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In the early 1990s, Nathaniel Landau, a young virologist who began his career in HIV research. But he and his colleagues were already on the verge of making a historic breakthrough. Several labs around the world were hot on the heels of their team.
“We slept in the lab, only to keep the jobs running day and night because there were so many labs competing against others,” Landau says. “Of course, we wanted to be the first to do it. We were totally stressed. “
Other scientists had met teams from other people who gave the impression of being absolutely resistant to HIV. “People who knew they had been exposed to HIV repeatedly, most commonly through unprotected sex, but who were obviously not infected,” Landau says.
And so began the race to figure out why: “Are those other people just lucky or do they have a mutation in their genes that protected them from infection?”he says.
Now, 25 years later, scientists around the world are looking to answer the same thing about another virus: SARS-CoV-2.
At this point in the pandemic, most Americans have had at least one episode of COVID. For young people under the age of 18, more than 80 percent of them have been infected, the Centers for Disease Control and Prevention estimates.
But like HIV, some other people have been exposed several times but have never had symptoms and have never tested positive.
“We’ve heard countless anecdotes about nurses and fitness personnel exposed without any coverage and who continue to be negative over and over again,” says pediatrician Jean-Laurent Casanova, who studies the genetics of viral resistance at Rockefeller University. who you’ve been coughing with for a few weeks, and a user is still negative. “
So why haven’t those other people stuck to COVID?
After two years of hunting, a team from the University of California, San Francisco is about to answer the question.
“These discoveries have just come out of print,” says immunogeneticist Jill Hollenbach, who led the research. “We haven’t published them yet. That’s all that happened this summer. “
Hollenbach and his team discovered a genetic mutation that doesn’t prevent the virus from infecting cells — that’s what Landau was looking for in his HIV studies — but it still does something remarkable: it prevents a user from having COVID symptoms.
It turns out that preventing an infection is an incredibly difficult challenge for our framework to solve.
Throughout human history, scientists have known only two instances of true super-criminals of the virus. That is, an express mutation in your genes makes other people absolutely resistant to a virus. So it escapes from its cells, “like water sliding out of a window,” as Casanova puts it.
In 2003, a team in London showed how some other people never get a virus in the abdomen, called norovirus, which causes vomiting and diarrhea. The researchers found that a mutation in their genes prevents them from producing a molecule that the virus wants to infect the cell. .
(In 1995, French researchers discovered why some other people seemed to never be inflamed with a species of malaria known as Plasmodium vivax. However, over the past decade, other studies have clarified that those super scammers are inflamed with the parasite; they just don’t have symptoms. )
By far the most well-known super scammers are other HIV people: the ones Landau and his colleagues were reading in the early 1990s.
In 1996, his team came close to solving this puzzle. One morning they discovered a huge clue. The night before, they had organized an experiment to verify the molecules HIV needed to infect a human cell. The experiment yielded impressive results.
It showed that HIV did not enter mobile phones as scientists believed. Instead, he needed a little extra help. Specifically, HIV wants an express molecule, called CCR5, on the surface of the mobile to “open the door” and let the virus in, Landau says. Without CCR5, the virus only sticks to the surface of the mobile and still enters. “It’s a bit like the virus knocking on the door, but no one is opening the door. The door is closed,” he says.
“It’s what we call a eureka moment,” Landau says. That moment where we can simply say, ‘We discovered something that has never been noticed before. ‘
Landau and his colleagues ran to the computer and wrote the effects as temporarily as possible. Then he literally ran to the FedEx store to submit the paper to the journal Nature, knowing that other groups would soon make the same observation.
“At that point, you may not just send your work through your computer,” he says. on time. “
Just a few weeks later, Landau and his colleagues made another big discovery and, in doing so, solved the last piece of the HIV puzzle. “We were surprised that everything happened so quickly,” Landau said.
In collaboration with a study organization at the end of the corridor, Landau and his colleagues sequenced the CCR5 gene in two other people who were completely resistant to HIV. There you have it! The other two people had the same mutation in the gene, and it’s a difficult mutation. It completely paralyzes the molecule so that it doesn’t appear on the surface of cells, the organization reported in the journal Cell. Remember, without CCR5, HIV can not infect the cell.
“You can put as many traces of virus as you need into those cells, and they may not get infected,” he says. “So in the case of HIV resistance, the story was very clear. “
The discovery absolutely replaced the HIV box. This led to the first, and only, way to cure a user of HIV and suggested a new avenue, gene editing with CRISPR. But it did something else: It showed scientists that a mutation can simply make a user absolutely resistant to infection. A mutation in his genes can turn him into a real super criminal.
“So when SARS-CoV-2 occurred, of course, a lot of labs looked at whether the same could be true for this virus,” Landau says. And encouraged by the history of CCR5, they looked for mutations in the genes needed for SARS. -CoV-2 to enter and infect cells.
For COVID super scammers, the scenario appears to be more complex than for HIV-resistant people, Landau says, because SARS-CoV-2 infects cells is different from HIV.
Instead of CCR5 to “open the door of the mobile”, SARS-CoV-2 uses the ACE2 receptor. People can’t live without ACE2. ” The receptor regulates blood pressure,” Landau says. So unlike CCR5, it can’t just knock out the ACE2 receptor, he says. “You’re not going to have a lot of other people who don’t have ACE2.
“Of course, there are possibly more sophisticated mutations in ACE2 that may also play a role in resistance to SARS-CoV-2,” he adds. “But there doesn’t seem to be an apparent and dramatic mutation like there is for HIV. “
But what’s more likely, he says, is that other people have mutations in genes other than ACE2, and those mutations probably aren’t due to an infection, but to a disease.
So having one of those mutations would make you kind of a covid mini scammer, so to speak. There are other tactics for an infection besides denying the virus access to the cell, Landau says. And they probably involve your body’s immune system.
This is precisely what the UCSF team discovered.
Since the beginning of the pandemic, Jill Hollenbach and her ucSF colleagues have been reading to other people who tested positive for COVID but have no symptoms. “Not even a cold or itchy throat,” she says. “
After analyzing the DNA of more than 1,400 people, they learned of a mutation that is helping a SARS-CoV-2 user so temporarily that his condition has no possibility of presenting symptoms.
The mutation occurs in a gene called HLA, which is imperative in the early stages of infection. Hollenbach and his colleagues found that having a specific mutation in this gene increases the risk of being asymptomatic nearly 10 times.
They initially filed those effects online last September.
Since then, they have continued to show how this mutation works. And it has to do with its immune formula for SARS-CoV-2 even before the pandemic begins in 2019.
When a virus first enters the cells, HLA signals to the immune formula that the cells are invaded and need help. This signal triggers a cascade of events that eventually lead his body to craft hard weapons, specially designed to combat SARS-CoV-2. These weapons come with antibodies and T cells that recognize fragments of this virus uniquely. Once those targeted weapons are available, their immune formula has far less difficulty clearing the infection. But those weapons take time to manufacture. And this delay allows the infection to spread and symptoms to develop.
But what if, for some fortunate reason, its immune formula already had particular weapons directed against SARS-CoV-2?
This summer, Hollenbach and his colleagues showed that with an express mutation in HLA, some other people have T cells that are already preprogrammed to recognize and fight SARS-CoV-2. Therefore, there is no time frame for producing express COVID weapons. It’s already there.
“Their immune reaction and those T cells cause much faster [than in a user without an HLA mutation],” Hollenbach says. “So, for lack of a broader term, it neutralizes the infection even before it starts having symptoms. “
But here’s the catch. For the HLA mutation to be painted (and for you to have those pre-assembled T cells), you first had to have been inflamed with coronavirus.
“Most of us have been exposed to a bloodless coronavirus at some point in our lives,” he explains. And we all generate T cells to fight those without blood. But if you also have this mutation in your HLA, Hollenbach says, then, through By Chance, the T cells it produces can also fight SARS-CoV-2.
“It’s definitely luck,” she says. But, you know, this mutation is quite common. We estimate that 1 in 10 more people have it. And in other asymptomatic people, it will be 1 in 5. “
While Hollenbach and his team continue to search for other mini-dodge genes, Rockefeller University’s Casanova and his colleagues are still looking for genuine genes from super-scammers. And lately it is looking for participants for its study.
“Complete an online questionnaire about your exposures to SARS-CoV-2,” he says. And then, if you meet the criteria for a super evader, the team sends you a kit. Basically, he spits into a cup and returns it to Casanova and his collaborators.
“We’re going to extract their DNA and sequence their genome,” he explains. “We hope that in an organization of another 2000 to 4000 people, some other people will have genetic mutations that tell us why they are resistant to infection. “
And maybe, as with HIV, this discovery will one day replace the COVID study box and lead to a vaccine that does what all of our existing vaccines do: turn everyone into a COVID super scammer.
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