 from South Africa today. For the most part, there's been little substantial change in BA.3.2 over the past few months—mostly synonymous mutations & very little happening in spike.

But this new one has 3 spike mutations & looks quite interesting. 1/7 Image
For those not following closely, here's a 🧵 I made about BA.3.2 (not yet designated at the time) that I made some months ago, when it first burst upon the scene. 2/7
The spike mutations are T124I, N478T, & T678I.

N478T is a reversion to the ancestral AA, meaning it's gone from T->K->N->T in this lineage.

There and back again.

S:478 has been by far the most active site recently. We've seen K, T, I , E, R, N, L, M, and Q there of late. 3/7 Image
Read 7 tweets
Sep 26
Attenuation of the SARS-2 furin-cleavage site (FCS) continues apace. It's beginning to look as if some form of FCS-weakening mutation might well become fixed in the near future. Collectively, they are at ~12% globally—a totally unprecedented level—& rising quickly. 1/4 Image
In South America, this may have already happened. Recent sequences are scarce, but they nearly all have some sort of FCS-weakening mutation, mostly S:S680P in XFG.3.4.1, but with several others (S680F, S680Y, R683Q, R683W) contributing as well. 2/4 Image
The enigmatic anti-correlation between S:∆S31 & FCS ablaters—clear since summer 2024—is strong as ever. Here are the recent CovSpectrum stats for T22N & ∆S31 among all seqs & seqs w/FCS weakeners.

How exactly a 1-AA deletion in a distant region affects the FCS is unknown. 3/4 Image
Read 4 tweets
Sep 4
There's been some speculation about why, despite persistent immune activation, germinal center activity, & overall elevated Ab levels, LC patients here had very low anti-spike Ab titers. I want to highlight one interesting speculative hypothesis & offer another possibility. 1/10
The ever-fertile mind of @Nucleocapsoid proffers the possibility that exosomes could be responsible for viral spread in some tissue reservoirs. I don't know much about this topic and so don't have much to say at the moment, but I'm trying to l learn. 2/
I'll offer one other possibility: the deep lung environment (or some other tissue reservoir) favors either an extreme RBD-up or extreme RBD-down conformation.

Background: The receptor-binding domain (RBD) of the spike trimer can be up or down. It has to be up to bind ACE2... 3/ Image
Read 10 tweets
Sep 2
A fascinating new preprint w/one very unexpected finding suggests, I believe, that a large proportion of Long Covid may be due to chronic infection in a particular bodily niche, which could be crucial for finding effective LC treatments. It requires some explaining. 🧵 1/33 Image
First, a brief summary of the relevant parts of the preprint. They examined 30 people (from NIH RECOVER cohort) for 6 months after they had Covid, taking detailed blood immunological markers at 3 time points. 20 had Long Covid (PASC), 10 did not (CONV). 2/ biorxiv.org/content/10.110…Image
The PASC group showed signs of persistent, pro-inflammatory immune activation over the 6-month time period that suggested ongoing mucosal immune responses, including elevated levels of mucosa-associated invariant T cells (MAIT). 3/ Image
Read 33 tweets
Jul 30
Wow, BA.3.2 hits its 4th continent with a new sequence from Western Australia.

Reminder: BA.3.2 is a saltation variant resulting from a ~3-year chronic infection. It is very different from and more immune-evasive than all other current variants. 1/4 Image
It was collected July 15, & is most closely related to the recent S African seqs from May & June.

It has an NSP5 mutation known to be beneficial (ORF1a:K3353R) & 2 new NSP12 mutations, which is unusual. Its 9 synonymous mutations indicate it has been circulating somewhere. 2/4 Image
Seems clear now that BA.3.2 is not going away anytime soon. Its overall impact so far has been negligible, but at first BA.2.86's was as well. Once it got S:L455S (becoming JN.1) the dam burst & it set off a new wave in the global North. The question now is.... 3/4 Image
Read 4 tweets
Jul 7
BA.3.2 update: another sequence from the Netherlands, June 18 collection.

It belongs on the same branch as the GBW travel seq (tree gets confused by ORF7-8 deletion). Also, there are 3 artifactual muts in the GBW sequence (as usual), so the branch is shorter than it looks. Image
Bottom line, in my view: BA.3.2 has spread internationally & is likely growing, but very slowly. If nothing changes, its advantage vs circulating lineages, which seem stuck in an evolutionary rut, will likely gradually grow as immunity to dominant variants solidifies... 2/9
So far, this seems like a slow-motion version of what we saw with BA.2.86, which spread internationally & grew very slowly for months. But then it got S:L455S & exploded, wiping out all competitors. Will something similar happen with BA.3.2? I think there's a good chance... 3/9 Image
Read 9 tweets

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