Scientists report finding second person ‘naturally’ cured of HIV

OOn the evening of March 2020, a doctor walked out of a hospital in the Argentinian town of Esperanza, cradling a Styrofoam cooler. He handed it to a young man who had been waiting outside for hours, who tucked it safely in his car and drove 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, the Argentine president ordered a nationwide lockdown to prevent further spread of the coronavirus, SARS-CoV-2 , including strict controls entering and leaving the national capital. If the brother couldn’t do it, the contents of the cooler – over 500 million cells in his sister’s placenta – would be lost, along with any secrets they might hold.

The woman was a scientific curiosity. Although she was diagnosed with HIV in 2013, she had never shown any signs of illness. And traditional tests failed to prove that the virus was alive and reproducing in his body. Only the presence of antibodies suggested that she had already been infected. Since 2017, researchers in Argentina and Massachusetts had taken blood samples from her, meticulously scanning the DNA of more than a billion cells, looking for signs that the virus was still hiding, dormant, ready to roar at. life if the conditions were right. . They wanted to do the same with her placenta because even though it is an organ of the fetus, it is loaded with maternal immune cells – an environment rich in targets for stealth viruses to exploit.

Like scientists reported Monday in Annals of Internal Medicine, they found none. Which means the woman, whom they call “Esperanza’s patient” to protect her privacy, appears to have eradicated the deadly virus from her body without the aid of drugs or a bone marrow transplant – which would make her the second person to believe they were cured of HIV, without drugs or other treatment.

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“This gives us hope that the human immune system is strong enough to control HIV and eliminate all functional viruses,” said Xu Yu, an immunologist at the Ragon Institute of MGH, MIT and Harvard and lead author of 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, the researchers said.

Only twice in history have doctors effectively cured HIV – in the 1990s 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. These cases proved that a cure was possible, but transplants are expensive and dangerous, and donors are hard to find.

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“Curing HIV has always been considered impossible,” said Steven Deeks, a longtime HIV researcher and professor of medicine at the University of California at San Francisco who was not involved in the study. He and Yu have teamed up in the past to study HIV-positive patients whose immune systems fought more fiercely than most. In a Nature study published last year, they discovered that these individuals had intact viral genomes – meaning the virus is able to replicate – but they were embedded in places in the chromosomes of patients that were far from the sites of active transcription. . In other words, they were chased away and locked in a dusty corner of the DNA archive.

In a patient they examined, a 67-year-old Californian named Loreen Willenberg, the researchers found no intact virus in more than 1.5 billion of her cells. Willenberg had maintained control of the virus for nearly three decades without using antiretroviral drugs. If Esperanza’s patient is the second person known to have been naturally cured of HIV, Willenberg is the first.

“With these possible natural remedies providing a roadmap for a cure, I hope we can come up with an intervention that one day might work for everyone,” Deeks said.

About a decade after the start of the AIDS pandemic, doctors began to find a handful of patients who tested positive for the HIV virus but showed no symptoms, and were subsequently found to have extremely low levels of the virus in their body. their body. At the time, these case studies were supposed to be ad hoc; maybe these lucky few caught a glitch strain of HIV that wasn’t particularly good at replicating, giving their immune systems a rare advantage against a disease that was considered universally fatal until the first drugs antiretrovirals are developed.

But the more the doctors looked, the more they discovered such patients. The past decades have revealed that people with exceptionally strong immune responses constitute about 0.5% of the 38 million people infected with HIV 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 find out what makes it special, perhaps they could incorporate it into drugs, gene therapies, or other one-time treatments that could free millions. people in a lifetime of antiretrovirals. To take drugs. They might even find ways to boost the immune system of non-responders – people whose natural defenses have been so ravaged by HIV that they are now hypersensitive to a host of other health problems.

One of HIV’s dirtiest tricks is that when it enters a cell – usually a T cell or other immune cell – it makes a copy of the DNA of itself that fits into the genome of this cell. So when this cell’s protein-making machinery encounters this piece of viral code, it unintentionally builds more copies of the invading HIV. Antiretroviral drugs disrupt this process, giving patients’ immune systems time to find and kill these hijacked cell factories. But some DNA copies of the viral pattern persist – scientists call them proviruses. In theory, they could wake up and start creating a virus at any time.

Paula Cannon, a molecular microbiologist who studies HIV and gene editing at the Keck School of Medicine at the University of Southern California, likens proviruses to the lingering embers behind the fire of the first infection, smoldering for years. If the wind just picks up, the fire comes alive. This is why people have to take antiretroviral drugs for life and why they can never be cured; we have no way of attacking or annihilating these latent integrated HIV genomes. And until recently, there weren’t even any good methods to detect them. But Yu’s group has been at the forefront of developing methods that allow scientists to open billions of immune cells and sort their DNA for the smoldering remains of past infections.

“This article is a great showcase of the level of sophistication of analysis that can be performed now,” Cannon said. “Finding someone who is an elite controller who not only currently has no HIV RNA viruses in their body, but who also doesn’t seem to have the potential to do so at any time in the future, doesn’t isn’t really surprising, but it’s exciting. The more we study people like this, the more I think some clues will come out that we can apply more broadly to people with HIV.

Deeks said he was very curious to find out more about what happened in the first days and weeks after Esperanza’s patient was infected. For some reason, her body did not develop antibodies against all of the different HIV proteins one would expect. This suggests that its natural defenses quickly put the brakes on viral replication, before the virus spreads and overwhelms its immune system. Usually this only happens if someone starts antiretroviral drugs very early.

It can be a bit difficult to study what happened in someone’s body almost ten years ago. What remains is the memory of patient Esperanza’s immune response once mounted. Many players in the immune system are transient molecules, and digging up evidence for them now can be nearly impossible – like trying to find a jellyfish or flatworm fossil. But Deeks said comparing his DNA or gene expression in immune cells to that of other patients might reveal something interesting.

These are the types of analyzes that Yu’s group is currently working on, together with patient Esperanza’s doctor, Natalia Laufer, HIV researcher at El Instituto de Investigaciones Biomédicas en Retrovirus y SIDA in Buenos Aires who is studying disease controllers. ‘elite. Their hope is that by combining data from their cohorts with others from around the world, including South African children whose bodies started to control the virus after taking HIV drugs for most of their lives, patterns of protection will begin to emerge and may one day be harnessed to produce cures.

In an email, Esperanza’s 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 could help cure this virus makes me feel a great responsibility and a great commitment to make it 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 declined to be named.

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

“That individuals can be cured on their own is a shift in the HIV paradigm,” said Laufer. She added the caveat that scientists might never be able to say “cure” for sure, as it would require the impossible task of sequencing each of the patient’s cells. But, said Laufer, “We are seeing indications that it is possible for some people to fully control HIV infection. And it’s very, very different from what we thought 40 years ago.