The next Berlin Patient: What can the latest case of long-term HIV remission teach us about a potential cure?

The latest report of sustained HIV remission without antiretroviral therapy (ART) marks a new milestone on the long road toward interventions that can effectively cure HIV. The experience of a man dubbed “the next Berlin patient,” whose HIV viral load became undetectable after allogeneic stem cell transplantation, features a unique facet that could significantly expand the transplant donor pool. The case was featured among the scientific highlights at the 25th International AIDS Conference (AIDS 2024) in Munich, Germany.

The 60-year-old German man, who chose to remain anonymous, tested positive for HIV in 2009 and was diagnosed with acute myeloid leukemia (AML) in 2015. He discontinued ART in late 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 their patient remains virally suppressed almost six years later, joining the ranks of six other people who previously achieved HIV remission after stem cell transplantation.

Background: The Original “Berlin Patient”

Timothy Ray Brown was the first person to be cured of HIV. Brown, a U.S. citizen, was diagnosed with HIV in 1995, while living in Berlin. Years later, he received two stem cell transplants as treatment for AML at the Charité hospital. The stem cells harvested from a donor with a rare, homozygous C-C chemokine receptor 5 (CCR5)-delta 32 mutation successfully treated Brown’s leukemia while also eradicating the HIV. The homozygous CCR5-delta 32 mutation, which is inherited from both parents, eliminates a receptor that the HIV virus uses as a gateway to its target cells. Brown maintained HIV remission until his death, which was caused by an AML relapse in 2020.

New Findings Highlight Role of Genetic Determinants

The donor’s genetic characteristics likely play a key role in depleting the recipient’s HIV reservoir after stem cell transplantation. Prior HIV cure cases include four individuals who received stem cells from donors with homozygous CCR5-delta 32 mutations and have experienced sustained viral suppression after interrupting ART.

Unlike those individuals, the new HIV remission case presented at AIDS 2024 involves a person who received stem cells from a donor with a single, heterozygous CCR5-delta 32 mutation. Heterozygous mutations, inherited from only one parent, are significantly more common than homozygous mutations and do not confer HIV immunity. In Europe, roughly 1% of individuals possess the homozygous mutations, while about 16% possess a heterozygous mutation, Christian Gaebler, MD, the research group leader in the Department of Infectious Diseases and Critical Care Medicine at Charité, explained in a media briefing ahead of the AIDS 2024 conference. (Gaebler will formally present the case study in an oral abstract session on July 24.)

“We believe that this remarkable case and the results of our studies suggest that … it is possible to cure HIV even when a functional receptor for the virus is present,” Gaebler said. “We have performed comprehensive HIV reservoir testing, including in the blood, but also in various tissues from tissue reservoirs, and we have found no signs of HIV. In addition, HIV-specific antibody levels decreased since the transplantation and HIV-specific T-cell responses were undetectable.”

While the possibility of future viral rebound cannot be excluded, especially after a limited observation period, the chances of a relapse years after transplantation are slim, the researchers noted.

This latest cure case from Berlin suggests that people living with HIV and cancer who are candidates for stem cell transplantation may have access to a broader donor pool than previously identified. “It’s also promising for cure strategies for HIV, because it suggests that you don’t have to [eliminate] every single piece of CCR5 for gene therapy to work,” said Sharon Lewin, M.D., Ph.D., the current IAS president and the director of the Peter Doherty Institute of Infection and Immunity at the University of Melbourne, during a press conference.

The results are in line with findings from a previous HIV cure case report regarding a person dubbed “the Geneva patient,” who had undetectable HIV viral loads after receiving stem cells from a donor without a CCR5-delta 32 mutation. The Geneva case, presented last year at the 12th International AIDS Society Conference on HIV Science in Brisbane, Australia, suggested that homozygous CCR5-delta 32 mutations may not be a make-or-break factor for achieving long-term HIV remission.

Ongoing Debate Over Role of HIV Reservoir Dynamics

The mechanisms underlying the depletion of the HIV reservoir after stem cell transplantation could provide a scaffold for developing gene therapies that effectively target HIV. Multiple factors may drive the remission in these cure cases, including the number of target cells susceptible to infection and other immunologic and genetic determinants, Lewin explained.

A prospective observational study of individuals 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 drive the evolution of the HIV reservoir after transplantation.

“The speed at which the new immune system replaces the old one might play a part,” Gaebler added. “In the second Berlin patient, that was done relatively quickly, 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.”

The development of HIV therapies that mimic the protective factors found in certain donor cells may provide new answers in the search for a cure.

Implications for Future Therapies to Treat — and, One Day, Cure — HIV

The second Berlin patient is the latest in a series of highly publicized cases of patients who have been declared cured of HIV. While these reports may have little impact on daily clinical decision-making, they provide a mold for shaping future therapies and interventions that may be able to cure HIV on a wider scale. “[With] every case, you learn more about what is possible and, therefore, what could be mimicked in an intervention,” Lewin said. “Case in point, here [we learn] that we do not need to eliminate every single CCR5 to achieve remission, and that has implications for gene therapy.”

Gaebler urged the research community not to lose sight of the ultimate target: curing HIV. “Owing to the significant risks associated with stem cell transplantation, this method cannot be used as a standard treatment of HIV,” he said. “Once we have a better understanding of which factors in the second Berlin patient contributed to the virus being eradicated from all its hiding places, then those findings can hopefully be used to develop novel treatment concepts such as cell-based immune therapies or therapeutic vaccines.”

By Iulia Filip