A 53-year-old man in Germany is at least the third HIV-infected person to be declared virus-free after a procedure in which his bone marrow cells were replaced with HIV-resistant stem cells from a donor.
For years, people living with HIV have received antiretroviral therapy (ART) with the aim of reducing the virus to almost undetectable levels and preventing transmission to other people. But the immune system keeps the virus trapped in reservoirs in the body, and when a person stops taking ART, the virus can begin to replicate and spread.
A true cure would eliminate this reservoir, and that is what appears to have happened in the last patient whose name was not released. The man, referred to as the “Düsseldorf patient”, discontinued ART in 2018 and has been HIV-free ever since.
Stem cell technology was first used to treat Timothy Ray Brown, often referred to as the Berlin patient. In 2007 he had a bone marrow transplant in which these cells were destroyed and replaced with stem cells from a healthy donor to treat acute myeloid leukemia. The team that treated Brown selected a donor with a genetic mutation called CCR5Δ32/Δ32 that prevents the CCR5 cell-surface protein from being expressed on the cell surface. HIV uses this protein to enter immune cells, so the mutation effectively makes the cells resistant to the virus. After the procedure, Brown was able to stop taking ART and remained HIV-free until his death in 2020.
In 2019, researchers revealed that the same procedure appeared to have cured London patient Adam Castillejo. And in 2022, scientists announced they thought a New York patient who had remained HIV-free for 14 months might also be cured, although researchers warned it was too soon to be sure.
Ravindra Gupta, a microbiologist at the University of Cambridge, UK, who led the team that treated Castillejo, says the latest study “consolidates the fact that CCR5 is currently the most manageable target to achieve a cure.”
Low virus levels
Thanks to ART, the Düsseldorf patient had extremely low HIV levels when he was diagnosed with acute myeloid leukemia. In 2013, a team led by virologist Björn-Erik Jensen at the University Hospital Düsseldorf in Germany destroyed the patient’s cancerous bone marrow cells and replaced them with stem cells from a donor with the CCR5Δ32/Δ32 mutation.
Over the next five years, Jensen’s team took tissue and blood samples from the patient. In the years after the transplant, scientists kept finding immune cells that responded specifically to HIV, suggesting that a reservoir remained somewhere in the man’s body. It’s not clear, says Jensen, whether these immune cells were targeting active virus particles or a “graveyard” of viral remnants. They also found HIV DNA and RNA in the patient’s body, but these never seemed to replicate.
To understand more about how the transplant works, the team conducted further tests, including transplanting the patient’s immune cells into mice engineered to have a human-like immune system. The virus failed to replicate in the mice, suggesting it was dysfunctional. The final test was for the patient to stop taking ART. “It shows that it’s not impossible — it’s just very difficult — to get HIV out of the body,” says Jensen.
The patient, who received the treatment, said in a statement that the bone marrow transplant had been a “very rocky road,” adding that he intends to dedicate part of his life to helping fundraise for the research.
Timothy Henrich, an infectious disease researcher at the University of California, San Francisco, says the study is very thorough. The fact that several patients have been successfully treated with a combination of ART and HIV-resistant donor cells makes the chances of an HIV cure in these individuals very high.
Gupta agrees, although he adds that in some cases the virus mutates inside a person and finds other ways to enter their cells. It’s also unclear, he says, whether the chemotherapy people received for their cancer before their bone marrow transplants might have helped eliminate HIV by preventing infected cells from dividing.
But bone marrow replacement is unlikely to be introduced in people who don’t have leukemia because of the high risk associated with the procedure, particularly the possibility of a person rejecting a donor’s bone marrow. Several teams are testing the possibility of using stem cells taken from a person’s own body and then genetically modified to have the CCR5Δ32/Δ32 mutation, which would eliminate the need for donor cells.
Jensen says his team has performed transplants for several other people affected by both HIV and cancer, using stem cells from donors with a CCR5Δ32/Δ32 mutation, but it’s too early to say if these people are virus-free. His team plans to study whether a larger HIV reservoir in a person at the time of transplantation affects how well the immune system recovers and eliminates any remaining virus from the body.
This article is reproduced with permission and was first published on February 21, 2023.