Scientists report finding a second person to be 'naturally' cured of HIV, raising hopes for future treatments - STAT

One evening in March 2020, a doctor walked out of a hospital in the Argentine city of Esperanza cradling a styrofoam cooler. He handed it to a young man who'd been waiting outside for hours, who nestled it securely in his car and sped off. His destination, a biomedical research institute in Buenos Aires, was 300 miles away, and he only had until midnight to reach it. That day, while his sister was inside the hospital giving birth to her first child, Argentina's president had ordered a national lockdown to prevent further spread of the coronavirus, SARS-CoV-2, including strict controls on entering and leaving the nation's capital. If the brother didn't make it, the contents of the cooler — more than 500 million cells from his sister's placenta — would be lost, along with any secrets they might be holding.

The woman was a scientific curiosity. Despite being diagnosed with HIV in 2013, she'd never shown any signs of illness. And traditional tests failed to turn up evidence that the virus was alive and replicating in her body. Only the presence of antibodies suggested she'd ever been infected. Since 2017 researchers in Argentina and in Massachusetts had been collecting blood samples from her, meticulously scanning the DNA of more than a billion cells, searching for signs that the virus was still hiding out, dormant, ready to roar to life if the conditions were right. They wanted to do the same with her placenta because even though it's an organ of the fetus, it's loaded with maternal immune cells — a target-rich environment to mine for stealth viruses.

As the scientists reported Monday in Annals of Internal Medicine, they didn't find any. Which means that the woman, who they are calling the "Esperanza Patient" to protect her privacy, appears to have eradicated the deadly virus from her body without the help of drugs or a bone marrow transplant — which would make her only the second person believed to have cured herself of HIV, without drugs or any other treatment.

"This gives us hope that the human immune system is powerful enough to control HIV and eliminate all the functional virus," said Xu Yu, an immunologist at the Ragon Institute of MGH, MIT, and Harvard and senior author on the new report. "Time will tell, but we believe she has reached a sterilizing cure." The discovery, which was previously announced at the Conference on Retroviruses and Opportunistic Infections in March, could help identify possible treatments, researchers said.

Only two times in history have doctors effectively cured HIV — in 2009 with the Berlin Patient and in 2019 with the London Patient — both times by putting the virus into sustained remission with a bone marrow transplant from a donor with a rare genetic mutation that makes cells resistant to HIV invasion. Those cases proved a cure was feasible, but transplants are expensive and dangerous, and donors difficult to find.

"Curing HIV was always assumed to be impossible," said Steven Deeks, a longtime HIV researcher and professor of medicine at the University of California, San Francisco who was not involved in the study. He and Yu have teamed up in the past to study HIV patients whose immune systems put up a fiercer fight than most. In a Nature study published last year, they found that such individuals had intact viral genomes — meaning the virus is capable of replicating — but they were integrated at places in the patients' chromosomes that were far from sites of active transcription. In other words, they were squirreled away and locked up inside a dusty corner of the DNA archives.

In one patient they examined, a 67-year old California woman named Loreen Willenberg, the researchers didn't find any intact virus in more than 1.5 billion of her cells. Willenberg had maintained control of the virus for nearly three decades without the use of antiretroviral drugs. If the Esperanza Patient is the second person known to have been naturally cured of HIV, Willenberg is the first.

"With these possible natural cures providing a roadmap for a cure, I am hoping we can come up with an intervention that one day might work for everyone," said Deeks.

About a decade into the AIDS pandemic, doctors began to find a handful of patients who tested positive for the HIV virus but experienced no symptoms, and were later found to have vanishingly low levels of the virus in their bodies. At the time, these case studies were presumed to be one-offs; maybe these fortunate few caught a glitchy strain of HIV that wasn't particularly good at replicating, giving their immune systems a rare edge against a disease that was considered universally deadly until the first antiretroviral drugs were developed.

But the more doctors looked, the more such patients they discovered. The past few decades have revealed that people with unusually potent immune responses make up about 0.5% of the 38 million HIV-infected people on the planet. Scientists call these people "elite controllers," and in recent years they have become the subject of intense international study.

Because their bodies represent a model of a cure for HIV, if researchers can figure out what makes them special, they might be able to bottle it up into medicines, gene therapies or other one-time treatments that could free millions from a lifetime of antiretroviral drug-taking. They might even find ways to boost the immune systems of non-responders — people whose natural defenses were so ravaged by HIV that they're now hyper-susceptible to a host of other health woes.

One of HIV's dirtiest tricks is that when it enters a cell — usually a T cell or other immune cell — it makes a DNA copy of itself that integrates into that cell's genome. So when that cell's protein-making machinery comes across that bit of viral code, it unwittingly builds more copies of the HIV invader. Antiretroviral drugs disrupt this process, buying patients' immune systems time to find and kill these hijacked cellular factories. But some DNA copies of the viral blueprint persist — scientists call them proviruses. In theory, they could wake up and start making a virus at any time.

Paula Cannon, a molecular microbiologist who studies HIV and gene editing at the University of Southern California's Keck School of Medicine, compares proviruses to embers lingering behind the fire of first infection, smoldering for years. If the wind kicks up just right, the fire rages to life. That's why people need to take antiretroviral drugs for life and why they can never be cured; we have no way of attacking or wiping out these latent integrated HIV genomes. And until recently, there weren't even good methods for detecting them. But Yu's group has been at the forefront of developing methods that allow scientists to crack open billions of immune cells and sort through their DNA looking for the smoking remains of infections past.

"This paper is a nice showcase of the level of sophistication of the analyses that can be done now," said Cannon. "Finding somebody who is an elite controller who not only is currently not exhibiting any HIV RNA viruses in her body, but also doesn't look like she has the potential to do that any time in the future, isn't exactly surprising, but it is exciting. The more we study people like this, the more I think some clues are going to come out that we'll be able to apply to HIV-infected individuals more broadly."

Deeks said he's most curious to learn more about what happened during the first few days and weeks after the Esperanza Patient was infected. For some reason, her body didn't develop antibodies to all the various HIV proteins one might expect. That suggests her natural defenses slammed the brakes on viral replication early, before the virus could spread and overwhelm her immune system. Usually, that only happens if someone starts antiretroviral drugs very early.

It can be a little tricky to study what happened in someone's body nearly a decade ago. What's left is the memory of the immune response the Esperanza Patient once mounted. Many of the immune system's players are transient molecules, and unearthing evidence of them now may prove nearly impossible — like trying to find a fossil of a jellyfish or a flatworm. But Deeks said comparing her DNA or immune cell gene expression to other patients' might reveal something interesting.

Those are the types of analyses Yu's group is now working on, together with the Esperanza Patient's physician, Natalia Laufer, an HIV researcher at El Instituto de Investigaciones Biomédicas en Retrovirus y SIDA in Buenos Aires who studies elite controllers. Their hope is that by combining data from their cohorts with others from around the world — including children in South Africa whose bodies have begun to control the virus after being on HIV drugs for most of their lives — that patterns of protection will begin to emerge that might one day be harnessed to produce cures.

In an email, the Esperanza Patient told STAT that she doesn't feel special, but rather, blessed for the way the virus behaves in her body. "Just thinking that my condition might help achieve a cure for this virus makes me feel a great responsibility and commitment to make this a reality," she wrote. Her first child is healthy and HIV-free, and she and her partner are now expecting a second, said the woman, who did not want to be named.

"It is such a beautiful coincidence that Esperanza is where she lives," said Laufer. "Esperanza" translates, literally, to "hope." That's what Laufer said she felt when she met her patient in 2017.

"That individuals can be cured by themselves is a change in the paradigm of HIV," Laufer said. She added the caveat that  scientists may never be able to say "cure" for sure, because that would require the impossible task of sequencing every one of the patient's cells. But, Laufer said, "we are seeing indications that it's possible for some individuals to completely control infection with HIV. And that's very, very different from what we thought 40 years ago."

This story has been updated with the correct year doctors reported on the successful treatment of the Berlin Patient, Timothy Ray Brown.

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