1. More Important than Realized
    Nate Klingenstein Nate Klingenstein United States says:
    June 30, 2021 at 1:30 AM

    If P272L is the optimal amino acid change for CD8+ T-cell escape, its failure to emerge thus far in B.1.617.2, B.1.1.7, or other widely circulating strains in a somewhat vaccinated population is vexing.  It might be constrained by protein stability.  Mutations have occurred at sites 273 and 274 as well, and the entire 269-277 epitope is important, so that area bears very close watching.  There may need to be a compensatory reversion or mutation that lowers the binding energy of these variants before a potentially destabilizing P272L or other mutation in the epitope can succeed.

    Reply
    • Goog point
      Suliban Helix Suliban Helix United Kingdom says:
      June 30, 2021 at 4:45 AM

      B.1.1.7 is pretty much a dinosaur now (like B.1.177 before it). Delta and epsilon will be the ones to watch. The compensatory mutation idea is good and happens in HIV. A222V seems like the most likely candidate if this were the case as it defined B.1.177 where the P227L mutation really took off and appears to be unassigned (no clear function) in figure above. *I should point out that I'm not a viral phylogenetics expert!* 😝

      Reply
      • Also a good point
        Nate Klingenstein Nate Klingenstein United States says:
        August 21, 2021 at 12:53 AM

        I agree with most of what you wrote, but I wouldn't write off Alpha as a dinosaur.  The evolutionary machinery of SARS-CoV-2 is amazing, and 8 new spike mutations just popped out in an Alpha descendant.  We really don't know what any given variant might spit out as long as it's extant.

        The paper does show that P272L escapes a very common dominant CD8+ T-cell response.  A222 is in an immunodominant epitope for CD4+ cells for one HLA allele and an immunodominant epitope for CD8+ cells for many alleles, so mutations there could very well have T-cell evasive effects.  I would imagine your theory is also accurate.

        The two mutations are not mutually exclusive.  There are 1468 known CD4+ and CD8+ epitopes in SARS-CoV-2.  Each T-cell recognizes approximately 35 epitopes.  We should expect to see more evasion.

        Reply
        • More essential than essential?
          Phil Ip Phil Ip United States says:
          October 5, 2021 at 1:45 AM

          Hi Nate - thanks for your insights.  As a layman with only a few years of life sciences, I'm looking to ask someone a fundamental question: is it possible the mutation in P272L was merely from Proline unavailability and Leucine was "grabbed" during replication?  I know Leucine is an essential amino and Proline is synthesized from various glutamates, BUT if competition for Proline (perhaps due to an mRNA vaccine being given to a silently infected covid patient, as we know covid-19 impairs mitochondrial dyanmics) existed in even certain tissues/cells, could that not force the mutation?

          If you're able to answer, please take a shot.

          Reply
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