Sun. Oct 2nd, 2022
Ribbon diagram of the structure of the coronavirus spike protein.
enlarge The structure of the SARS-CoV-2 spike protein.

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 new to their hosts, often pick up mutations that help them adapt to their new habitat, or evade drugs or immune attacks. But SARS-CoV-2 seemed to pick up mutations at a relatively slow pace, in part because the virus-copying enzymes had a function that allowed them to correct some errors.

But all of a sudden there seem to be new variants everywhere, and some seem to amplify the threat of the virus. A new study helps explain the apparent difference: While new base changes in the virus’s genetic material 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 alter 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 endured the infection for more than two months without being able to clear the virus. Samples obtained late in infection revealed two different virus strains, each of which had a deletion in the gene encoding the spike protein that SARS-CoV-2 uses to attach to and invade 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 prompted them to go back and check out 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 were clustered in four different regions of the spike gene.

That could be for two reasons. It is possible that these viruses are related by common descent and all inherited the same ancestral deletion. Or these removals may be useful from an evolutionary perspective, and so when they do occur, they stay 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, apart from the deletions, the viruses were often distantly related. This indicates that the latter option is probably true: the deletions often happened independently and were simply kept at an unusually fast pace. One specific removal appears to have occurred at least 13 different times, and some of the removals 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 gene’s mutant form. 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’d 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 deletion versions of the spike protein and tested whether an antibody that can neutralize the virus can stick to them. For one antibody, the answer was “yes”: two of the deletions completely blocked the ability to stick 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 contain a mix of antibodies) against the mutated forms, some of the antibodies present were still able to stick to them. So while all of these deletions appear to be able to limit the immune system’s ability to neutralize the virus, the deletions don’t completely eliminate that ability.

And while these mutations are worrisome, they pose no apparent threat yet.

Some of these deletions have already been observed in strains whose distribution appears to have increased in recent months. And while the research team was doing all these experiments, reports came out of four additional strains spreading rapidly and showing deletions in spikes.

Again, so far there is no evidence that any of these strains can evade the immunity built from a 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’s response to it, and we can’t guarantee that further changes won’t make COVID-19 more difficult for our immune systems to keep at bay.

Science, 2021. DOI: 10.1126/science.abf6950 (About DOIs).

By akfire1

Leave a Reply

Your email address will not be published.