Is a variant worse than Delta en route? Viral evolution offers clues.

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Somewhere in India last October, a person – likely immunocompromised, possibly taking medication for rheumatoid arthritis or with an advanced case of HIV / AIDS – developed COVID-19.

Their case may have been mild, but due to their body’s inability to clear the coronavirus, it persisted and multiplied. As the virus replicated and moved from cell to cell, parts of the genetic material incorrectly copied each other. Maybe the person was living in a crowded house or going out to buy food in a busy market, but wherever it happens, the altered virus has spread to others. Experts believe that this singular situation in an individual is probably the reason why the Delta variant which is now wreaking havoc in the United States and around the world was born.

During the COVID-19 pandemic, thousands of variants have been identified, four of which are considered ‘variants of concern’ by the World Health Organization – Alpha, Beta, Gamma and Delta, all closely followed by scientists on websites such as GiSAID and CoVariants. The delta is by far the most contagious, around 97% more than the first virus in circulation, according to European researchers. But is it the worst the world can see? Understanding how mutations develop can help us understand whether more worrisome versions may still emerge.

This turn of events in India – or others that may take place elsewhere – was expected by microbiologists who study viruses, although they could not predict where it would occur, exactly when, and what lines of genetic code would occur. would move inside the germ. “Every time the virus enters a cell, it replicates its genome so that it can spread to other cells, and that can potentially make a mistake,” says Bethany Moore, chair of the Department of Microbiology and Immunology from the University of Michigan.

Mutations usually appear randomly and spontaneously, rather than systematically.

Most mutations kill the virus or die from lack of spread, victims of an infected person isolating or transmitting the germs to a small number of others who then stay at home.

But when enough mutations are created, some will get lucky (from a virus perspective) and hang on, perhaps when an infected person attends a crowded sporting event or a large indoor gathering like a wedding. . “It’s like there’s an evolutionary storm over a lot of smoldering embers of hopeful little mutants that might normally go away, but when you have a widespread infection, natural selection takes over,” says Vaughn Cooper, professor of microbiology and molecular genetics at the University of Pittsburgh School of Medicine.

Coronaviruses more prone to mutations than other germs

Scientists always expected to see variants with SARS-CoV-2 because coronaviruses inevitably copy their genomes more carelessly as humans and animals, or even some other pathogens, mimic their own genetic codes. Rather than a double helix deoxyribonucleic acid (DNA) carrying their genes, coronaviruses contain single stranded ribonucleic acid (RNA). “Due to very old accidents in history, enzymes that make new copies of RNA are more prone to errors,” says Cooper, although he notes that coronaviruses do not produce as many mutations as they do. other RNA viruses such as influenza due to a proofread enzyme responsible for rechecking its work. “The majority of viruses that enter a patient and leave that patient are the same,” says Cooper. For coronaviruses, the estimate is that an error occurs in a million or more units of replicated RNA, says Moore.

But it doesn’t take a lot of shoddy copies of a virus to wreak havoc on the world. “There’s a reason healthcare professionals have always been concerned about pandemic respiratory threats,” says Sten Vermund, infectious disease epidemiologist at the Yale School of Public Health. Germs transmitted when we breathe or speak spread faster than those that require contact or sex or poor sanitation. The threat of this coronavirus is compounded by the fact that we can pass it on, and its mutated versions, before we even know we have it.

So far, the genome, or the complete set of genetic material, of more than one million SARS-CoV-2 viruses has been sequenced by scientists, who wish to stay abreast of the evolution of the virus in order to to determine the best way to protect people from it. Earlier this year, the UK, a leader in this endeavor, launched a $ 3.5 million effort to study the effects of emerging mutations. Sequencing got off to a slow start in the United States, but in the fall of 2020, the Centers for Disease Control and Prevention launched the National SARS-CoV-2 (NS3) Strain Surveillance Program which contracts with universities and private laboratories to sequence the coronaviruses circulating here. . Hundreds of thousands of genomes have already been sequenced under this program.

Sets of random mutations found in a virus are only classified as variants when they give the pathogen an advantage, Moore explains. Within each variant are sub-variants (as shown in the alternate naming system known as Pango, where Delta is known as B.1.617.2, with the last numbers indicating sublines). However, the general plan of the genome remains the same. If SARS-CoV-2 mutates in a way that changes its essential nature, it could become a new species, possibly SARS-CoV-3, she notes.

Convergent evolution

Mutations that do take hold, Cooper says, survive for a reason, such as helping the virus to increase transmissibility, infectivity, virulence, or the ability to evade our immunity.

But scientists are less concerned with a specific mutation than with similar changes occurring in multiple independent variants, Cooper says, “because it suggests they make the virus more evolutionary.” This phenomenon is known in evolutionary biology as convergent evolution.

For example, in all of the worrisome variants, a common mutation occurs in a section of the spike protein, with protrusions dotting the surface of the virus that help it infect human cells. At position 614, one type of amino acid (called aspartic acid) has been replaced by another (glycine). This mutation, known as D614G, makes the virus more transmissible and infectious.

Another common mutation, L452R, converts the amino acid leucine to arginine, again on the spike protein. The fact that mutations in L452 are seen in more than a dozen distinct lineages indicates that this mutation confers a significant advantage on the coronavirus, researchers recently noted after sequencing hundreds of virus samples in the United States. our cells, L452R may help infect people with some immunity.

Because the spike protein has been essential for the development of vaccines and treatments, more research has been done to study mutations there compared to other proteins in the coronavirus. But it’s important to pay attention beyond this area, says Nash Rochman, an evolutionary virology expert at the National Library of Medicine at NIH. Rochman co-authored a recent paper which concludes that while the spike protein is an important site, so is another part of the virus called the core protein, which makes up the coating that surrounds the RNA genome. virus.

In fact, the two areas could work together, Rochman says. “A variant with a mutation in the [spike protein] without any change in the nucleocapsid protein could behave very differently from another variant which has mutations in both regions. Clusters of mutations working together are a concept known as epistasis, and modeling by Rochman and colleagues shows that a small cluster of mutations in various locations could collectively have the major impact of helping the virus to escape antibodies and therefore make vaccines less effective.

The mutations that have appeared in the United States this year are the reason the pandemic is not under control. “Just as we were making progress with the vaccination, Delta is coming,” says Vermund, and rather than the expected reductions in vaccine cases, rates have increased due to Delta’s increased transmissibility. “If we had only had Alpha circulation at that point, the increase in the number of cases would not have happened,” he says.

Whether the virus can get mutations that help it evade vaccines is of course everyone’s biggest concern. Currently, the three vaccines authorized in the United States remain protective. (Mu, the more recent “variant of interest” appears to weaken the effectiveness of the vaccine, but it is not spreading widely at this time.) Some people believe that the small percentage of people vaccinated testing positive or developing symptoms is a sign the virus is foiling the shots, but Vermund says it isn’t. “I hate the term ‘revolutionary infection’ because it is misleading about science,” he says. Vaccines are not like energy shields that distract Klingons, he says. Instead, they allow the enemy to board the ship (hence the positive tests) but they are immediately surrounded by a well-armed crew.

With such a small portion of the world’s population vaccinated (around 43 percent have received at least one injection, but only 2 percent of those in low-income countries have), the virus is yet to be seen much. ‘incentives to override the immune system of those who have been vaccinated. “Vaccine breakout is not what the virus is looking for right now,” Cooper said. It’s easier for germs to find new and improved ways to infect the billions of people who don’t yet have this immunity.

Yet no one knows what mutations await us and how much damage they could cause. Vermund points out that 95% of people on Earth can visit another location within 48 hours – during the incubation period of COVID-19 – which is why a variant emerging even in a remote, low-population area can become a problem. global.

“Mutations occur when there is viral replication. So the best way to stop future variants is to drastically limit the amount of viral replication that occurs around the world, ”says David Peaper, a Yale Medicine pathologist who heads the clinical microbiology lab at Yale New Haven Hospital. . That’s why getting everyone in the United States and around the world vaccinated is the most important thing we can do, he says. “As long as there is SARS-CoV-2 anywhere in the world, dangerous variants will have a chance to emerge.”


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