New research based on adults who were cured of HIV after stem cell transplants may offer hope to ultimately have a global impact on HIV care.

A total of 10 individuals with HIV have been cured to date. Most of these patients have remained anonymous, but three have agreed to collaborate with a team at Oregon Health and Science University (OHSU), Portland, Oregon, on finding a cure for HIV, according to the school.

The National Institutes of Health recently awarded an $8.4 million grant to researchers at OHSU to pursue a unique collaboration with the three individuals who were cured of HIV, according to a press release from the university.

The three, Adam Castillejo, Paul Edmonds, and Marc Franke, will work with the OHSU research team and provide biological samples. The research team will analyze the samples to explore the immune responses that contributed to their being cured of HIV.

Why Study Stem Cells

All three participants in the OHSU project (as well as other patients cured of HIV) underwent stem cell transplants as part of cancer therapy, said Jonah Sacha, PhD, the co-principal investigator of the project.

“Stem cell transplantation has produced the only documented cases of HIV linked to a medical procedure,” Sacha said in an interview. The immune consequences of stem cell transplant have been studied since the first procedures were performed in the 1950s, he noted. Consequently, there is a vast storehouse of knowledge about the potential mechanisms of stem cells that could drive an HIV cure, but only isolated cases of cured HIV existed, he added.

For the first time, multiple individuals cured of HIV have released their identities and are willing to collaborate with scientists to understand how they were cured, said Sacha. “This is an unprecedented and exciting time in HIV cure as we can reverse engineer a stem cell transplant-mediated cure for HIV,” he explained.

Sacha’s research will be informed by his previous work in primates, published in 2023 in the journal Immunity. “The most surprising finding for us was that we achieved cure in two macaques despite using stem cell donors that express CCR5, the HIV entry receptor,” Sacha told Medscape Medical News. The CCR5 (C-C chemokine receptor 5) gene is a co-receptor for HIV that allows the virus to enter and infect cells, but individuals with a CCR5 mutation are resistant to HIV infection.

“At that point, all of the reported cases of HIV cure via stem cell transplant were achieved using donors that do not express CCR5,” Sacha said. Based on the findings in macaques, Sacha hypothesized that it would be possible to achieve an HIV cure using a stem cell donor that expresses CCR5.

When the cases of successful cures in human patients with HIV were announced that involved donors expressing CCR5, Sacha and colleagues were excited that their macaque data were correct.

“Cumulatively, these cases have changed our thinking about the role of CCR5 in cure mediated by stem cell transplant,” Sacha said. “Instead of requiring a complete absence of CCR5, these cases suggest it is likely more about the expression level of CCR5. This points to an unanswered question and one that will require more research into the role and expression level of CCR5 in the setting of HIV cure,” he said.

Overcoming HIV’s Inherent Hurdles

A number of barriers must be overcome to achieve an HIV cure, Sacha said. “First and foremost is that once integrated into the host DNA, HIV is nearly impossible to remove; consequently, this is what makes the documented cases of HIV cure following stem cell transplant so incredible,” he said.

“We have almost no treatments that can remove HIV from the genome, and where those treatments do exist, safely and effectively delivering them to the correct cells in the body is effectively impossible with today’s technology,” he noted. “My hope is that new gene therapy delivery modalities are developed to address this gap in our treatment technology; such a development would not only advance HIV cure but also a plethora of other inherited and acquired diseases for which there are no curative treatments,” he added.

Intriguing Promise of Cure

The OHSU research will be of great interest because of the opportunity to explore the mechanism behind cures of patients with HIV after stem cell transplants, said David J. Cennimo, MD, associate professor of medicine and pediatrics and an infectious disease specialist at Rutgers New Jersey Medical School, Newark, New Jersey, in an interview.

The initial cures of patients with HIV occurred in patients who received double CCR5-deleted stem cells (stem cells modified to lack the CCR5 gene and resist HIV), said Cennimo. The simple answer to how the cure occurred was that these patients’ infected immune systems were wiped out by the conditioning chemotherapy, and then the new donor immune system could not be infected by HIV virus because of the CCR5 mutations, he said.

“Later, cures happened without having double deletions, so this might not be the only mechanism,” Cennimo noted.

“One of the biggest obstacles to an HIV cure is the latent viral reservoir that infects cells,” Cennimo told Medscape Medical News. “This is a pool of virus that could retrigger replication and ongoing infection,” he said. HIV affects not only T cells, so the pool is potentially quite large, he added. Whether the stem cell transplant alters this pool remains unclear, and it is something very important to study, said Cennimo. However, stem cell transplant is too risky, too costly, and too intense to be a viable HIV cure strategy outside of also curing a malignancy at the same time, he said.

“I hope the researchers deduce what is actually happening at the interaction of the immune system and virus, and if so, whether these mechanisms could be triggered in other less intensive ways to result in cure,” Cennimo said.

This research is funded by the National Institutes of Health. Sacha disclosed no financial conflicts of interest. Cennimo disclosed no financial conflicts of interest.