There are likely more. As well as lots of other mutations in other proteins of SARS-CoV-2 A SARS-CoV-2 protein interaction map reveals targets for drug repurposingthat predict for attenuation. This Nature paper last week was really interesting. nature.com/articles/s4158…

Sorry about the typo there. I'm kind of new to twitter. The Nature paper, if looked at carefully, suggests lots of targets for stable SARS-CoV-2 attenuation through mutation.

When you look at COVID Glue, D614G is the top mutation found right now. But others are catching up. Like Q57H.

In a paper before Journal of Translational Medicine right now, we try to make the case that Q57H of ORF 3a is right in the middle of an ion channel that affects viral expulsion from the phagolysosome of the dendritic cell. ORF3a deletions of SARS-CoV do this in culture.

By infection of the dendritic cell (DC), the virus just sits there (like SARS-CoV). The immune system to gets messed up a bit (lose T cells, etc) since the DC is the master controller. Then spits it out in something called the "viral synapse." HIV does this as well.

If virus is spit out at the wrong time, there will be lots of virus and then the immune system (now trying to recover) hits back big. Hence cytokine storm and the rest. Mutations that affect endosomal processing should affect virulence of the virus

40% of the protein-protein interactions in the Nature paper affect endosomal processing and transport. Thus a rich area for attenuation mutations of the viral synapse.

Of all the mutations in SARS-CoV-2, only D614G appears so far to predict for virulence. We never know, there could be more. But viral evolutionary theory predicts that viruses when introduced into a new host trend towards attenuation.

Most of the mutations in SARS-CoV-2 now seen appear to predict for attenuation. So this is kind of supportive of the hypothesis. Even in D614G the Q57H is appearing more in that class over time. Suggesting that D614G is also attenuating.

Now I have put this out there not as the absolute truth. But a possible framework for what is going on. To be tested for truth or not. That is what theories are supposed to do. But it can be tested.

I'm not a virologist or an immunologist. I'm a medical oncologist with a molecular biology background and training. Mike is a world class dendritic cell immunologist.

Sorry, not a twitter expert. Someone told me you have to read this from the bottom up!