Thread by @LongDesertTrain

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

https://twitter.com/LoonaOT124ever/status/1855020635216658940

…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

For example, if 80% of nuc subs in coding regions cause an AA change, that’s a very high nonsynonymous rate. The branch leading to Delta has 17 AA changes—from just *15* nuc subs! That’s over 100%. How is this possible? 3/15

First, in addition to 100% of coding-region nuc subs being non-synonymous, Delta had an out-of-frame deletion in spike causing AA change. 4/15

This deletion is unique to Delta & was likely quite important. @GuptaR_lab showed that Delta's NTD had a long-distance, indirect (i.e. allosteric) impact on Delta spike cleavage & fusogenicity. 5/15 cell.com/cell-reports/f…

Curiously, BA.2.86, from which all current circulating lineages descend, has a 3-nuc mutation that also causes R158G. It's unclear if it has a similar effect as Delta's ∆156-157 + R158G, but it's notable that both Delta and BA.2.86* have S:681R, known to enhance fusion 6/15

Second, one nuc sub in Delta caused AA changes in both N and ORF9b, whose coding regions overlap. ORF9b:T60A/N:D63G is another Delta peculiarity that's never reappeared in any other lineage. Delta remains a sphinx-like outlier, defying easy explanation. 7/15

More on this topic & other ORF9b-related matters below (+ more ORF9b matters in a forthcoming paper I’m working on daily). 8/15

https://x.com/LongDesertTrain/status/1673488093637234689

So the posited chronic infection leading to Delta would’ve lasted a bit longer than those leading to Alpha/Beta/Delta, maybe 9-11 months. Delta dominated more thoroughly and for longer than previous VOC. 9/15

BA.1/BA.2 evolved in a chronically infected host for longer still, well over one year. Their dominance was short-lived but they were replaced by BA.5, which derived from some complex, ill-understood mix of BA.2 recombination & intrahost evolution. 10/15

https://x.com/CorneliusRoemer/status/1550807266009530369

It’s not as widely known, but 77% of the XBB genome—including the spike NTD & ~70% of the RBD—came from BJ.1, a BA.2-derived saltation variant that almost certainly originated in a chronic infection that lasted ~4-5 months, during which it acquired 13 spike mutations. 11/15

BA.2.86 incubated in its chronically infected host for a considerably longer period of time, well over 1 year. Does the duration of intrahost evolution influence the staying time of a variant? Delta & the OG Omicron hint this could be so. But… 12/15

…several very long-term chronic-infection variants have had less success. BA.2.87.1 had a similarly long period of intrahost evolution. It spread across parts of South Africa & even made its way to Thailand (which we know thanks to @dr_leshan), but… 13/

https://x.com/Tuliodna/status/1752996491948327126

…from there, BA.2.87.1 faded away, & now appears to be extinct, at least as far as circulation is concerned. A similar story can be told for B.1.640. So it’s unclear if there’s any real relationship between duration of intrahost evolution & real-world staying power. 14/15

. @Asinickle1 has done some interesting analysis on this subject that seems to show an intriguing gap in the intrahost period of saltation variants. The meaning of it, if any, is unclear. I’ll let him share his work on this if he wants. 15/end