Deep Dive: More on Attribution, the Origin of SARS-CoV-2 and Other Coronaviruses Crossing to Other Species and Humans: Can a Leopard Change its Spots?

It’s not that easy for a virus like a coronavirus, which is very host species specific and has a proofreading replicating enzyme, RNA dependent RNA polymerase, to mutate to infect a new species without considerable environmental selection pressure. Even all the hype about the mutated strain of SARS-CoV-2, D614G, implying it will evade immunity, is not quite that bad. SARS-CoV-2 isolates, with the D614G mutation in the viral spike (S) protein, predominate over time in infected populations, the change enhancing viral transmission. This change is not about better binding to receptors but about better processing for the virus to enter the cell and complete its replication, likely changing its infectious dose. Although ideally it takes only one virion to infect a cell, in practice many fail and a certain number of viral particles are required per cell to have successful infection and replication (multiplicity of infection). However, S^G614 (the new mutant) did not bind ACE2 more efficiently than S^D614 (original virus) and the viruses containing these S proteins were neutralized with comparable efficiencies by convalescent plasma from recovered patients. These results show S^G614 is more stable than S^D614, consistent with epidemiological data suggesting that viruses with S^G614 transmit more efficiently, but are not more pathogenic nor would they escape vaccination.(https://www.scripps.edu/news-and-events/press-room/2020/20200611-choe-farzan-sars-cov-2-spike-protein.html). The origin of the original human version of the virus, unlike implied by the retroactive gene analysis mentioned in an earlier post, is not by simple mutation. A proactive study, using pseudo type viruses, not a coronavirus, but a vesicular stomatitis virus chimera with a plasmid-produced coronavirus spike protein added after its replication and carrying a light-producing firefly luciferase gene as a marker of infection, showed that the changes needed to crossover to humans were greater than could reasonably be accounted for by mutation alone. In contrast to changing individual amino acids, the proactive constructs showed that clade 2 and 3 (different genetic groups with other host specificities) receptor binding domains containing the clade 1 closest receptor-contacting amino acid residues are compatible with human ACE2. Coronaviruses frequently undergo recombination, gaining large amounts of genetic material at once. The data of the study indicated it is possible that recombination with a clade 1 virus provided compatibility with human ACE2. Interestingly, the SARS-CoV-2 contains most of the contact points with human ACE2 that are found in clade 1, as well as some amino acid variations that are unique to clades 2 and 3. Taken together with the chimera receptor assay results, the implication is that SARS-CoV-2 arose from recombination between clade 1 and the other clades (https://www.nature.com/articles/s41564-020-0688-y.pdf). Some new data on binding of Pangolin coronavirus to human cells opens it again as an immediate source of SARS-CoV-2. However, the fact that the Pangolin virus binds better to human ACE2 than Pangolin ACE2, opens the unstated possibility that this virus might be a result of an anthroponosis event that transferred coronavirus from humans to Pangolins followed by recombination with another Pangolin virus to yield the current virus under discussion. This is an especially plausible scenario because of the long term illegal animal trade in Pangolins in the region https://www.nature.com/articles/s41467-021-21006-9.pdf.