The "Geneva patient": first case of HIV cure with stem cell transplant without protective mutation

The "Geneva patient" joins the group of people who have achieved an HIV cure after a stem cell transplant, becoming the first person in the world to do so without their donor having the CCR5Δ32 mutation, known for conferring protection against HIV infection. This unprecedented success, published in the journal Nature Medicine[i1] , was accomplished within the framework of the IciStem consortium, co-coordinated by IrsiCaixa –a center jointly supported by the "la Caixa" Foundation and the Catalan Department of Health– and Utrecht University, and led by the University Hospital of Geneva and the Pasteur Institute. To date, thirty-two months after discontinuing antiretroviral therapy (ART), no trace of the virus has been detected in the blood. "This case is particularly interesting because it shows us that HIV remission is possible even without the CCR5Δ32 mutation. Furthermore, we have identified potential mechanisms that may have allowed for the cure in this case, opening new research paths that bring us closer to eradicating HIV", explains Javier Martínez-Picado, ICREA research professor at IrsiCaixa and coordinator of IciStem.

Absence of viral reactivation without protective mutation

The individual, who has not made their identity public, was diagnosed with HIV in May 1990 and immediately began antiretroviral treatment. In January 2018, they were diagnosed with myeloid sarcoma, and in July of the same year, they underwent a stem cell transplant from a compatible donor. A month after the transplant, tests already showed that the patient's blood cells had been entirely replaced by those of the donor, accompanied by a decrease in HIV-carrying cells in their body.

Before the transplant, despite optimized antiretroviral treatment, the "Geneva patient" still had replicating HIV. However, after the transplant, the medical and scientific team observed a drastic reduction in HIV-related parameters: no viral particles, an undetectable reservoir, and no immune response indicating that the body was recognizing the presence of the virus. "Previously, transplants without the CCR5Δ32 mutation had been performed in other HIV patients. However, if treatment was stopped, viral rebound occurred, although more slowly than in a non-transplanted person with HIV. The 'Geneva patient' is the first to achieve a prolonged remission", comments Maria Salgado, IGTP researcher at IrsiCaixa and coordinator of IciStem.

Coinciding with the publication of the "Geneva patient" case, the second case of a cure after a stem cell transplant with cells susceptible to HIV infection was announced in July at the 25th International AIDS Conference (Munich, Germany). Specifically, the compatible donor for this patient only had one copy of the gene containing the CCR5Δ32 mutation, meaning their cells had significantly reduced protection against HIV. This new case reinforces the findings from the "Geneva patient" and provides further evidence of the possibility of achieving HIV remission without the protective mutation.

The role of immunosuppression and the interaction between donor and recipient immunity

The research team proposes several hypotheses to explain why the "Geneva patient" has managed to keep HIV under control without treatment. A key factor is alloimmunity, which refers to the interaction between the immune system of the donor and that of the recipient. This hypothesis aligns with a previous study, led by IrsiCaixa, that links this mechanism to the reduction of the viral reservoir during a stem cell transplant. "After a transplant, the recipient's immune cells perceive those of the donor as a threat, and vice versa, triggering an 'immune battle' between the two systems," explains Salgado. During this confrontation, many of the recipient's immune cells, including those infected with HIV, die and are eventually replaced by the donor's cells. Although this process is very aggressive on the body, it is crucial to eliminate latent HIV in cells that could reactivate the infection.

In the "Geneva patient's" case, the team administered ruxolitinib, an immunosuppressive drug designed to reduce the collateral damage caused by the immune battle. Laboratory studies have also shown that ruxolitinib can block HIV replication and prevent its reactivation, making it another factor contributing to the patient's HIV remission.

Finally, the team emphasizes the critical role of Natural Killer (NK) cells in this patient. These cells patrol the body, seeking out and destroying dangerous cells, including those infected with HIV, helping to keep the immune system vigilant and the virus at bay.

New perspectives for HIV cure research

Although stem cell transplantation is not a viable therapeutic option for all people with HIV, the exceptional nature of the "Geneva patient's" case opens up new perspectives for research into therapies that might exploit alloimmunity and immunosuppressive drugs to achieve an HIV cure.

"We are facing a discovery that could change the course of HIV cure research," concludes Martínez-Picado. "The next step will be to delve deeper into the mechanisms that allowed this remission and explore how we can replicate these results in a broader population of people with HIV", he adds.