A seventh person, dubbed "the next Berlin Patient," appears to be cured of HIV after a stem cell transplant for cancer treatment, according to a report at a press briefing ahead of the International AIDS Conference, which is now underway in Munich, Germany.
The anonymous man received a transplant to treat leukemia in October 2015. He stopped antiretroviral therapy in September 2018 and still has sustained viral remission nearly six years later, Dr. Christian Gaebler of ChariteĢ University of Medicine in Berlin told reporters.
This case is different because the man received donor cells with only one copy (known as heterozygous) of a rare mutation called CCR5-delta-32 that disables a receptor HIV uses to enter T cells. Most of the other people who were cured received stem cells with two copies (known as homozygous). Only about 1% of people of Northern European descent have two copies of the mutation, but about 16% have one copy, which expands the pool of suitable donors.
While these rare cases have become regular headline-grabbers at the International AIDS Society's annual meetings, the risky and expensive stem cell transplant procedure will never be an option for most people living with HIV. But researchers hope the knowledge gained will lead to more widely available strategies for a functional cure.
"All these cases are important scientifically — with every case, you learn more about what's possible, and therefore what could be mimicked in an intervention," IAS president and conference co-chair Dr. Sharon Lewin said at the briefing.
Berlin and beyond
The original Berlin Patient, former San Francisco resident Timothy Ray Brown, received stem cell transplants to treat leukemia in 2006. Acting on a hunch, his doctors found a donor with two copies of the CCR5-delta-32 mutation. Brown underwent intensive chemotherapy and radiation to prepare for the transplant, killing off existing malignant immune cells to make room for new ones from the donor. Afterward, he developed near-fatal graft-versus-host disease, which occurs when donor immune cells attack the recipient.
Brown stopped antiretroviral treatment, but his viral load did not rebound. Over the years, researchers tested his blood, gut, and other tissues, finding no evidence of functional HIV anywhere in his body. At the time of his death from recurrent leukemia in September 2020, he had been free of HIV for more than 13 years.
Experts initially assumed that Brown's cure was attributable to donor stem cells with a double CCR5-delta-32 mutation. More than a decade ago, Dr. Timothy Henrich, now at UCSF, reported that two HIV-positive men in Boston who received transplanted stem cells without the mutation appeared to control HIV for several months after stopping antiretrovirals, but eventually they experienced viral rebound.
Like Brown, three other people — Adam Castillejo (the London Patient), Marc Franke (the Düsseldorf Patient), and Paul Edmonds (the City of Hope Patient) — were also cured after receiving stem cell transplants to treat leukemia or lymphoma from donors with a double mutation. All of them remain off antiretroviral therapy without viral rebound, their cancer is in remission, and they will appear together at the conference.
But in 2022, researchers reported that a woman appeared to be cured after receiving a mix of umbilical cord stem cells with the CCR5-delta-32 mutation and cells without the mutation from a relative. And attendees at last summer's IAS Conference on HIV Science heard about an anonymous man in Geneva who appears to be cured after a transplant of wild-type stem cells with no copies of the mutation.
Despite having just one copy of CCR5-delta-32, the new Berlin Patient has maintained an undetectable viral load since stopping antiretrovirals more than five years ago. What's more, he has no detectable HIV DNA in peripheral blood cells, gut biopsies tested negative, he has no HIV-specific T cell responses, and his HIV antibodies are declining. Although Gaebler is hesitant to declare a cure, he said that if the man was going to experience viral rebound, it likely would have happened by now.
Clues to a cure
Researchers are still trying to figure out why these seven people were cured after stem cell transplants while other attempts have failed, as there does not seem to be a single decisive factor common to all cases. In addition to the donor's CCR5-delta-32 status, the type of conditioning therapy prior to the transplant, the severity of graft-versus-host disease, the size of the pre-existing viral reservoir, and differences in individual immune response may all play a role.
Gaebler said that the immune response of the donor stem cells likely depleted the reservoir of latent HIV in his patient, while using stem cells with a single copy of the mutation provides "an additional safety layer."
Henrich thinks the conditioning regimen and graft-versus-host reaction may be key, while using donor cells with one copy of the mutation leaves the virus with fewer targets.
"By dramatically reducing the pre-transplant HIV reservoir and maintaining this reduction over time with beneficial graft-versus-host effects, long-term remission remains a possibility for a small number of people even without CCR5-delta-32 homozygous donor cells," he told the Bay Area Reporter.
Stem cell transplantation is an arduous procedure, which limits it to people with advanced cancer, but each new case provides clues that could lead to more widely applicable interventions for long-term remission. Some researchers, for example, are exploring whether gene editing approaches such as CRISPR could be used to delete or disable CCR5 receptors to make an individual's own immune cells resistant to HIV.
"These cases are inspirational to both people living with HIV and scientists," Lewin said. "We need to give people hope but make it realistic."
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