During the summer, you could almost hear a sigh of relief from the part of the research community that was following the evolution of the SARS-CoV-2 virus. Viruses, especially those that are new to their hosts, often pick up mutations that help them adapt to the new habitat or prevent drugs or immune attacks. But SARS-CoV-2 appeared to be picking up mutations at a relatively slow pace, in part because its virus copy enzymes had a feature that allows them to correct some errors.
But suddenly, new variants seem to be everywhere, and several of them seem to increase the threat posed by the virus. A new study helps to explain the apparent difference: while new base changes in the virus’s genetic material remain rare, some deletions from various bases appear to have evolved several 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 looks familiar
Researchers’ interest in exclusions began with their involvement with a patient with immunocompromised cancer, who held the infection for more than two months without being able to eliminate the virus. Samples obtained at the end of the infection revealed two different virus strains, each with 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 go back and examine a collection of almost 150,000 viral genomes. They found that more than 1,100 of them carried deletions in the peak protein. But critically, they found that they were not randomly distributed. Ninety percent of the deletions are grouped into four distinct areas of the spike gene.
This can 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 exclusions can be useful from the point of view of evolution and, therefore, whenever they occur, they end up being maintained.
To find out what’s going on, the researchers built an evolutionary tree of the viruses using mutations that occurred outside the protein spike. This showed that, apart from exclusions, viruses used to be remotely related. This indicates that the latter option is probably true: exclusions generally occurred independently and were kept at an unusually high rate. A specific exclusion appears to have occurred at least 13 different times, and some of the deletions have existed since the beginning of the pandemic.
Selected
If these exclusions are maintained, the obvious question is “Why?” To find out, the researchers discovered how each deletion 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 peak protein. None of the regions turned out to be essential for the spike protein to do its job (which you would expect, since excluding them would probably disable it). Instead, some of the sites had already been identified as sites where antibodies to the spike protein would stick together.
So the researchers produced these exclusion versions of the spike protein and tested whether an antibody that can neutralize the virus can stick to them. For an antibody, the answer was “yes”: two of the deletions completely blocked its ability to adhere to the peak, while the other two had no effect.
This is bad news. But the immune response usually involves a collection of different antibodies that can bind 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. Therefore, while any of these exclusions appear to be able to limit the immune system’s ability to neutralize the virus, deletions do not entirely eliminate that ability.
So while these mutations are worrying, they are not yet a clear threat.
Some of these deletions have already been seen in strains that appear to have increased spread in recent months. And while the research team was doing all of these experiments, reports of four additional strains were appearing that were spreading rapidly and contained peaked deletions.
Again, so far, there is no indication that any of these strains can escape the immunity developed by a previous infection or one of the vaccines currently in use. But the results make it clear that the virus is evolving in response to the immune system’s reaction to it, and we cannot guarantee that further changes will not make COVID-19 more difficult to keep under control by our immune system.
Science, 2021. DOI: 10.1126 / science.abf6950 (About DOIs).