In 2008, one man, Timothy Ray Brown, was cured of HIV.
Also known as the “Berlin patient,” Brown was considered cured of his infection after receiving two bone-marrow transplants to treat a separate disease he had been diagnosed with a few years earlier: acute myeloid leukemia.
The bone marrow he received came from a donor whose genes carried a rare mutation that made them resistant to HIV, known as CCR5-delta 32, which was transferred on to Brown.
Traces of the virus were seen in his blood a few years later, but remained undetectable despite him not being on antiretroviral treatment, meaning he was still clinically cured of his infection, according to his clinicians.
Despite various attempts on patients after him by scientists using this same approach, including a similar transplant in two Boston patients, Brown remains the only person known about who has been cured of HIV.
But a new study presented Sunday at the 2016 Towards an HIV Cure Symposium — ahead of the 21st International AIDS conference in Durban, South Africa, this week — revealed data on a new set of HIV positive patients whose reservoirs of HIV have fallen to very low levels after receiving a range of stem cell transplants similar to Brown’s.
The study is part of the EPISTEM project, a European project to investigate the potential for an HIV cure using stem cell transplantation, and provides further insight into the science underlying Brown’s success.
Everyone included in the project is in need of stem cell transplantation to cure severe blood disorders, in addition to being infected with HIV.
Can stem cells bear a cure?
The 15 patients monitored in the study to date are still on antiretroviral treatment, unlike Brown, but have received stem cell transplants. Three of them had their operations three years ago and have been studied in detail since.
“In two of the three patients we were unable to detect infectious virus in the blood of the patients,” said Annemarie Wensing, a virologist at the University Medical Center Utrecht who led the study. Tissue samples were also studied and one patient also had just traces of the virus hiding there.
“All HIV-infected patients that received a stem cell transplantation had a significant reduction of the viral reservoir in their body. This has not been demonstrated with other cure strategies,” Wensing said.
The minute levels of the virus that have been seen to date were not considered competent enough to replicate, according to the team.
“[This] will help us shape future HIV eradication strategies that could be applied at a larger scale than stem cell transplantation,” said Wensing.
But there’s a long road ahead.
“What’s interesting is that these patients have survived more than a year,” said Sharon Lewin, director of the Peter Doherty Institute for Infection and Immunity and co-chairwoman of the symposium. “There was concern that maybe when you take a CCR5-delta32 bone marrow it doesn’t engraft as well, but these patients have survived to 12 months.”
The next step will have to explore how they fare without treatment, Lewin added.
How the transplant works
The process of transferring resistance to HIV is extremely complicated — and rare.
Firstly, only 1% of Caucasians are estimated to carry the CCR5-delta 32 mutation that confers resistance to HIV, with other races having even fewer numbers. The genetic change means people lack a protein needed by HIV to enter blood cells.
The team also cannot be 100% sure whether the mutation is the only cause of the resistance to HIV or whether the many other stages of the transplant process play a role.
These include the body being totally cleared of its immune system using chemotherapy and irradiation ahead of it being rebuilt by the donor stem cells, and the potential for the newly formed immune cells to attack any remaining old ones that may be harboring HIV. Patients can also have one or two transplants.
“All those factors may be really important and we’re trying to tease it out,” said Monique Nijhuis, also from the Utrecht Medical Center who works on the project.
The unique and rare nature of the blood disorders affecting the patients also means they receive different treatments rather than everyone receiving the same treatment for comparison.
“Each person is like a micro-clinical trial in himself or herself,” said Asier Saez-Cirion from the Institut Pasteur, also involved in the project.
What the team does know, however, is that monitoring these patients and the new participants being recruited globally will help them understand where the virus hides within the body — known as reservoirs — and the biology involved in clearing these reservoirs to leave levels of the virus undetectable.
“We want to know the mechanisms behind HIV cure … to understand [what] is important for the decline in HIV and why there was a cure in the Berlin patient,” said Nijhuis. “This will give us a sense of biomarkers … for the HIV reservoirs and to predict what will happen after we stop treatment.”
The main drawback, however, is the impracticality of applying this process to more than a handful of people and the resulting unlikelihood of it becoming a generic cure.
In 2015, almost 37 million people were living with HIV, of which only 46% were receiving antiretroviral therapy, and 2,1 million were newly infected.
“It’s impractical to think we’re going to do that for millions of people,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Disease. “It’s the practicality of saying what is better: a single or two pills a day, or getting chemotherapy, getting a stem cell transplant and then having chemotherapy for a period of time after you get the transplant versus just taking a drug,” he said.
What Fauci instead feels may be more feasible, and scalable, is using this insight to inform future therapies that involve gene editing, where people may have the CCR5 gene edited out of their cells so HIV can no longer invade them.
“It’s interesting science and what it might do is serve as the proof of concept that you can do gene editing of someone, as opposed to stem cell transplantation,” said Fauci. He highlighted the fact that the HIV community currently does not have enough budget to provide pills to everyone who needs them, let alone transplants.
Saez-Cirion agreed. “Bone marrow transplant won’t be applied widely … it’s extremely complex,” he said.
But with so few cases to date showing either a cure or remission, the EPISTEM team hopes its group of patients will at least provide data to build on the existing — and limited — body of evidence.
Targeting remission instead
Fauci does believe the possibility of HIV remission, where levels of HIV are brought down to undetectable levels when people are not taking antiretroviral drugs, is realistic, but by other means such as the use of broadly neutralizing antibodies, which, as their name suggests, could neutralize HIV reservoirs hiding in cells.
“We should not give up on eradication … but I would put my major emphasis on sustained virological remission … to keep people suppressed as low as they can possible be.” Fauci said.
Remission has been shown in other groups of patients, including one known as the VISCONTI cohort where 14 adults treated for HIV soon after infection stopped taking their drugs three years later and showed no resurgence in the amount of virus found in their blood. The group is considered to be post-treatment controllers of the virus.
Last year a French teenager was also reported to have similar control, 12 years after stopping treatment. Both groups are monitored by Saez-Cirion’s team at the Institut Pasteur.
“Remission will be the first step in any case,” said Saez-Cirion. “Then when we get more data on survival in this remission period and more sensitive techniques we can being to talk about a cure.