Initially, SARS-CoV-2's focus was on improved infectiousness.  However, as the virus continues to spread, that may become less relatively important, unless it were antigenically drifting enough, in which case the focus would remain on transmissivity.  But we're seeing trends in isolates that immune escape is becoming relatively more important.  That may abruptly flip if sufficient antigenic drift occurs or the virus somehow evolves the ability to evade antibodies created against it well enough..  This will be particularly true if it exhibits better ADE through mutations.


Anyway, with more antibodies from vaccination and natural infection accumulating but sufficient escape from them to mutate, the virus will want to start working on the adaptive immune response so that it can reside in the body longer for better transmission, especially with its ability to form syncytia and the rapid mutation that occurs in protracted infection.
 
 
That means fighting more against T-cells than antibodies, which typically implies greater pathogenicity.  This is a general overview of T cells in SARS-CoV-2.


Severe cases of COVID-19 also exhibit generalized lymphopenia, especially for CD8+ T cells, which often wave white flag exhaustion markers.  This correlation is so strong that T-cell to neutrophil ratios can actually be used as a disease severity predictor.


Conversely, neutrophil counts in severe and fatal cases are often very high, indicating that, if anything, SARS-CoV-2 is made more virulent by them.


However, neutrophils rank low on overall disease severity predictors, so I don't think they will shape evolution much.


ORF3a and ORF7a can kill cells directly, and they do so much better in SARS-CoV-1 than SARS-CoV-2, which makes them prime candidates for generally increasing pathogenesis.


Apart from these, T-cell abuse is its best shot.  How might SARS-CoV-2 attempt to become more resistant to T-cells, thus increasing its severity?

#1:  Insertion of glycan shields in S protecting large numbers of vulnerable, common CD8+ T-cell epitopes
#2:  A particularly effective OR particularly distinct combination of mutations in T-cell epitopes in S.  This is harder to do than it is for antibodies because T-cells recognize ~35 epitopes each in SARS-CoV-2(I forget where I sourced the precise number), but it has been done in some instances.  P272L escapes an important CD8+ epitope and arose in B.1.177.
#3:  Amplifications of accessory protein production that screws up T-cell responses.  Options from prior experience include:


#3a:  Slowing down the clonal expansion of T-cells.
#3b:  Slowing down T-cell cytokine expression.
#3c:  Screwing up HLA presentation of antigens.

Multiple accessory proteins help out with each of these.

For 3a,  we can identify key genes: N, ORF6, ORF8, and ORF9b.  They suppress interferon responses via various mechanisms, which leads to the death of T-cells.


I haven't investigated 3b enough yet.

For 3c, we can identify a key gene: ORF7a.  Note that ORF7a may also help to infect T-cells.



That's a lot of options for the virus to choose from, which is bad.  Overall, the lowest hanging fruit right now is probably evolution of ORF7a or ORF3a.

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