As in the case of the other two patients (Berlin Patient and London Patient), the transplantation was undertaken to treat an acute hematologic disease, which had developed in addition to the HIV infection. The team of doctors in Düsseldorf headed by Dr Björn Jensen, a specialist in infectious diseases, and the hematologist Professor Dr Guido Kobbe, both from Düsseldorf University Hospital, now present the steps taken to cure the “Düsseldorf Patient” in their current peer-reviewed publication in the renowned scientific journal, Nature Medicine. Almost ten years after the stem cell transplantation from an unrelated donor and more than four years after ending the HIV therapy, he is now in good health. The fact that the virus has not returned is the result of extremely thorough scientific and therapeutic preparation and monitoring. To date, this is the longest and most precise diagnostic monitoring of a patient with HIV after stem cell transplantation.
The international research team headed by the medics in Düsseldorf hope the knowledge gained will provide starting points for planning future studies into cures for HIV. Due to the risks involved, stem cell transplantation is only carried out within the framework of treating other life-threatening diseases. Consequently, research must now be continued to enable patients to overcome HIV infections without the need for this strenuous intervention in the future.
Six months after starting his HIV therapy the “Düsseldorf Patient” was diagnosed with acute myeloid leukemia (AML), a form of blood cancer that is life-threatening. He underwent a stem cell transplantation for this disease in 2013. “From the outset, the aim was to treat both the leukemia and the HIV,” says Professor Guido Kobbe, who performed the transplantation in Düsseldorf. The stem cells taken from the donor exhibited a specific mutation in the CCR5 gene (CCR5Delta32 mutation). This rare genetic mutation, which is predominantly found in central and northern Europe, results in the absence of a docking site for HIV in immune cells, providing good protection against infection with the virus. The stem cell transplantation thus treated both diseases.
In 2018, following careful planning and with constant, close monitoring by the team of doctors treating the patient, the anti-viral HIV therapy – which had ensured that any residual HIV was kept under control up to that point – was ended.
To ensure it was ultimately possible to talk of a cure, extensive tests were conducted throughout this period, for example to establish whether evidence of replicable signs of replication-capable HI-viruses can still be found. In the publication in Nature Medicine, the authors describe in detail which additional indicators they reviewed to enable them to exclude any remaining active HIV infection and thus now assume a cure after the stem cell transplantation.
Following the world’s first report in 2009 that a stem cell transplantation from a donor with this specific gene mutation (see background) can in principle cure an HIV infection, many questions about the prerequisites remained unanswered.
The detailed virological and immunological analysis of the blood and tissue of the Düsseldorf Patient now provides important insights.
On behalf of the international team, Dr Björn Jensen says: “Following our intensive research, we can now confirm that it is fundamentally possible to prevent the replication of HIV on a sustainable basis by combining two key methods. On the one hand, we have the extensive depletion of the virus reservoir in long-lived immune cells, and on the other hand, the transfer of HIV resistance from the donor immune system to the recipient, ensuring that the virus has no chance to spread again. Further research is now needed into how this can be made possible outside the narrow set of framework conditions we have described.”
“Our team decided to take a very cautious and extremely thorough approach. The focus naturally lay on achieving the greatest possible benefit for our patient. However, we were also aiming to make a significant contribution to understanding the success factors of such a therapy,” says Professor Dr Tom Lüdde, co-author and Director of the Department of Gastroenterology, Hepatology and Infectiology at Düsseldorf University Hospital, where the treatment was carried out.
Background:
The gene mutation of the stem cell donor is a homozygous CCR5Delta32 (CCR5Δ32) mutation. The CCR5 co-receptor plays a key role in enabling HIV to enter immune cells. The homozygous CCR5Δ32 mutation is a 32-base pair deletion mutation in both copies (maternal and paternal) of the CCR5 gene (CCR5Δ32/Δ32) and is only found in around 1% of the Caucasian population. It results in extensive resistance to HIV-1 as no functional CCR5 co-receptors can be produced and are thus absent from the surface of immune cells.
Allogeneic stem cell transplantation
In allogeneic stem cell transplantation, a diseased organ – in this case the hematopoietic system of the patient – is replaced by a healthy donor organ, i.e. the healthy hematopoietic system of the donor, in a similar way to other transplantation processes. The donor may be a relative or an unrelated person, but the blood stem cells need to be transplanted from a donor who is as identical as possible with regard to genetic tissue characteristics.
Virus reservoir in long-lived immune cells
HIV-1 is capable of forming a long-lived viral reservoir by inserting “viral blueprints” into the genetic material of long-lived immune cells, from which replicable virus cells can subsequently be produced.
IciStem consortium
The IciStem consortium is an international research collaboration of scientists and medical doctors following up people with HIV who had or will have a bone marrow transplantation for serious hematological conditions. The consortium has registered over 50 individuals with HIV who received/will receive either CCR5d32/d32 or wildtype donorcells and is performing in depth and advanced investigations of the innate and adaptive immune system and HIV reservoirs pre and post transplantation. Icistem is open for new registrations and is coordinated by Annemarie Wensing of the University Medical Center Utrecht in the Netherlands and Dr. Javier Martinez-Picado of the IrsiCaixa AIDS research institute in Spain. See for more information: www.icistem.org
Original publication:
Jensen, B. E-O., Knops, E, Cords, L. et al., In-depth virological and immunological characterization of HIV-1 cure after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation. Nat Med (2023). DOI number: 10.1038/s41591-023-02213-x
The online version: https://www.nature.com/articles/s41591-023-02213-x
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