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It sounds like a fairy tale steeped in HIV stigma: A woman wakes up one morning and, poof, the HIV she’s been living with for 8 years is gone. But for a 30-year-old Argentinian woman from the aptly named village of Esperanza, that’s close to the truth, advances experimental medicine biology according to an article published in Annals of Internal Medicine.

The woman, the so-called Esperanza Patient, appears to be the second person whose immune system cleared the virus without the use of stem cell transplantation. The first was Loreen Willenberg, a California woman who, after living with HIV for 27 years, no longer had replicating HIV in her system. That case was reported last year.

“That’s the beauty of this name, right? Esperanza,” said Xu Yu, MD, principal investigator of the Ragon Institute of Massachusetts General Hospital, the Massachusetts Institute of Technology, and Harvard University, Boston, Massachusetts, referring to the Spanish word for “hope.” “This makes us hopeful that a natural cure of HIV is actually possible.”

Two other people appear to have cleared HIV, but only after full replacement of the immune system via stem cell transplantation — the Berlin Patient, Timothy Ray Brown, and the London Patient. Another man, from Brazil, appeared to have an undetectable viral load after receiving intensified antiretroviral treatment plus supplemental vitamin B3.

The Rarest of the Rare

The Esperanza Patient is among a rare group of people living with HIV called elite controllers. These people’s immune systems can control HIV without antiretrovirals. Most elite controllers’ immune systems, however, can’t mount the immune attack necessary to eliminate all replicating HIV from their systems. Instead, their immune systems control the virus without affecting the reservoirs where HIV continues to make copies of itself and can spread.

The Esperanza Patient and Willenberg, however, appear to be the rarest of the rare. Their own immune systems seem not only to have stopped HIV replication outside of reservoirs but also to have stormed those reservoirs and killed all virus that might have continued to replicate.

The two women are connected in another way: At an HIV conference in 2019, Yu was presenting data on Willenberg’s case. At that conference, she met Natalia Laufer, MD, PhD, associate researcher at the Instituto de Investigaciones Biomédicas en Retrovirs y SIDA at the University of Buenos Aires. Laufer had been studying the Esperanza Patient at the time and asked Yu whether she and her team at the Ragon Institute could help her sequence the patient’s HIV genome to see whether, indeed, the virus had been spontaneously cleared from the patient’s system.

So that’s what the pair did, in collaboration with several other researchers into cures for HIV. The Esperanza Patient first acquired HIV in 2013, but in the 8 years that followed, results of 10 conventional viral load tests indicated the virus was undetectable (ie, below the level of quantification for standard technology). During that time, the woman’s boyfriend, from whom she had acquired HIV, died of AIDS-defining illnesses. She subsequently married and had a baby. Both her partner and baby are HIV negative. She only received HIV treatment for 6 months while she was pregnant.

A Fossil Record of HIV

Yet, there was still HIV in the woman’s system. Laufer and Yu wanted to know whether that HIV was transmissible or whether it was a relic from when HIV was still replicating and was now defective and incapable of replicating. They performed extensive genome sequencing on nearly 1.2 billion cells that Laufer had taken from the patient’s blood in 2017, 2018, 2019, and 2020, an additional 503 million cells that were from the placenta of the baby she gave birth to in 2020, and 150 million resting CD4 T cells. Proviral sequencing was undertaken of the full DNA of the HIV to detect whether the virus was still intact. The DNA was then analyzed by use of an algorithm and was tested for mutations. The investigators tested the patient’s CD4 cells to determine whether the cells still harbored any latent HIV.

In this way, they conducted a full viral workup using tests that are far more sensitive than the viral load tests the woman had undergone in the clinic. The investigators then assessed the patient’s immune system to see what the various cells of the immune system could tell them about how well her natural immune system could identify and kill HIV. They isolated the Esperanza Patient’s immune cells and subjected those cells to HIV in the lab to see whether the cells could detect and eliminate the virus.

And just to be safe, they checked to make sure there were no antiretroviral drugs in the patient’s system.

What they found was that without treatment, her CD4 count hovered around 1000 cells — a sign of a functioning immune system. DNA sequences revealed large chunks of missing DNA, and one sequence had an immune-induced hypermutation. In total, seven proviruses were found, but none were capable of replicating. The CD4 cells they evaluated showed no evidence of latent HIV.

In other words, they had uncovered a fossil record.

“These HIV-1 DNA products clearly indicate that this person was infected with HIV-1 in the past and that active cycles of viral replication had occurred at one point,” Yu and colleagues write in their recent article.

What may be more useful to researchers looking to turn this spontaneous cure into treatment for millions of people living with active HIV was the evidence that the woman’s immune system had trained itself to attack HIV through a number of genetic mutations. What they found, the researchers write, was evidence of “an incomplete seroconversion” — that is, when the patient was acquiring HIV, the infection was stopped in its tracks.

Yet, Yu and colleagues say that they can’t prove that the woman is fully cured of HIV.

“Although this might sound unsatisfying, it reflects an intrinsic limitation of scientific research,” they write. “Scientific concepts can never be proved through empirical data collection; they can only be disproved.”

There Are More Out There

Are these women the only ones to have spontaneously cleared HIV? That’s the question, said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases at the National Institutes of Health. Just like they can’t disprove that the women cured themselves, they can’t prove that she and Willenberg are the only two people to have experienced this cure.

“We’re all struggling with this,” Dieffenbach told Medscape Medical News. “The goal is to get enough of these people so maybe there’s a road map to how to induce, trigger, change immunity. But this could well be a unique event at the time of initiation of infection. We just don’t know.”

What is needed, Yu said, is for clinicians to reach out to them regarding cases that could mimic the cases of Willenberg and the Esperanza Patient. Elaborate testing couild then be conducted to see whether these cases are similar to those of Willenberg and the Esperanza Patient.

“We do think there are more out there,” Yu told Medscape Medical News.

Asked whether we’re still far away from applying these one-off cures to the millions of people taking HIV treatment daily, Yu responded, “We might be close. That’s the beauty of scientific discovery. We don’t know, but that’s why we need more engagement of the community and care providers to help us.”

The research was funded by the Bill and Melinda Gates Foundation and the National Institutes of Health. Yu and Dieffenbach have reported no relevant financial relationships.

Ann Intern Med. Published online November 16, 2021. Abstract

Heather Boerner is a science journalist based in Pittsburgh, Pennsylvania. Her book, Positively Negative: Love, Pregnancy, and Science’s Surprising Victory Over HIV, was published in 2014.

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