New variants of SARS-CoV-2 have major impacts around the globe, driving up COVID-19 case and mortality numbers (see main story, p. [844][1]). But each of those viruses picks up its crucial changes as it divides in the cells of an infected human being. The nature of those infections—how fast the virus replicates and for how long—may determine the odds that they will give rise to new and more troublesome mutants, researchers say.
After someone is infected, the virus starts to multiply at a dizzying rate, producing billions of viral particles within days. Because small copy mistakes happen during every replication cycle, a huge variety of slightly different genomes quickly emerges. With SARS-CoV-2’s genome spanning just 30,000 nucleotides, and only three ways to change any one position, every possible mutation likely arises in an infected individual.
The vast majority of those changes offer the virus no benefit, and even those that do only have a small chance of being passed on to the next person. A paper published in 2020 estimated that about 1000 viral particles are transmitted when one person infected another, but a reanalysis by Katia Kölle of Emory University and a colleague, published as a preprint in February, concluded that 99% of all successful transmissions come from three or fewer virus particles. A study published in Science in April by evolutionary biologist Katrina Lythgoe at the University of Oxford put the number of transmitted virus particles at infection between one and eight.
This means that, unless a mutation arises early and gives the virus so big an advantage that it quickly becomes dominant in the host, it has a low chance of being transmitted, which puts the brake on virus evolution. “It’s generally thought that when transmission bottlenecks are tight, that slows adaptive evolution at the population level,” Kölle explains.
That may sound like good news for humanity, but it is offset by the huge number of SARS-CoV-2 infections globally, says Jesse Bloom, an evolutionary biologist at the Fred Hutchinson Cancer Research Center. Besides, the virus may have a shortcut. In most people, the immune system curbs the infection within days, but a few develop a chronic infection lasting months. That gives time for mutations to accumulate and become dominant, increasing their chances of transmission. In a short-lived acute infection, evolution is “more like roulette,” Kölle says, but in chronic cases, “you have the time needed to adapt to that environment.”
Chronic infections may explain why the Alpha variant, first seen in the United Kingdom in late 2020, appeared to emerge with a slew of mutations all at once. In theory, Alpha could have picked up those changes one by one before arriving in the country, says Andrew Rambaut of the University of Edinburgh, but the fact that most of its genome resembles other U.K. viruses at the time suggests instead that a local virus underwent extended evolution in a single patient. “I am still reasonably confident that a chronic infection is the best explanation,” Rambaut says.
COVID-19 treatments may accelerate evolution in chronic patients. In July, researchers in Germany published data on six immunocompromised patients treated with a monoclonal antibody that targeted SARS-CoV-2. In five of them, the virus acquired E484K, a mutation known to help it elude the immune system, and the virus rebounded in all five patients.
Still, the evidence that chronic patients are the source of new variants is circumstantial, Bloom cautions. People who don’t develop chronic infections but do take longer than average to clear SARS-CoV-2 could also generate and spread mutants, Lythgoe says—and they are more numerous. “Are these the infections that really drive the evolution of acute viruses like SARS-CoV-2? There’s really interesting questions there.”
[1]: http://www.sciencemag.org/content/373/6557/844
