1 March 2020
More than a decade after Timothy Ray Brown, an American man known as the Berlin patient, was cured of HIV following a bone marrow transplant, news of a similar case, the London patient, emerged last March. The case sparked hope, with reports suggesting that Brown’s case may be replicable, and that science is close to finding a cure to HIV.
There are approximately 37.9 million people in the world living with human immunodeficiency virus(HIV), the virus that causes AIDS, according to the latest available data from UNAIDS. Over 23 million of those are on some form of antiretroviral therapy, a standard regimen that consists of a combination of two or more HIV drugs to suppress and control the progression of the virus.
In March 2019, and coming on the heels of the news of the London patient, an anonymous Dusseldorf man, who stayed HIV-free for five years after a bone marrow transplant and for months after ceasing antiretroviral treatment, appears to be the third person who may have been cleared of HIV.
His case is less celebrated since, at the time of announcement, he had only been in remission for three months, which is “an early stage” according to Björn Jensen, the doctor overseeing his case. His case study has also not been published yet.
All three patients had leukaemia, an aggressive type of blood cancer, and they had undergone bone marrow transplants as part of their cancer treatment. Their transplants specifically came from donors carrying a rare CCR5 genetic mutation, known as CCR5-delta 32, which is resistant to HIV and which only appears in people of European descent. The London patient, for instance, had stage-four Hodgkin’s lymphoma and had failed multiple lines of chemotherapy. He then had to undergo stem cell transplantation, and was matched with a donor holding the CCR5-delta 32 mutation in both copies, replicating the Berlin patient’s profile.
When it enters the body, HIV targets immune cells that fight infection, but carriers of the mutated gene CCR5-delta 32, are not susceptible to the attack.
The transplanted ‘Gandalf’ cells, which the London, Berlin and Dusseldorf patients received, cause CCR5 co-receptors, gateways which sit outside the cell, to shrink and collapse inwards, preventing the virus from passing through. In other words, the transplant from CCR5-mutation-carriers turns cancerous bone marrow cells into HIV-resistant cells, preventing the virus from returning.
In 2016, the London patient was taken off antiretroviral treatment 16 months after his transplant and remains in remission. The Berlin patient has been in remission for more than 10 years. Neither experienced a relapse when they stopped their HIV medication.
HIV cure science: cautious optimism
The recovery process of stem cell therapy is lengthy and complex. It took about three years post-transplant for rigorous tests to confirm that the London patient was HIV-free, and five years for the Dusseldorf patient. Disruption of antiretroviral medications occurred months after that. Researchers must wait months before they can confirm that the patient has become HIV-free.
The media was quick to brand the case a breakthrough and the treatment a win in the war against AIDS, a syndrome of HIV which causes irreparable damage to the immune system.
And it seems to be a remarkable step forward, as many have noted. “In the three cases where CCR5-delta 32 transplantation was successfully performed, we have achieved an eradication,” Gero Hütter, the haematologist who pioneered stem cell therapy for HIV and who treated the Berlin patient, told KAIMRC Innovations. The evidence is suggestive that “CCR5 depletion is responsible for the comparable outcome.”
But independent experts wonder if it’s too early to claim, unequivocally, that the second and third patients have been cured, as opposed to being in long-term remission. The leader of the research team, Ravindra Gupta, himself cautioned against newspapers describing it as a cure, without reservations. “I think that the press release [we wrote] was cautionary. I think that if people interpret it in a certain way, that’s not good journalism. I’m hoping that people would read between the lines,” said Gupta. He is also a professor at the University College London and the University of Cambridge.
The treatment is feasible, and modifications to it can be as effective as the original transplants, according to Hütter.
“Berlin, London and Dusseldorf show us that the approach is reproducible,” Gupta said. “But it’s more a symbolic victory, it’s not an option for everyone.”
How repeatable are the cases of London, Berlin and Dusseldorf?
The potential bone marrow donors who are eligible CCR5-mutation-carriers, and thus resistant to HIV infection, represent only 1% of the Northern European population. The mutation has not been found in people from Africa or East Asians, for instance. What complicate matters more is that donors must be homozygous carriers; in other words, they must have inherited a copy of the rare mutation from both parents.
Can millions of HIV patients reboot their infected cells with this type of stem cell therapy? The short answer is that it’s not even nearly possible for most patients.
“I think it's impossible to consider it as a common treatment to people with HIV because people who were so-called cured all had an underlying leukaemia [and] lymphoma that required the chemotherapy for the leukaemia, plus a stem-cell transplant, plus immuno-suppression to prevent the rejection of it, so the process itself was quite dangerous,” said Anthony Fauci, Director of NIH's National Institute of Allergy and Infectious Diseases, USA. “It can never be done for someone unless they really needed a transplant for another reason.”
Islam Hussein, virologist, drug discovery researcher, and senior scientist at Microbiotix, seconded that this type of stem cell transplant cannot become the method of choice for most patients. “[It] is a very expensive and risky procedure that might be justifiable only for HIV patients who are also suffering from lymphoma,” he said. “We already have an arsenal of HIV therapies that are safe, effective and affordable.”
When Hütter himself was asked if stem cell therapy can live to its promise as a possible lifetime cure for HIV, he said, “not in the setting we did in Timothy Brown.”
He agreed that stem cell transplantation from matching donors “is not an option for HIV patients without cancer” adding that, “the treatment related morbidity and mortality is too high. New developments use autologous cells or manipulated allogeneic cells with much fewer side effects.”
In a paper evaluating 30 years of stem cell therapy in HIV patients, Hütter contended that the therapy is unlikely to achieve complete eradication of the virus. HIV persists in pockets of cells, and infected macrophages become stable reservoirs for the virus. It is why antiretroviral treatments could never finish the job.
Alternative pathways to HIV treatment and prevention
Less risky interventions, such as the discovery that combining broadly neutralizing HIV-1 antibodies can replace antiretroviral medications and may result in longer remission, are in development, and are more realistic, according to Fauci.
“We have monoclonal antibodies — broadly neutralizing antibodies — that you can modify genetically to make them last for a very long time,” he said. “If you can get passive transfer of a combination of antibodies that's directed against the virus, we strongly anticipate that you’ll likely be able to stop anti-retroviral therapy and just have a person come in every four to six months for an antibody infusion.” After a year or less, Fauci explained, the person might not ever need further passive antibody transfers.
Immune enhancement treatment, targeting the immune system’s T-cells, is another potential option, although it’s still in the animal study phase. Discovered by University of California, Los Angeles scientist, Scott Kitchen, and his team, the T-cell-based therapy modifies blood-forming stem cells and safely engrafts them in the bone marrow.
The therapy can potentially guard against rebounds by destroying HIV-infected cells that may reappear months or years following treatment.
A study, published in September, focused on macrophage cells, the HIV dormant reservoirs. These reservoirs help the virus survive and later resurface, and typically have higher expressions of long non-coding RNAs (IncRNAs), which are tissues and cell-type specific genes. By genetically modifying IncRNAs in HIV-infected macrophages, scientists may have found “a key switch that the HIV field has been searching for, for three decades,” said Tariq Rana, lead scientist of the study, according to a press release by the University of California, San Diego.
There are also stem cell therapy and gene modification studies to treat HIV, but Fauci explained that “they're so far into the experimental stage that you really can't say anything about their practical use yet.
“It's impossible to give a timeline or to predict whether we'll have a true cure to eradicate the virus from the body. In fact, it is conceivable that it would be impossible to do that.”
But that’s not necessarily bad news; Fauci said that science is, in fact, closer than ever to replacing the daily need of antiretroviral pills. “With modifications, combination with gene therapy and autologous sources, I believe that some kind of cell therapy will impact HIV treatment in the future,” said Hütter.
Gupta, R.K. et al. HIV-1 remission following CCR5Δ32/Δ32 haematopoietic stem-cell transplantation Nature 568, 244-248 (2019) | article