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During the summer, you could almost hear a sigh of relief coming from the part of the research community that was following the evolution of the SARS-CoV-2 virus. Viruses, especially those new to their hosts, often acquire mutations that help them adapt to their new habitat, or evade drugs or immune attacks. But SARS-CoV-2 appeared to be detecting mutations at a relatively slow rate, in part because its virus-copying enzymes had a role to correct for some errors.
But suddenly, new variants appear everywhere, and several of them seem to increase the threat posed by the virus. A new study helps explain the apparent difference: While new base changes in the virus’ genetic material remain rare, some multi-base deletions appear to have evolved multiple times, indicating that evolution was selecting for them. The research team behind this new work found evidence that these changes alter the way the immune system can respond to the virus.
This seems familiar
The researchers’ interest in the deletions began with their involvement in an immunosuppressed cancer patient, who contained the infection for more than two months without being able to clear the virus. Samples obtained at the end of the infection revealed two different virus strains, each of which had a deletion in the gene that encodes the spike protein that SARS-CoV-2 uses to bind and enter cells.
When the researchers searched a database of other viral genomes, they found six other cases in which the same or similar deletions appear to have evolved in other patients. This caused them to look back at a collection of nearly 150,000 viral genomes. They found that more than 1,100 of them carried deletions in the peak protein. But critically, they found that these were not randomly distributed. Ninety percent of the deletions were grouped into four different areas of the spike gene.
That could be for one of two reasons. It is possible that these viruses are related by common descent and all inherit the same ancestral deletion. Or these deletions could be useful from an evolution perspective, so each time they occur, they end up sticking around.
To find out what’s going on, the researchers built an evolutionary tree of the viruses using mutations that occurred outside of the spike protein. This showed that, outside of the deletions, the viruses were often distantly related. This indicates that the last option is likely to be true: the eliminations often occurred independently and were simply kept at an unusually high rate. A specific deletion appears to have occurred at least 13 different times, and some of the deletions have been around since the beginning of the pandemic.
Selected
If these deletions hold up, the obvious question is “Why?” To find out, the researchers discovered how each of the deletions would alter the spike protein produced by the mutant 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 was to be expected, since removing them probably inactivates it). Instead, some of the sites had already been identified as places where antibodies against the spike protein would adhere.
The researchers then produced these deletion versions of the spike protein and tested whether an antibody that can neutralize the virus can adhere to them. For an antibody, the answer was “yes”: two of the deletions completely blocked its ability to adhere to the peaks, while the other two had no effect.
That is bad news. But the immune response generally involves a collection of different antibodies that can attach to a virus. And, when the researchers tested the patients’ plasma (which should have a mixture of antibodies) against the mutant forms, some of the antibodies present were still able to adhere to it. So while any of these deletions appear to be capable of limiting the immune system’s ability to neutralize the virus, the deletions 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 observed in strains that appear to have increased their spread in recent months. And, while the research team was doing all these experiments, reports emerged of four additional strains that were spreading rapidly and had peak deletions.
Again, so far, there is no indication that any of these strains can evade the immunity built up by a previous infection or one of the vaccines currently in use. But the results make clear that the virus is evolving in response to the immune system’s reaction, and we cannot guarantee that further changes will not make COVID-19 more difficult for our immune systems to keep in check.
Science, 2021. DOI: 10.1126 / science.abf6950 (About DOIs).
