A man dubbed the Geneva Patient may be the sixth person to be functionally cured of HIV after a stem cell transplant for cancer treatment, researchers reported ahead of the International AIDS Society Conference on HIV Science, taking place starting this weekend in Brisbane, Australia. But unlike the other five cases of people being cured of the disease, he received stem cells from a donor who does not have a rare mutation that protects against HIV.
"What has happened to me is wonderful and magical," the unidentified man said in a statement. "We can now focus on the future."
The man, who was diagnosed with HIV in 1990, received chemotherapy and radiation followed by a stem cell transplant to treat an aggressive type of sarcoma in July 2018. The procedure used so-called wild-type stem cells that lack the CCR5-delta-32 mutation, which knocks out receptors HIV uses to enter cells. After the transplant, he developed graft-versus-host disease — which occurs when donor immune cells attack the recipient's body — and was treated with immunosuppressive medications.
The man maintained an undetectable viral load, and three years after the transplant, he and his doctors decided to try an antiretroviral treatment interruption in November 2021. Now, 20 months later, he shows no evidence of HIV rebound, Asier Sáez‐Cirión, Ph.D., of Institut Pasteur in Paris, reported at a preconference media briefing on July 19.
The man has no detectable HIV RNA in his blood according to the most sensitive tests, and the researchers have only been able to find traces of defective, not intact, virus in his T-cells and bone marrow. What's more, he does not show HIV-specific T-cell immune responses and his HIV antibodies have declined, suggesting there may be no remaining virus.
"All the immunological markers we have analyzed have been unable to detect HIV products," Sáez‐Cirión said. "We cannot exclude that there is still some virus present ... so there may be viral rebound in the future, although we hope this situation of viral remission remains permanent."
Experts caution that continued monitoring and further testing are needed, as transplants using non-mutated stem cells have failed to cure HIV in the past. The virus inserts its genetic blueprints into host cells and establishes a long-lasting viral reservoir that has proved nearly impossible to eliminate.
"This is great news, but case reports are case reports," IAS president Dr. Sharon Lewin of the University of Melbourne said at another media briefing. "This individual will need to be watched closely over the next months to years."
Previous cures and failures
Former San Francisco resident Timothy Ray Brown, known as the Berlin Patient, was the first person to be cured of HIV. His physician in Germany, Dr. Gero Hütter, came up with the idea to use cells from a donor with the CCR5-delta-32 mutation, hoping that it might cure both his leukemia and HIV. The second transplant was successful, but Brown nearly died from graft-versus-host disease.
Brown, a gay man, stopped antiretroviral treatment at the time of his first transplant, but his viral load did not rebound. Over the years, researchers extensively tested his blood and tissue samples, finding no evidence of functional HIV anywhere in his body. At the time of his death from leukemia in September 2020, he had been free of HIV for more than 13 years.
Marc Franke, dubbed the Dusseldorf Patient, received a double CCR5-delta-32 stem cell transplant more than a decade ago and stopped antiretroviral treatment nearly five years ago. In April, his doctors finally declared that he's cured. A man in London, a woman treated in New York City, and a Southern California man also received transplants using stem cells with the same mutation and have had undetectable HIV for two to six years after stopping antiretrovirals.
Many experts assumed the CCR5-delta-32 mutation was the key to success, but the latest case calls this into question. Pre-transplant chemotherapy and radiation, the graft-versus-host reaction, and post-transplant immunosuppressive drugs may have also played a role.
Previous attempts to cure HIV with stem cells lacking the mutation have not led to long-term viral remission. A decade ago, Dr. Timothy Henrich, now at UCSF, reported that two HIV-positive men in Boston appeared to be in remission after transplants using wild-type stem cells. But hopes were dashed when they experienced viral rebound three and eight months after stopping antiretrovirals.
The Geneva patient "has already achieved far longer durable HIV remission without treatment than the Boston patients, lasting 20 months so far," said Lewin. But those cases showed that even a single remaining viral particle could trigger a rebound, so "this individual will need to be watched closely over the next months to years."
According to Henrich, the new case raises several interesting possibilities. The man's chronic graft-versus-host disease and long-term use of the immunosuppressive drug ruxolitinib might be helping to keep HIV in check. The fact that he used on-demand PrEP on two occasions after stopping antiretroviral treatment might also be important.
"It is possible that in the setting of a very low reservoir with a very rare chance of viral reactivation events, intermittent [antiretroviral] exposure may have partially suppressed whatever low-level residual viral activity was smoldering in tissues, leading to longer-term remission," Henrich told the Bay Area Reporter. "Whatever the contribution of each of these factors, there is a suggestion that long-term remission following allogeneic stem cell transplant with CCR5 wild-type donor cells may be possible, but is likely to be rare."
Using stem cells without a double CCR5-delta32 mutation — which only occurs in about 1% of Caucasians — could offer more HIV-positive cancer patients the chance to be cured of HIV as well. But the costly procedure is too risky for people who don't have a life-threatening malignancy, and it is far from feasible for the vast majority of people living with HIV worldwide.
Nonetheless, each new case provides clues that could lead to a more widely applicable functional cure for HIV. Scientists are now exploring various strategies, including CRISPR gene editing, that could be used to delete or disable CCR5 receptors and make an individual's own immune cells resistant to HIV.
"I agree that case reports are case reports ... but I think that these kind of reports have a lot of value," Sáez‐Cirión said. "Once we understand the mechanism, even if it's from a case report, it can give us a lot of valuable information."
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