What the next Berlin patient means for HIV cure

A rare mutation also aided in the functional HIV cure for the first Berlin patient, Timothy Ray Brown, who was diagnosed with HIV in 1995 while living in Berlin. Brown received two stem cell transplants harvested from a donor with a rare homozygous C-C chemokine receptor 5 (CCR5)-delta 32 mutation. Although the transplants were meant to treat only Brown’s leukemia—and they did—they also eradicated HIV infection, and he remained in HIV remission until his death in 2020.

Since then, six other people achieved HIV remission, all after stem cell transplantation, including a person dubbed “the Geneva patient,” with results presented at the 12th International AIDS Society Conference on HIV Science in Brisbane, Australia, last year.

In an oral abstract presentation Christian Gaebler, MD, of Charité University of Medicine in Berlin explained the apparent success of an anonymous man called the next Berlin patient, a 60-year-old German man who tested positive for HIV in 2009 and was diagnosed with acute myeloid leukemia (AML) in 2015. The man stopped antiretroviral therapy in 2018, approximately three years after receiving a stem cell transplant as treatment for AML. The clinical team at the Charité-Universitätsmedizin hospital in Berlin reported that this patient remains virally suppressed almost six years later.

After nearly six years, the second Berlin patient’s plasma viral load remains suppressed, and he has no detectable HIV DNA in peripheral blood cells, Gaebler said. In addition, researchers could not induce virus production from his CD4 cells in the lab. No HIV-specific T cell responses were detected, and his HIV antibodies have been decreasing, which Gaebler said suggests there is no remaining virus to trigger an immune response.

“We see waning HIV-specific antibody and T cell responses and we really think that effective reservoir reductions, durable HIV remission and potential cure can be achieved with functional viral co-receptors,” he said. “And we believe that allergenic immunity really fundamentally contributes to HIV eradication.”

The speed at which the new immune system replaced the old one might play a part in the quick depletion of the HIV reservoirs, Gaebler said, in a press conference just prior to AIDS 2024. “In the second Berlin patient, that was done… in less than 30 days. But the donor’s immune system might also have special characteristics, such as highly active natural killer cells, which ensure that even minor HIV activity is detected and eliminated.”

Gaebler defined an HIV cure as enabling a person living with HIV to safely stop therapy and live a long and healthy life. “And this includes strategies for achieving HIV remission through reservoir modulation or immunological control, but also the eradication of the HIV reservoir.”

Gaebler and other experts have emphasized that stem cell transplantation cannot be used as a standard treatment for HIV because the procedure is too risky for people who don’t have life-threatening malignancies.

The mutation

Genetics likely played an important role in depleting the next Berlin patient’s HIV reservoir after the stem cell transplant. Four of the previous six patients who received stem cells from donors with homozygous CCR5-delta 32 mutations experienced sustained viral suppression after interrupting ART. The second Berlin patient had a single copy of the CCR5-delta 32 mutation, known as heterozygous. While CCR5-delta 32 heterozygous people can acquire HIV, the mutation causes the disease to progress more slowly. Less than 20% of Northern Europeans have a single copy of the mutation, and about 1% have two copies, meaning it was inherited from both parents, Gaebler said. 

The common denominator in four of the seven people cured with stem cell transplants is the CCR5-delta 32 mutation, whether heterozygous or homozygous, Gaebler said. “What I think is happening is this combination of effects between allogenic stem cell transplantation and donor immunity, in addition to, in the case of homozygous CCR5 mutation, an additional safety layer… contributes to these successful cases of long-term HIV remission. We’re shifting a little towards the allogenic immunity part that is leading to the depletion of the HIV reservoirs and thinking that CCR5 is an additional safety layer that gives us protection with a resistant immune system.” 

Sharon Lewin, MD, PhD, the outgoing IAS president and the director of the Peter Doherty Institute of Infection and Immunity at the University of Melbourne, agreed that viral remission might not be only due to the CCR5-delta 32, either heterozygous or homozygous. In a press conference, Lewin said that multiple factors, differing from patient to patient, may play a role in remission. Lewin added that the seven patients who’ve experienced long-term HIV remission from stem cell transplants can be a positive sign for HIV cure research because they suggest it’s not necessary to eliminate every piece of CCR5 for gene therapy to work. “[With] every case, you learn more about what is possible and what could be mimicked in an intervention,” she said.

A study of people with HIV who received allogeneic stem cell transplants recently showed that factors beyond CCR5-delta 32 mutations, such as the immunity of the donor cells, may affect the HIV reservoir after transplantation.

Gaebler noted that it’s possible that the second Berlin patient could relapse in the future, but added that the length of time he had been in remission means viral rebound is unlikely.

LARRY BUHL is a multimedia journalist based in Los Angeles. He has covered HIV/AIDS and other infectious diseases for more than two decades. In addition to POSITIVELY AWARE, he is a regular contributor to TheBody.com, Everyday Health and capitalandmain.com. His work has appeared in USA Today, Salon, Undark, KQED, The New York Times and others.