The Perfect Enemy | So You Haven’t Caught COVID Yet. Does That Mean You’re a Superdodger?
November 15, 2023

“In those days you couldn’t just submit your paper through your computer,” he says. “You had to mail a hard copy of it to the journal. And my job was to sprint over to the FedEx store so we could get the paper mailed on time.”

Then only a few short weeks later, Landau and his colleagues made another huge discovery, and in the process solved the final piece of the HIV puzzle. We were quite amazed that it all happened so quickly,” Landau says.

In collaboration with a research group down the hall, Landau and his colleagues sequenced the CCR5 gene in two people completely resistant to HIV. Lo and behold! Both people had the same mutation in the gene — and it’s a powerful mutation. It completely cripples the molecule so that it doesn’t appear on the cells’ surface, the group reported in the journal Cell. Remember, without CCR5, HIV can’t infect the cell.

“You can put as many virus particles as you want onto those cells, and they will not get infected,” he says. “So in the case of resistance to HIV, the story was very clear.”

The finding completely shifted the field of HIV. It led to the first — and only — way to cure a person of HIV and suggested a new route, using gene editing with CRISPR. But it did something else: It showed scientists that one mutation could make a person completely resistant to an infection. One mutation in their genes could make them a true superdodger.

Trying to find out if there really are COVID superdodgers

“So when SARS-CoV-2 came along, of course, many labs looked to see if the same might be true for this virus,” Landau says. And inspired by the story of CCR5, they went looking for mutations in the genes required for SARS-CoV-2 to enter and infect cells.

For COVID superdodgers, the situation appears to be more complex than for people resistant to HIV, Landau says, because the way SARS-CoV-2 infects cells is different from that of HIV.

Instead of using CCR5 to “open the cell’s door,” SARS-CoV-2 uses the ACE2 receptor. People can’t live without ACE2. “The receptor regulates your blood pressure,” Landau explains. So, unlike CCR5, you can’t simply knock out the ACE2 receptor, he says. “You’re not going to have many people walking around that don’t have ACE2.

“Of course, there may be more subtle mutations in ACE2 which could play a role in resistance to SARS-CoV-2,” he adds. “But there doesn’t seem to be an obvious and dramatic mutation as is the case for HIV.”

But perhaps what’s more likely, he says, is that people have mutations in genes other than ACE2, and these mutations probably don’t protect them from getting infected per se but do protect them from getting sick.

Maybe there are … mini-dodgers?

So having one of these mutations would make you a sort of COVID mini-dodger, if you will. There are other ways to resist an infection besides denying the virus entrance into the cell, Landau explains. And they likely involve your body’s immune system.

That’s exactly what the team at UCSF has found.

Since the pandemic began, Jill Hollenbach and her colleagues at UCSF have been studying people who test positive COVID but show no symptoms. “Not even a sniffle or a scratchy throat,” she says. “So they are entirely asymptomatic.”

After analyzing DNA from more than 1,400 people, they identified a mutation that helps a person clear out a SARS-CoV-2 so fast that their body doesn’t have a chance to develop symptoms.

The mutation occurs in a gene called HLA, which is critical during the earliest stages of infection. Hollenbach and her colleagues found that having a particular mutation in that gene increases a person’s chance of being asymptomatic by almost 10 times.

They reported those preliminary findings online last September.

Since then, they’ve gone on to show how this mutation works. And it has to do with your immune system preparing for SARS-CoV-2 before the pandemic even began back in 2019.

When a virus first enters cells, HLA signals to the immune system that cells are invaded and need help. That signal triggers a cascade of events that ultimately leads your body to make potent weapons specifically designed to fight SARS-CoV-2. These weapons include antibodies and T cells that uniquely recognize pieces of this virus. Once these targeted weapons are available, your immune system has a much easier time clearing up the infection. But these weapons take time to manufacture. And that delay allows the infection to spread and symptoms to develop.

But what if, for some lucky reason, your immune system already had weapons specifically targeted to SARS-CoV-2?

This summer, Hollenbach and her colleagues demonstrated that, with a specific mutation in HLA, some people have T cells that are already pre-programmed to recognize and fight off SARS-CoV-2. So there’s no delay in generating COVID-specific weaponry. It’s already there.

“Your immune response and these T cells fire up much more quickly [than in a person without the HLA mutation],” Hollenbach says. “So for lack of a better term, you basically nuke the infection before you even start to have symptoms.”

But here’s the kicker. For the HLA mutation to work (and for you to have these pre-armed T cells), you first had to have been infected with another coronavirus.

Most of us have been exposed to some common cold coronavirus at some point in life,” she explains. And we all generate T cells to fight off these colds. But if you also have this mutation in your HLA, Hollenbach says, then just by mere luck, these T cells you make can also fight off SARS-CoV-2.

“It’s definitely luck,” she says. “But, you know, this mutation is quite common. We estimate that maybe 1 in 10 people have it. And in people who are asymptomatic, that rises to 1 in 5.”

Seeking possible superdodgers who’ll spit into a cup

While Hollenbach and her team continue to look for more mini-dodger genes, Casanova over at Rockefeller University and his colleagues are still trying to determine if there are true superdodger genes. And he’s looking for participants right now for his study.

“You fill out a questionnaire online about your exposures to SARS-CoV-2,” he says. And then if you meet the criteria of a superdodger, the team sends you a testing kit. Basically you spit in a cup and mail it back to Casanova and his collaborators.

“We’ll extract your DNA and sequence your genome,” he explains. “We hope that in a group of 2,000 to 4,000 people, some people will have genetic mutations that tell us why they’re resistant to infection.”

And perhaps, like with HIV, that finding will one day shift the field of COVID research and lead to a vaccine that does what everyone wishes our current vaccines would do: turn everyone into a COVID superdodger.