Different roads, same destination: Study shows COVID variants evolve to suppress immunity

The spike protein on the surface of SARS-CoV-2, the virus that causes COVID-19, has basked in the spotlight since the pandemic began. And for good reason: After all, that spike is what enables it to enter human cells.

But despite its notoriety, the protein is just one of several that make SARS-CoV-2 a tricky foe, as scientists from the University of California, San Francisco’s Quantitative Biosciences Institute (QBI), Icahn School of Medicine at Mount Sinai and University College London show in an article published online Sept. 21 in Cell. The findings shed light on how the virus is evolving and support a combination approach that tackles the proteins that help it suppress the immune system, study lead and QBI founder Nevan Krogan, Ph.D., told Fierce Biotech Research.

“We’ve figured out how this virus is going to behave as it goes forward, or at least a big part of it,” he said. “And what we need to do, just like we do with HIV, is fight it with a cocktail of therapies.”

The new findings build on the 50-plus studies published over the course of the pandemic by the QBI Coronavirus Research Group, a network of scientists founded by Krogan that has been tracking COVID’s evolution and identifying potential therapies since the virus emerged in 2020. Besides a plethora of papers, the collaboration has also led to two clinical trials, including one with Spanish pharma PharmaMar assessing the use of cancer drug plitidepsin as a treatment for immunocompromised patients with COVID.

“We now have a deep mechanistic understanding of how this virus works,” Krogan said.

That now includes an explanation for the convergent evolution of different strains of the virus—that is, the way it mutates via different mechanisms but seemingly ends with the same result: suppression of the innate immune response.

“It’s converging on the same kind of final output, but it’s doing so through different kinds of evolutionary trajectories through different mutations,” Krogan said. “It’s almost like if you try to force it to go one way, it’ll go another way and do what it wants.”

To map this out, the researchers took healthy lung cells and cultured sets of them with major strains of the virus, from alpha through omicron BA.1. Then they used various computational tools to examine how protein and gene expression changed between strains as well as how the virus affected genes within the host cells.

While the way the virus evolved to outsmart the immune system changed depending on the strain, as expected, there was a common mechanism involving a handful of select proteins. One of them, ORF9b, stood out as being especially complicit in enabling pre-omicron variants of the virus to suppress the innate immune response, the body’s first line of defense against pathogens, and invade cells.

Interestingly, the original strain of omicron was less effective than alpha or delta in getting around that defense system, the researchers noted—potential evidence for the theory that it arose from a chronically ill, immunocompromised patient. Future offshoots, including BA.5, made up for that by expressing higher levels of another protein, ORF6, which once again bumped up the virus’s ability to suppress innate immunity. (The researchers went into more detail on ORF6 in a second paper, also published Sept. 18, in Cell Host & Microbe.)

Now that the researchers have a clear idea of the proteins at play, the next step will be to try to develop new treatments that target them from multiple angles. Work is ongoing now to develop therapies that would target the SARS-CoV-2 proteins that manipulate the immune response.

“Ultimately, these drugs could effectively be used in a ‘cocktail’ with therapies that target viral entry involving the spike protein,” Krogan said in an email. Meanwhile, his COVID research efforts will be helped along by a $200,000 award he received Sept. 20 as the first-ever recipient of Research!America’s Discovery | Innovation | Health prize, sponsored by Pfizer.