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Ryan Hisner Profile picture
Ryan Hisner
@LongDesertTrain
Teacher "Be ruthless with systems and be kind to people." Michael Brooks, 1983-2020
32 subscribers
Dec 23 • 64 tweets • 20 min read
Fantastic review on chronic SARS-CoV-2 infections by virological superstars Richard Neher & Alex Sigal in Nature Microbiology. I’ll do a short overview, outline a couple minor quibbles, & defend the honor of ORF9b w/some stats & 3 striking sequences from the past week.
1/64 Image First, let me say that this is well-written, extremely readable, and accessible to non-experts, so you should go read the full paper yourself, if you can find a way to access it. (Just realized it’s paywalled, ugh.) 2/64nature.com/articles/s4157…
Dec 6 • 33 tweets • 9 min read
In SARS-2 evolution, amino acid (AA) mutations get the lion’s share of attention—& rightfully so, as noncoding & synonymous nucleotide muts—which cause no AA change‚ are mostly inconsequential. But there are many exceptions, including a possible new one I find intriguing. 1/30 I’ll discuss four categories of such “silent” mutations, two of which might be involved in the recent growth of one synonymous mutation.

#1. Kozak sequence changes
#2. Secondary RNA structure
#3. TRS destruction/improvement
#4. TRS creation 2/30
Nov 24 • 4 tweets • 2 min read
@SolidEvidence There was yet another paper this week describing someone chronically infected, with serious symptoms, but who repeatedly tested negative for everything with nasopharyngeal swabs. On bronchoalveolar lavage (BAL), they were Covid-positive. 1/ ijidonline.com/article/S1201-…Image @SolidEvidence BAL is very rarely performed, yet there must be dozens of documented cases now where NP-swab PRC-negative patients who were very ill tested positive by BAL. This has to be way more common than we realize.

If we had a similar GI test, I imagine we'd find something similar. 2/
Nov 22 • 6 tweets • 2 min read
Superb thread here by @jbloom_lab that meshes well with what we've seen over the last few months in SARS-CoV-2 spike evolution: not much.

IMO, nothing significant has happened since the NTD-glycan-adding muts (T22N, ∆S31) & Q493E appeared. This 🧵 explains why. 1/6 Read full 🧵for explanation, but the short story is that the best apparent escape mutations all interact w/something else—like a nearby spike protomer or other important AA—making mutations there prohibitively costly.

In short, the virus has mutated itself into a corner. 2/6
Nov 10 • 15 tweets • 5 min read
It's an interesting thought. I think the evidence is strong that all new, divergent variants have derived from chronic infections. The first wave of such variants—Alpha, Beta, Gamma—IMO involved chronic infections lasting probably ~5-7 months. It's controversial to say.... 1/15 …that Delta originated in a chronic infection, but I think the evidence that it did is strong. One characteristic of chronic-infection branches is a high rate of non-synonymous nucleotide (nuc) substitutions (subs)—i.e. ones that result in an amino acid (AA) change. 2/15 Image
Nov 3 • 4 tweets • 2 min read
I'd add that XEC's had no noticeable impact on cases & isn't likely to going forward barring a serious change, which we've not seen since S:Q493E & the glycan-adding S:S31-/S:T22N appeared months ago. Next major change seems likely to take the form of an entirely new variant. 1/4 I've been in lockstep with @SolidEvidence and @JPWeiland on this front. Despite the sensational early growth advantages XEC appeared to have, it never seemed likely to me ever to have a noticeable real-world impact. 2/4
Oct 11 • 6 tweets • 3 min read
Molnupiravir-created mutants still show up intermittently, mostly in Australia and Japan. A remarkable one popped up today: A KP.3.1.1 with 94 private mutations. 1/6 Image The closest related sequences are from the same region and from about 1 month earlier, suggesting these 94 consensus mutations were acquired in about one month, and possibly a shorter period of time. 2/6 Image
Oct 5 • 5 tweets • 2 min read
There aren't many convergent mutations in ORF1b in chronic-infection sequences. But many of the ones that do show up repeatedly are also highlighted in this study looking at NSP12 mutations that developed in immunocompromised pts treated with remdesivir. 1/4 I've spent hundreds of hours compiling a list of >3500 likely chronic-infection sequences & have created an imperfect, approximate measure for how overrepresented a mutation is in chronic sequences compared to circulating sequences (as measured by independent acquisitions). 2/4
Sep 25 • 7 tweets • 3 min read
It seems more certain than ever: getting Covid is bad for your brain.

This study, which found cognitive effects at 1 year post Covid to be equivalent to brain aging from age 50 to 70, looked only at hospitalized patients. But as Dr. Topol says.... 1/7 ...another recent study—a controlled experimental one involving young (18-30), healthy volunteers—found significant negative cognitive effects from mild illness 1 year after the challenge trial.
Mild illness. Healthy 18-30-year-olds. 1 yr later. 2/7
Sep 21 • 20 tweets • 7 min read
I’ve mostly pooh-poohed the rise of XEC for 2 reasons:

#1. Its spike is almost identical to the dominant KP.3.1.1
#2. I don’t think its advantage over KP.3.1.1 is large enough to make a significant real-world impact.

But one aspect of XEC is noteworthy: The demise of N*.
1/20 I’ve talked a lot about nucleocapsid before, mostly in this 120-tweet thread that was too long for anyone to want to read. Nucleocapsid is by far the most abundant SARS-CoV-2 protein. Nothing else comes close. It is very, very important. 2/20
Sep 8 • 15 tweets • 5 min read
Update on XEC: the weekly growth advantage of XEC relative to KP.3.1.1 has withered to approximately zero in Germany, the country XEC has been in longest and which has by far the highest proportion of XEC sequences. 1/13
Image The country of origin is generally the best place to compare a new variant to others. But globally, most seqs have been collected outside Germany (World: ~225, Germany: ~60), & these deserve some weight.

And globally, it looks like an XEC massacre. 2/13 Image
Sep 1 • 6 tweets • 2 min read
Lots of talk about the XEC variant lately. It's a fast variant, but I want to emphasize two things.

First, I don't think XEC is much faster than the dominant KP.3.1.1. Germany is the only country w/enough seqs for a reliable growth estimate & it's pretty modest & uncertain. 1/6 Image A variant w/such a small growth advantage (assuming it's accurate) takes months to grow to dominance. And such modest advantages do not result in any noticeable change in case levels, so I don't expect XEC to have any real impact. By the time it would become dominant... 2/6
Jul 17 • 25 tweets • 9 min read
KP.3, w/the unusual Q493E mutation, now dominant globally. To me, it's the first major spike change—involving real structural/epistatic change as opposed to treadmilling, stepwise antibody-evasion mutations merely keeping pace w/population immunity—since JN.1 emerged. 1/23 Most spike mutations affect ACE2 binding similarly in BA.2, XBB.1.5, & JN.1—e.g., Y453F confers a large incr in ACE2 affinity in all—so the XBB.1.5 deep mutational scanning info from @bdadonaite & @jbloom_lab is still invaluable. But Q493E is different. 2/
Jul 3 • 4 tweets • 2 min read
AI is a disaster for journalism. Here are a two examples of AI hallucinations on the FLiRT variants of JN.1, which are named after spike mutations F456L & R346T.

This one from @NewstalkFM says FLiRT stands for "F-Type Recombinant Lineage," a term invented from whole cloth. 1/3 When I Googled that name, a clear AI hallucination dutifully copied & pasted by "journalists," I accidentally stumbled on another.

This one, from the Manchester Evening News via Yahoo News, says FLiRT stands for "Fresh Lineage of Rapid Transmission." 2/3 Image
Jun 29 • 5 tweets • 2 min read
@suprion_verlag @dfocosi @yunlong_cao @RajlabN @BenjMurrell @SystemsVirology @SimonLoriereLab @EricTopol @TRyanGregory @tylernstarr @JPWeiland @siamosolocani @CorneliusRoemer The basic pattern has been that we occasionally see huge evolutionary jumps with no intermediate sequences (BA.1, BA.2, BA.5, BJ.1/XBB, BA.2.3.20, BA.2.86, & many others), which in reality evolved stepwise within a single, chronically infected individual. @suprion_verlag @dfocosi @yunlong_cao @RajlabN @BenjMurrell @SystemsVirology @SimonLoriereLab @EricTopol @TRyanGregory @tylernstarr @JPWeiland @siamosolocani @CorneliusRoemer Then, after such a variant begins circulating, it begins to pick up mutations, primarily in the spike protein, which evade antibodies that are widespread in the population. The specific mutations vary somewhat with each new variant, but there's a lot of common ground as well...
Jun 18 • 16 tweets • 6 min read
. @BenjMurrell is doing the best variant growth modeling in the world, & his latest results confirm most of what we've thought: KP.3 is the fastest large variant, & its sublineage KP.3.1.1—w/the highly advantageous, glycan-creating S:∆S31—is easily the fastest in the world. 1/15 It can be a difficult to decipher the meaning of these graphs if you don't have an encyclopedic knowledge of the latest variants—which I think only @siamosolocani possesses—so I tried to add some context to Ben's graph, which I'll explain below. 2/15 Image
May 8 • 8 tweets • 3 min read
KP.3 (w/the rare Q493E) has been my pick since I first noticed it emerging from numerous travel seqs from India. F456L & R346T are the typical stepwise immune-evasion mutations that, as @shay_fleishon noted, very likely impose a fitness cost. Q493E may be different. 1/ Q493E involves the rarest of all nucleotide mutations, C->G, and occurs at a key residue that we've seen very little action from of late. 493 mutations, however, are common in the Cryptics, usually Q493K I believe. (@SolidEvidence can correct me if I'm wrong on that). 2/8 Image
May 1 • 23 tweets • 7 min read
We have a new record for mutations in a non-molnupiravir sequence. It's a BA.2.12.1 with >100 private mutations. There are 4 seqs from early April, all from the same patient. I'll discuss four interesting features it has in this 🧵. 1/23 Image #1) Reversions
Reversions are extremely rare. They almost never appear in circulating lineages. There are, however, a large number of reversions that are convergent in chronic-infection sequences. This one has more than usual. 2/23 Image
Apr 19 • 124 tweets • 43 min read
What connects two regions on opposite ends of NSP12, a narrow slice of an obscure NSP3 region (DPUP/SUD-C), & a 3-AA sliver of nucleocapsid (N)? I have no idea, but I’m convinced there’s a link that could help reveal the inner workings of SARS-CoV-2. 1/120
Image
Image I previously wrote a thread about the strange connection between ORF1a:4395-4398 and ORF1b:820-824 (NSP12_3-6 & NSP12_829-833). There is no known connection between these regions, & they are not close to each other in the NSP12 protein structure. 2/120
Apr 13 • 7 tweets • 3 min read
Always nice to run across a possible function of a rare mutation that's shown up in multiple chronic-infection SARS-CoV-2 seqs. Thanks to an excellent paper by @TheMenacheryLab & @J_Paul_Taylor, I think I now know why N:L13P (a reversion) shows up. 1/6 They proved that the N:1-25 region, esp. the ITFG AA motif from N:15-18, is the essential element in N's ability to suppress the formation of stress granules (SGs) in cells, which capture & disable long viral RNAs & help organizing innate antiviral immune responses. 2/6
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Apr 4 • 5 tweets • 2 min read
BA.2.86, a clear chronic infection-derived variant, has obtained near-total global dominance in the form of JN.1. This may have squeezed out any room for new CI-derived variants to take hold & spread, but they're still out there. A recent one had ~38 private spike mutations. 1/5 BN.1.3 is a BA.2.75 descendant that emerged in Aug 2022, but much older variants still exist.

Alpha, for example, has disappeared from circulation, but it's not extinct—it's still evolving within an unknown # of hosts. On rare occasions, we catch a glimpse of this. 2/5 Image