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Third patient HIV-free after virus-resistant cell transplant

A man known as “the Duesseldorf patient” has become the third person declared cured of HIV after receiving a stem cell transplant that also treated his leukaemia, according to a study published this week.

Two other cases with both HIV and cancer, patients in Berlin and London, have previously been reported as cured in scientific journals after the high-risk procedures.

Details of the Duesseldorf patient’s cure were published in the journal Nature Medicine, which explained that the 53-year-old man was diagnosed with HIV in 2008, then three years later with acute myeloid leukaemia.

In 2013, he had a bone marrow transplant using stem cells from a female donor with a rare mutation in her CCR5 gene. The mutation has been found to stop HIV from entering cells.

He stopped receiving antiretroviral therapy for HIV in 2018. Four years later, consistent testing found no trace of HIV returning in his body.

The study said that “this third case of HIV-1 cure” provides “valuable insights that will hopefully guide future cure strategies”, reports AFP.

The stem-cell technique involved 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 those cells were destroyed and replaced with stem cells from a healthy donor, to treat acute myeloid leukaemia.

The team treating Brown selected a donor with a genetic mutation called CCR5Δ32/Δ32, which prevents the CCR5 cell-surface protein from being expressed on the cell surface.

Nature Journal reports that HIV uses that protein to enter immune cells, so the mutation makes the cells effectively resistant to the virus. After the procedure, Brown was able to stop taking ART and remained HIV-free until his death from cancer in 2020.

In 2019, researchers revealed that the same procedure seemed to have cured the London patient, Adam Castillejo. And in 2022, scientists announced that they thought a New York patient who had remained HIV-free for 14 months might also be cured, although researchers cautioned that it was too early to be certain.

Ravindra Gupta, a microbiologist at the University of Cambridge, UK, who led the team that treated Castillejo, says the latest study “cements the fact that CCR5 is the most tractable target for achieving a cure right now”.

Low virus levels

The Düsseldorf patient had extremely low levels of HIV, thanks to the ART, when he was diagnosed with acute myeloid leukaemia. In 2013, a team led by virologist Björn-Erik Jensen at Düsseldorf University Hospital in Germany destroyed his 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, the scientists continued to find immune cells that specifically reacted to HIV, suggesting a reservoir remained somewhere in his body.

It’s not clear, Jensen says, whether these immune cells had targeted 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.

In an effort to understand more about how the transplant worked, the team ran further tests, which included transplanting the patient’s immune cells into mice engineered to have human-like immune systems. The virus failed to replicate in the mice, suggesting that it was non-functional. The final test was for the patient to stop taking ART.

“It shows it’s not impossible – it’s just very difficult – to remove HIV from the body,” Jensen says.

The patient who received the treatment said the bone marrow transplant had been a “very rocky road”, adding that he planned to devote some of his life to supporting research fundraising.

Timothy Henrich, an infectious-disease researcher at the University of California, San Francisco, said the study is very thorough.

That several patients have been successfully treated with a combination of ART and HIV-resistant donor cells makes the chances of achieving 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 that the people received for their cancer before their bone marrow transplants might have helped to eliminate HIV by preventing infected cells from dividing.

But it’s unlikely that bone-marrow replacement will be rolled out to people who don’t have leukaemia because of the high risk associated with the procedure, particularly the chance that an individual will reject a donor’s marrow.

Several teams are testing the potential to use 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 that 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 that it is too early to say whether those individuals are virus-free.

His team plans to study whether, if a person has a larger reservoir of HIV at the time of receiving a transplant, this affects how well the immune system recovers and eliminates any remaining viruses from the body.

Celebrating

The Dusseldorf patient said he was “proud of my worldwide team of doctors who succeeded in curing me of HIV – and at the same time, of course, of leukaemia”, and celebrated “in a big way” the 10-year anniversary of his transplant on Valentine's Day this month, with the donor being the “guest of honour”.

The recoveries of two more people with HIV and cancer, the so-called New York and City of Hope patients, were announced at different scientific conferences last year, though research has yet to be published on those cases.

While a cure for HIV has been long sought after, the bone marrow transplant involved in these cases is a severe and dangerous operation, making it only suitable for a small number of patients suffering from both HIV and blood cancers.

Finding a bone marrow donor with the rare CCR5 mutation can also be a major challenge.

One of the study's co-authors, Asier Saez-Cirion of France’s Pasteur Institute, said that during the transplant “the patient’s immune cells are completely replaced by those of the donor, which makes it possible for the vast majority of the infected cells to disappear”.

“This is an exceptional situation when all the factors coincide for this transplant to be a successful cure for both leukaemia and HIV,” he said.

Study details

In-depth virological and immunological characterisation of HIV-1 cure after CCR5Δ32/Δ32 allogeneic hematopoietic stem cell transplantation

Björn-Erik Ole Jensen, Elena Knops, Leon Cords, Carsten Münk, Guido Kobbe et al.

Published in Nature Journal on 20 February 2023

Abstract

Despite scientific evidence originating from two patients published to date that CCR5Δ32/Δ32 haematopoietic stem cell transplantation (HSCT) can cure human immunodeficiency virus type 1 (HIV-1), the knowledge of immunological and virological correlates of cure is limited. Here we characterise a case of long-term HIV-1 remission of a 53-year-old male who was carefully monitored for more than 9 years after allogeneic CCR5Δ32/Δ32 HSCT performed for acute myeloid leukaemia. Despite sporadic traces of HIV-1 DNA detected by droplet digital PCR and in situ hybridisation assays in peripheral T cell subsets and tissue-derived samples, repeated ex vivo quantitative and in vivo outgrowth assays in humanised mice did not reveal replication-competent virus. Low levels of immune activation and waning HIV-1-specific humoral and cellular immune responses indicated a lack of ongoing antigen production. Four years after analytical treatment interruption, the absence of a viral rebound and the lack of immunological correlates of HIV-1 antigen persistence are strong evidence for HIV-1 cure after CCR5Δ32/Δ32 HSCT.

 

Nature Journal study – In-depth virological and immunological characterisation of HIV-1 cure after CCR5Δ32/Δ32 allogeneic haematopoietic stem cell transplantation (Open access)

 

Nature Journal article – Third patient free of HIV after receiving virus-resistant cells (Open access)

 

AFP article – Third patient cured of HIV after receiving stem cell cancer treatment (Open access)

 

See more from MedicalBrief archives:

 

Fourth person cured of HIV, fifth success in the wings: AIDS 2022 conference

 

UK man the second to be cleared of the Aids virus

 

‘Berlin Patient’ patient speaks in Cape Town on HIV cure research

 

‘London Patient’ steps out of the shadows

 

 

 

 

 

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