The Esperanza Patient: More Hope for a Sterilizing HIV-1 Cure: A Possible Sterilizing Cure of HIV-1 Infection Without Stem Cell Transplantation
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Scientists report finding a second person to be 'naturally' cured of HIV, raising hopes for future treatments
Nov. 15, 2021
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."
Editorials16 November 2021
The Esperanza Patient: More Hope for a Sterilizing HIV-1 Cure
Fewer than 1% of people living with HIV are able to control viral replication to below the limits of detection by commercial assays without antiretroviral therapy (ART). These patients are called "elite controllers" or "elite suppressors," and they represent a model of a cure for HIV-1 (1). However, it has not always been clear whether they are models of a functional cure, where replication-competent virus remains but is controlled by host factors (analogous to the control of herpes viruses), or a sterilizing cure, where the virus is eradicated by the host (analogous to the control of most viruses).
In order to distinguish between these models, one has to be able to determine whether or not replication-competent virus is present in elite controllers. It is important to specifically detect replication-competent virus because most HIV-1 DNA contains large deletions and/or mutations that render the virus replication-incompetent. The most rigorous way to do this is to culture virus from the latent reservoir, which consists primarily of rare, quiescent infected CD4+ T cells that have the genome of replication-competent virus integrated into the host genome. When these cells become activated, productive viral replication is reinitiated. Studies of the latent reservoir in elite controllers have provided significant evidence that some of them harbor replication-competent virus. Indeed, the viral isolates cultured from some elite controllers can replicate robustly in vitro and cause AIDS in humanized mice (2). However, these culture assays and studies that have used elegant molecular tools to approximate the frequency of cells harboring replication-competent virus have shown that the latent reservoir is markedly smaller in elite controllers compared with patients with progressive disease who are receiving ART (3–6), and it has recently become clear that it can be challenging to detect any form of virus in some elite controllers (4, 5, 7, 8).
In their article, Turk and colleagues describe a young woman from Esperanza, Argentina, who tested positive for HIV in 2013 and has maintained undetectable viral loads since then (9). She received ART for just 6 months in 2019 and 2020 during the second and third trimesters of a pregnancy and has continued to maintain undetectable viral loads since the drugs were discontinued. In a heroic effort, the authors analyzed more than a billion of the patient's CD4+ T cells and found no evidence of replication-competent virus.
Why is this exciting? It suggests that some elite controllers may have gone beyond simply controlling the virus and instead have managed to eradicate it. Viral eradication has previously been believed to have occurred only in the Berlin patient and the London patient, 2 individuals who underwent stem cell transplants with cells from donors who had a mutation of the CCR5 gene that prevents the surface expression of this HIV coreceptor (10). The authors are careful to point out that the absence of evidence of replication-competent virus is not evidence of absence of this virus. Also, it should be noted that the most rigorous way of proving a cure for HIV in patients receiving ART is to perform an analytical treatment interruption, where ART is discontinued and one determines whether the patient develops viremia. Unfortunately, treatment interruptions do not distinguish between functional and sterilizing cures and cannot be used in elite controllers because they have already controlled viral replication without ART for many years. So, there is no definitive way to prove a sterilizing cure in an elite controller. However, by screening so many cells, the authors show that the largest possible size of the latent reservoir in this patient is less than 1 infected cell per billion cells. Similar estimates were recently seen for another elite controller (5) and a patient who has maintained virologic control for 12 years after discontinuing ART (8). At such low frequencies, the likelihood that an infected cell would become activated and lead to a recrudescence of viremia is extremely low, so the line between a functional cure and a sterilizing cure becomes blurred. However, it should be noted that although a sterilizing cure is much harder to accomplish than a functional cure, there are at least 2 advantages associated with this form of cure. The complete eradication of virus means there is no possibility of the loss of control of viral replication leading to rebound viremia, as has been reported in some elite controllers (1). Some elite controllers also have higher levels of immune activation and inflammation than patients with progressive disease who are receiving ART (1). This is likely the result of the immune response to residual virus; thus, viral eradication should solve this problem.
If the Esperanza patient has indeed achieved a sterilizing cure, defining the mechanisms responsible for it becomes important. Elite controllers have potent CD8+ T-cell responses that can kill productively infected CD4+ T cells (1), but it seems unlikely that quiescent latently infected cells would be recognized and killed since they probably do not make viral proteins. If this is the mechanism, then how does this patient differ from many other elite controllers who control viral replication but are unable to achieve complete eradication? The authors show that her CD4+ T cells could easily be infected with laboratory strains in vitro, so a unique restriction factor in this patient seems unlikely. The patient's partner eventually died of AIDS. Could it be that due to prior exposure to the virus, the patient had developed an HIV-specific immune response before becoming infected and thus was able to kill the majority of infected cells during primary infection before the reservoir was effectively seeded? It would be interesting to use her cells to develop avatars of her immune system in humanized mice to determine what happens after infection with primary HIV-1 isolates. In the meantime, it is perhaps not a coincidence that she hails from Esperanza, which translates to "hope" in English. If a spontaneous sterilizing cure of HIV is in fact possible, we may eventually be able to do more than just hope that we can replicate this phenotype on a large scale.
A Possible Sterilizing Cure of HIV-1 Infection Without Stem Cell Transplantation
Annals of Internal Medicine
A sterilizing cure of HIV-1 infection has been reported in 2 persons living with HIV-1 who underwent allogeneic hematopoietic stem cell transplantations from donors who were homozygous for the CCR5Δ32 gene polymorphism. However, this has been considered elusive during natural infection.
To evaluate persistent HIV-1 reservoir cells in an elite controller with undetectable HIV-1 viremia for more than 8 years in the absence of antiretroviral therapy.
Detailed investigation of virologic and immunologic characteristics.
Tertiary care centers in Buenos Aires, Argentina, and Boston, Massachusetts.
A patient with HIV-1 infection and durable drug-free suppression of HIV-1 replication.
Analysis of genome-intact and replication-competent HIV-1 using near-full-length individual proviral sequencing and viral outgrowth assays, respectively; analysis of HIV-1 plasma RNA by ultrasensitive HIV-1 viral load testing.
No genome-intact HIV-1 proviruses were detected in analysis of a total of 1.188 billion peripheral blood mononuclear cells and 503 million mononuclear cells from placental tissues. Seven defective proviruses, some of them derived from clonally expanded cells, were detected. A viral outgrowth assay failed to retrieve replication-competent HIV-1 from 150 million resting CD4+ T cells. No HIV-1 RNA was detected in 4.5 mL of plasma.
Absence of evidence for intact HIV-1 proviruses in large numbers of cells is not evidence of absence of intact HIV-1 proviruses. A sterilizing cure of HIV-1 can never be empirically proved.
Genome-intact and replication-competent HIV-1 were not detected in an elite controller despite analysis of massive numbers of cells from blood and tissues, suggesting that this patient may have naturally achieved a sterilizing cure of HIV-1 infection. These observations raise the possibility that a sterilizing cure may be an extremely rare but possible outcome of HIV-1 infection.
Primary Funding Source:
National Institutes of Health and Bill & Melinda Gates Foundation.