During the summer, you could almost hear a sigh of relief from the part of the research community that followed the evolution of the SARS-CoV-2 virus. Viruses, especially those that are new to their hosts, often incorporate mutations that help them adapt to their new habitat, or they evade drugs or immune attacks. But SARS-CoV-2 seemed to pick up mutations at a relatively slow rate, in part because the virus-copying enzymes had a function that allowed them to correct some errors.
But suddenly new variants seem to be everywhere, and some of them seem to increase the threat of the virus. A new study helps explain the apparent difference: While new base changes in the genetic material of the virus remain rare, some deletions from different bases appear to have evolved multiple times, indicating that evolution selected for them. The research team behind this new work found evidence that these changes change the way the immune system can respond to the virus.
This looks familiar
The researchers’ interest in deletions began with their involvement in an immunocompromised cancer patient, who kept the infection out for more than two months without being able to clear the virus. Samples obtained from late in the infection revealed two different strains of virus, each having a deletion in the gene encoding the spike protein that uses SARS-CoV-2 to attach to and enter cells.
When the researchers searched a database of other viral genomes, they found six other cases where the same or similar deletions appear to have evolved in other patients. This caused them to go back and look at a collection of nearly 150,000 viral genomes. They found that more than 1,100 of them carried deletions in the spike protein. But critically, they found that these were not randomly distributed. Ninety percent of the deletions clustered in four different regions of the spike gene.
This can be for two reasons. It is possible that these viruses are related by a common lineage and all inherited the same ancestral deletion. Or these deletions may be useful from an evolution perspective, and so, when they do occur, they are eventually tracked.
To find out what’s going on, the researchers built an evolutionary tree of the viruses using mutations that happened outside of the spike protein. This showed that, apart from the removals, the viruses were often distantly related. This indicates that the latter option is probably true: the deletions often occurred independently and were simply saved at an unusually high speed. One specific deletion appears to have occurred at least 13 different times, and some of the deletions have been around since the start of the pandemic.
Selected
If these deletions are kept, the obvious question is “why?” To find out, the researchers figured out how each of the deletions would alter the spike protein produced by the mutated form of the gene. They then compared this information with what we know about the structure and function of the spike protein. None of the regions turned out to be essential for the spike protein to do its job (which you would expect, since removing it would likely inactivate it). Instead, some of the sites had already been identified as sites where antibodies to the spike protein would stick to them.
So the researchers produced these removal versions of the spike protein and tested whether an antibody that can neutralize the virus can stick to it. For one antibody, the answer was “yes”: two of the removals completely blocked the ability to adhere to spikes, while the other two had no effect.
That’s bad news. But the immune response usually involves a collection of different antibodies that can stick to a virus. And when the researchers tested patients’ plasma (which should have a mix of antibodies) against the mutant forms, some of the antibodies present were able to attach to it. So while all of these removals appear to be able to limit the immune system’s ability to neutralize the virus, the removals do not completely eliminate that ability.
So while these mutations are concerning, they are not yet a clear threat.
Some of these deletions have already been seen in strains that appear to be more widespread in recent months. And while the research team was doing all of these experiments, reports came out of four additional strains that spread rapidly and carried deletions in peak.
Again, so far there is no indication that any of these strains can bypass the immunity built up by previous infection or any of the vaccines currently in use. But the results make it clear that the virus evolves in response to the immune system response, and we cannot guarantee that further changes won’t make COVID-19 more difficult for our immune system to keep at bay.
Science, 2021. DOI: 10.1126 / science.abf6950 (About DOIs).