There are already three people in the world who have defeated HIV. Following the so-called Berlin Patient, Ray Brown, who was the first person to beat the virus, and the London Patient, Adam Castillejo, the scientific journal Nature has just published the third case. Similar to the previous ones, HIV remission took place after a stem cell transplant. The third person, known only as the Düsseldorf Patient since the 53-year-old man’s identity has not yet been revealed, underwent a bone marrow transplant after being diagnosed with leukemia. The stem cells were from a donor who had a gene mutation, which prevented the virus from penetrating cells. Since the transplant four years ago, he has not had any antiretroviral treatment and has been virus-free.
Javier Martínez-Picado is a researcher at the IrsiCaixa AIDS Research Institute in Barcelona and co-leader of the IciStem Project, the groups that published the findings. He is cautiously optimistic about the third patient. “It’s no longer an anecdote: there are three. In medicine, nothing is categorical and surprises can always arise, but [in this case], we can talk about the [possibility] of a cure.” HIV is currently incurable. It can be controlled and kept at bay with antiretroviral treatments. However, if the medication is stopped, the virus replicates again in the human body. Except in very exceptional cases, it always comes back. In the words of Martínez-Picado, HIV “destroys the immune system, integrates into our cells and mutates very quickly.”
All of this makes its elimination enormously difficult. The virus either strikes down the immune cells that are supposed to protect us from external pathogens, or it hides within them, in a kind of latency state in the so-called viral reservoirs, which prevent it from being destroyed. HIV’s great variability also complicates the search for an effective vaccine that can treat all circulating variants.
For this reason, being able to cure certain patients represents a great scientific milestone in the fight against HIV. It opens a window of opportunity towards new research strategies to strike down the virus. “This [research] article has three virtues: it is proof that a person has been cured, it allows us to maintain hope that we can continue to cure patients with HIV, and it allows us to lay the groundwork to make this scalable,” Martínez-Picado said.
In 2011, the Berlin Patient was the first hope of a real cure for HIV. Diagnosed with the virus in 1995, Brown was diagnosed with leukemia 12 years later. He underwent a peculiar stem cell transplant: apart from being a match, the donor had a mutation in their CCR5 gene, which prevented the HIV virus from penetrating cells. To everyone’s surprise, the patient was cured of the blood disease and HIV. The virus disappeared from his body. Brown passed away in 2020, but from leukemia, not from HIV.
What was supposed to be an isolated case was replicated with the London Patient: in 2019, Nature published a study about a man who had been HIV-positive since 2003. He was diagnosed with Hodgkin’s lymphoma a decade later. But, in 2016, he underwent a bone marrow transplant from a compatible donor who also had a CCR5 mutation. For the past five years, Castillejo has been living without antiretroviral treatment . He, too, is virus-free.
The case of the new patient from Düsseldorf is very similar to its predecessors: he was diagnosed with HIV in 2008 and began antiretroviral therapy. In 2012, however, he was diagnosed with acute myeloid leukemia and had to undergo a bone marrow transplant. The surgeons looked for a compatible stem cell donor who also had the CCR5 gene mutation. About six years after the transplant – when the hematological disease had stabilized – the antiretroviral treatment was withdrawn. Now, four years later, there is no trace of HIV in the patient.
A key mutation
All three cases involve HIV infection and blood cancer. Because of the hematological disease, and after exhausting all therapeutic tools, the doctors opted for a bone marrow transplant from a compatible donor. To kill two birds with one stone, in addition to being compatible, the donor has that rare mutation, present in just 1% of the European population, which prevents the virus from entering the cells. “There is a protein, CCR5, which is usually expressed in the body’s cells, but in people with the mutation it is not expressed. The virus, in order to penetrate the cells, needs to open two doors, the CD4 molecule and CCR5. If CCR5 is not expressed, the virus cannot open this door and penetrate the cells,” Martínez-Picado explained.
With the transplant itself, the entire immune system of the recipient is wiped out. It is completely regenerated with the donor’s cells. “This makes the patient’s viral reservoir disappear. It’s not that it’s not there – it’s that we don’t see it.”
There is also a phenomenon that occurs in this type of transplant that could favor the successful elimination of HIV: graft-versus-host syndrome, explains Martínez-Picado. “With the previous chemotherapy [treatments] to eliminate the diseased lymphocytes, almost everything is killed, although some cells are difficult to eliminate. But when the transplant is performed, the donor’s cells destroy the recipient’s remaining blood cells,” so that any hidden cells still infected by the virus are killed. “Whenever there is this reaction, we see a good prognosis. It’s called a graft-versus-reservoir reaction,” the scientist said.
By adding the mutation into the transplantation equation, when the immune system regenerates, the cells are refractory to the virus. Patients could, in fact, be reinfected, but the chances are extremely low. “It’s virtually impossible for them to be infected by a virus that uses CCR5 [as a gateway]. There is a portion of viruses that, sometimes, instead of pushing that gate, use another one, CXCR4, and it is possible that they could be reinfected by viruses that use this gate,” Martínez-Picado pointed out. But the probabilities are low.
In the case of the Düsseldorf Patient, researchers were able to study the presence of the virus in blood, in lymph nodes and in the intestine, with increasingly sensitive techniques. And they found some traces of HIV, but in very small quantities and they consider that they do not have the capacity to replicate, according to Martínez-Picado: “We can continue to detect the presence of virus in some lymph nodes, but I believe that they cannot replicate. Because we know, from thousands of interruptions of antiviral treatment, that the virus returns within a few days of stopping it. And in this case we have gone four years without seeing the virus reappear in the blood.”
Another sign that the virus cannot resurge is that specific antibodies and immune cells that can fight HIV – which are usually activated when the virus is circulating in the human body – have not been detected. In the study, however, the scientists caution that “the presence of residual replication-competent viruses could not be completely ruled out.”
Martínez-Picado agrees with this prudent approach. “You have to be careful in the scientific field and beyond, because this article is also being read by people with HIV. We don’t want to send [grandiose] messages. Also, we cannot make a transplant scalable to all patients living with HIV, because it has a very high risk.”
The transplant is not for everyone
Not everyone with HIV can receive a bone marrow transplant. This procedure is only prescribed for hematological tumors when other therapeutic alternatives fail. The technique is very risky. It’s unethical to subject patients to these aggressive treatments to get rid of the virus, as there are effective and less dangerous antiretrovirals that keep HIV at bay. But the fact that this method cannot be applied directly at the moment does not mean that the strategy is not scalable in the long-term.
Martínez-Picado pointed out that gene therapy is being researched as a means to modify the cells of people with HIV. This would involve manipulating a specific population of cells from the patient (not from a donor) in a laboratory and re-infusing them into the patient. This would allow for sufficient mutated cells to exist, making it impossible for the virus to replicate.
The scientific community continues to add cases to the list of patients in remission. With an approach similar to the three cases described, another patient in New York and a fifth in the City of Hope Hospital in Duarte, California will be the subject of forthcoming articles.
José Alcamí – director of the AIDS Immunopathology Unit of the Carlos III Health Institute in Madrid – celebrated the “merit” of the study of the Düsseldorf Patient. However, he stressed that it will not have implications in daily practice. These cases, at least at present, are anecdotal and cannot be extrapolated to the majority of people living with HIV”, he warned, in statements to Science Media Centre. “This is a procedure not without high morbidity and mortality, so it would be unethical to perform it outside the context of treating very serious diseases such as acute leukaemia.” Alcamí – who did not participate in the study – told the Science Media Center that the notion of using gene therapy to mutate the CCR5 gene in patients living with HIV is “still a distant goal.”
The researchers are also closely monitoring two other patients who have managed to control the virus on their own, without medical intervention. These are the so-called “elite controllers,” a handful of people in the world who become infected but, due to their own particular immunological characteristics, have come to control the infection on their own, without the need for antiretroviral treatment or any clinical mediation. There is also another group – known as post-treatment controllers – who, after a period of antiretroviral treatment, stopped their medication and subsequently did not see the virus reappear.
Martínez-Picado explained the difference between the two: “They are different things, but everything helps us to understand antiviral persistence: the transplant cases are people with standard disease that we cure with an intervention. The elite controllers are people who have been followed for more than 20 years, without treatment or virus, but to whom we have done nothing to control HIV. The post-treatment controllers are people who have had the virus in their blood for a while, have received treatment for a while and, after stopping it, the virus does not reappear.”
All of these patients, in any case, continue to be carefully studied, especially after the confirmation of the Düsseldorf Patient, as it has given a boost to the search for a cure against HIV. The man – who is maintaining his anonymity – shared a statement, which was released by the University Medical Center of Utrecht: “I was diagnosed with HIV in 2008. I still remember very well the sentence of my family doctor: ‘Don’t take it so hard. We will experience together that HIV can be cured.’ still remember very well the sentence of my family doctor: ‘Don’t take it so hard. We will experience together that HIV can be cured.’ At the time, I dismissed the statement as an alibi. Today, I am all the more proud of my worldwide team of doctors who succeeded in curing me of HIV – and at the same time, of course, of leukaemia.”He added: “On Valentine’s Day this year, I celebrated the 10th anniversary of my bone marrow transplant in a big way: my donor was present as the guest of honor.”
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