First person may be cured of HIV after stem cell transplant without CCR5 mutation

A man dubbed the 'Geneva patient' appears to be the latest person cured of HIV after a stem cell transplant for cancer treatment. Unlike the other five known cases, however, he received stem cells from a donor who does not have a rare mutation that prevents HIV from entering cells. The man continues to have undetectable HIV 20 months after stopping antiretroviral therapy (ART).

"What has happened to me is wonderful and magical," the Geneva patient said in a press statement. "We can now focus on the future."

Dr Asier Sáez‐Cirión of Institut Pasteur in Paris and Dr Alexandra Calmy of Geneva University Hospitals in Switzerland outlined the findings at a media briefing ahead of the 12th International AIDS Society Conference on HIV Science (IAS 2023) in Brisbane, Australia. Full results will be presented on 24 July.

“All the markers of HIV infection very quickly decreased until they became undetectable by classic analysis within a few months,” Sáez‐Cirión said. “To date, 20 months after the treatment interruption, this person has not experienced viral rebound.”

This case suggests that using stem cells with the CCR5-delta-32 mutation may not be necessary to achieve long-term HIV remission. If so, this would make it easier to find suitable donors for HIV-positive cancer patients who need a transplant. But experts caution that continued monitoring and further testing are needed, as transplants using so-called wild-type stem cells have failed to eliminate HIV in the past. While antiretrovirals can keep HIV replication in check indefinitely, the virus inserts its genetic blueprints (known as provirus) into host cells and sets up a latent viral reservoir that is extremely difficult to eradicate.

“The likelihood of rebound is impossible to say, but all of the reservoir measurements to date could not find any intact virus,” said IAS president and conference co-chair Professor Sharon Lewin of the University of Melbourne. “This is great news, but case reports are case reports.”

The Geneva patient

The new case involves a Caucasian man in his early fifties who was diagnosed with HIV in 1990 and had been on continuous suppressive ART since 2005. Despite being on effective treatment, he had residual detectable plasma HIV RNA and HIV DNA in CD4 T-cells (reflecting the viral reservoir), according to ultrasensitive tests before the transplant.

The man developed a rare and aggressive type of sarcoma and underwent chemotherapy and whole-body radiotherapy before receiving an allogeneic stem cell transplant in July 2018. The unrelated donor did not have the CCR5-delta-32 mutation, which knocks out a receptor that most strains of HIV use to enter cells. No compatible donors with the mutation were available, Sáez‐Cirión said.

The man achieved full chimerism, indicating that all his immune cells originated from the donor. He experienced acute and chronic graft-versus-host disease and was treated with various immunosuppressive medications, including the JAK/STAT inhibitor ruxolitinib. Three years post-transplant, he undertook a closely monitored treatment interruption in November 2021. After this, he used on-demand pre-exposure prophylaxis (PrEP) twice.

Now, 20 months later, the man still has undetectable viral load using standard tests, and ultrasensitive tests have become negative too. HIV DNA in his T-cells and bone marrow decreased dramatically after the transplant, and the researchers could find only defective, not intact, virus. In laboratory studies, they could not induce virus production from the man’s CD4 cells, and HIV DNA was undetectable in gut biopsies. No HIV-specific T-cell responses were detected, and his antibodies progressively declined, suggesting there may be no remaining virus left to trigger the immune system.

“All the immunological markers we have analysed have been unable to detect HIV products, whether it’s the presence of provirus or low-level viral replication or viral RNA,” Sáez‐Cirión reported. “Some traces of HIV were found after the transplant, but when it was possible to go a bit deeper in the analysis, all these traces of [HIV] DNA were related to replication-incompetent viruses.”

Still, the study team acknowledges, they “cannot exclude the possibility that the virus is still present in anatomical or cellular sanctuaries.”

“There may be viral rebound in the future, although we hope that this situation of viral remission remains permanent,” Sáez‐Cirión said.

Five other stem cell cures

Only a small number of people have been cured of HIV after stem cell transplants. The first, Timothy Ray Brown, known as the Berlin patient, received two transplants to treat leukaemia in 2006. His oncologist, Dr Gero Hütter, came up with the idea of using stem cells with the CCR5-delta-32 mutation, speculating that it might cure both cancer and HIV.

As reported at the 2008 Conference on Retroviruses and Opportunistic Infections (CROI), Brown first underwent intensive chemotherapy and whole-body radiation, and he developed near-fatal graft-versus-host disease, which occurs when donor immune cells attack the recipient’s body. He stopped ART at the time of his first transplant, but his viral load did not rebound. Researchers extensively tested his blood, gut and other tissues, finding no traces of replication-competent HIV. At the time of his death in September 2020, he had been free of HIV for more than 13 years.

A third man, Adam Castillejo, dubbed the 'London patient', was cured after a stem cell transplant to treat Hodgkin lymphoma from a donor with a double CCR5-delta-32 mutation. He received less aggressive conditioning chemotherapy than Brown and developed milder graft-versus-host disease. As first described at CROI 2019, he stopped ART in September 2017, a year and a half after his transplant, and he remains free of HIV.

At CROI 2022, New York City researchers described a middle-aged woman with leukaemia who received a transplant using a combination of umbilical cord blood cells with the CCR5-delta-32 mutation and partially matched adult stem cells from a relative. She stopped ART three years after the transplant and remains free of HIV as of the last report.

Later that year at the 2022 International AIDS Conference, researchers announced that Paul Edmonds, the 'City of Hope patient', a southern California man who received an HIV-resistant stem cell transplant in early 2019 and stopped ART two years later, remains in long-term remission. Because he is older, he received a less harsh conditioning chemotherapy regimen and developed only mild graft-versus-host disease.

Finally, Marc Franke, known as the 'Düsseldorf patient', received a stem cell transplant from a donor with a double CCR5-delta-32 mutation more than a decade ago and stopped ART nearly five years ago. He is still free of HIV, and his doctors finally declared that he’s cured ahead of this year’s CROI.

What is the key to a cure?

Researchers are still working to learn why these patients were cured after stem cell transplants while other attempts have failed. Until now, many experts assumed that using stem cells from a donor with a double CCR5-delta-32 mutation was crucial. The new case reopens questions about the contributions of conditioning therapy, the graft-versus-host reaction and immunosuppressive medications used to manage it.

In particular, the Geneva patient received ruxolitinib for many years to manage ongoing graft-versus-host disease, and the researchers “believe it may have had an impact of reducing the reservoir and the absence of viral rebound,” Calmy said.

A decade ago at the 2013 IAS Conference, Dr Timothy Henrich, now at the University of California San Francisco, and colleagues described two HIV-positive men in Boston who received transplants to treat lymphoma using stem cells from donors without the CCR5-delta-32 mutation.

These cases generated considerable excitement, as the patients appeared to be controlling HIV after stopping antiretrovirals. The researchers suggested that graft-versus-host disease might be enough to eliminate the virus even after a wild-type stem cell transplant. But hopes were soon dashed when the men experienced viral rebound three months and eight months after ART discontinuation.

The Geneva patient “has already achieved far longer durable HIV remission without treatment than the Boston patients, lasting 20 months so far,” Lewin said. “So this is promising, but we learned from the Boston patients that even a single virion can lead to HIV rebound. This individual will need to be watched closely over the next months to years.”

While each new cure provides more clues, stem cell transplants are far too risky for people who do not need them to treat life-threatening cancer, and the intensive and costly procedure is far from feasible for the vast majority of people living with HIV worldwide.

Nonetheless, these cases could help scientists develop strategies that lead to a more widely applicable functional cure, or long-term remission without antiretrovirals. Some researchers, for example, are studying whether gene editing techniques such as CRISPR can be used to delete or disable CCR5 receptors to make an individual’s own immune cells resistant to HIV.

“I agree that case reports are case reports, and for each case, there are so many variables that in the absence of a controlled trial, it’s impossible to know for sure which is the critical factor,” Sáez‐Cirión said. “But I think that these kind of reports have a lot of value. The CCR5-delta-32 mutation was identified first in two case reports of people who were exposed and not infected with HIV. From that, there were drugs developed and new interventions, gene therapy strategies. Once we understand the mechanism, even if it’s from a case report, it can give us a lot of valuable information.”