During the summer, you could almost see a sigh of relief increase 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, find mutations that help them adapt to their new habitat, or evade drugs or immune attacks. But SARS-CoV-2 mutations appear to take up mutations at a relatively calm rate, in part because the virus-copying enzymes have a function that enables them to correct errors.
But suddenly new variants appear to be everywhere, and a number of them seem to increase the threat of the virus. A new study helps explain the apparent difference: although new base changes in the virus’ genetic material remain rare, it appears that some deletions of multiple bases have evolved multiple times, suggesting that evolution has opted for it. The research team behind this new work has found evidence that these changes change how the immune system can respond to the virus.
It looks familiar
The researchers’ interest in scraping began with their involvement with an immunocompromised cancer patient, who stopped the infection for more than two months without resolving the virus. Samples obtained from late in the infection revealed two different virus strains each removed in the gene encoding the muscle protein that SARS-CoV-2 uses 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 deletion appears to be in other patients. This led them to look back at a collection of nearly 150,000 viral genomes. They found that more than 1100 of them contained removers in the protein. But critically, they found that it was not randomly distributed. Ninety percent of the scrapes were pooled in four different parts of the spike gene.
This can be for one of two reasons. It is possible that these viruses are related by common ancestry and that they all inherited the same ancestral removal. Or these extinctions can be useful from an evolutionary perspective, and so they are always preserved when they happen.
To find out what’s going on, the researchers built an evolutionary tree of the viruses using mutations that occurred outside the vein protein. This showed that the viruses, outside of removal, were often closely related. This suggests that the latter option is likely to be true: the scraps often took place independently and were only held extraordinarily high. One specific deletion appears to have occurred at least 13 different times, and some of the deletions existed early in the pandemic.
Chosen
If these deletions are kept, then the obvious question is ‘Why?’ To find out, the researchers figured out how each of the removers would alter the protein of the peak produced by the mutant form of the gene. They compare this information with what we know about the structure and function of the vein protein. None of the regions were essential for the protein to do its job (which you would expect since its removal is likely to inactivate it). Instead, some of the sites have already been identified as sites where antibodies to the peak protein would adhere to it.
The researchers therefore produced these removal versions of the vein protein and tested whether an antibody that could neutralize the virus could adhere to it. For one antibody, the answer was ‘yes’: two of the scrapings completely blocked the ability to hold, while the other two had no effect.
This is bad news. But the immune response usually involves a collection of different antibodies that can stay with a virus. And when the researchers tested the plasma of patients (who would have a mixture of antibodies) against the mutant forms, some antibodies could still stick to it. Although any of these removers may appear to limit the ability of the immune system to neutralize the virus, the ability is not completely eliminated.
Although these mutations are of concern, they are not yet a clear threat.
Some of these scrapings have been seen in strains that have apparently increased in recent months. While the research team was doing all these experiments, there were four additional strains that spread rapidly, and it carried scratches in the tip.
Again, so far there is no indication that any of these strains can evade the immunity provided by previous infection or any of the vaccines currently in use. But the results make it clear that the virus develops in response to the immune system’s response to it, and we can not guarantee that further changes will not make COVID-19 more difficult for our immune systems.
Science, 2021. DOI: 10.1126 / science.abf6950 (On DOIs).