There are already three people in the world who have defeated the HI virus. After the Berlin patient Timothy Ray Brown and the London patient Adam Castillejo, the journal Nature has just published the third similar case of HIV remission after a stem cell transplant. This is the so-called Düsseldorf patient, a 53-year-old man whose identity has not been released: he underwent a bone marrow transplant after suffering from leukemia from a donor with a mutation that prevents it, in which the stem cells are found Viruses invade the cells and for four years there has been no antiretroviral treatment and no trace of the virus. Javier Martínez-Picado, researcher at IrsiCaixa and co-leader of the international consortium IciStem that published the finding, is always cautious but firm: “It’s no longer an anecdote. you are three There is nothing definite in medicine and surprises can always happen, but here we can speak of a cure.”
There is currently no cure for HIV infection. It can be controlled and kept in check with antiretroviral treatments, but when the drugs are stopped, the virus replicates again in the body. Except in exceptional cases, it always returns. HIV has, in the words of Martínez-Picado, “three curses”: “It destroys the immune system, integrates into our cells and mutates very quickly,” he laments. All this makes it extremely difficult to eliminate, because it either knocks down the immune cells that have the function of protecting us from external pathogens, or hides inside them in a kind of latency in the so-called viral reservoirs, which prevent it from being destroyed. Its high variability also complicates the search for an effective vaccine for all circulating variants.
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For this reason, achieving a cure for certain patients represents a major scientific milestone in the fight against HIV and opens a window of opportunity for new research strategies to combat the virus. “This article has three virtues: it healed a person, it allows us to maintain the confidence and illusion that we can cure patients with HIV, and it allows us to lay the foundations to make this scalable,” reflects Martínez-Picado, who coordinates the IciStem consortium of IrsiCaixa next to the University Hospital Utrecht (Netherlands).
In 2011, the Berlin patient gave birth to a real cure for HIV for the first time. In 1995 an infection with the virus was diagnosed, Brown suffered from leukemia 12 years later and underwent a peculiar stem cell transplant: in addition to being a match, the donor had a mutation in the CCR5 gene, which is responsible for the virus entering the cells was required. To everyone’s surprise, the patient was cured of the blood disease and HIV infection because the virus disappeared from his body. Brown died in 2020, but not from HIV but from leukemia.
What was thought to be an anecdote, an isolated case, was replicated with the London patient: in 2019 it was published in the journal Nature that a man who had had HIV since 2003 was diagnosed with Hodgkin lymphoma a decade later and underwent bone marrow surgery in 2016 was transplanted from a compatible donor and also with the CCR5Δ32 mutation, which prevents the virus from entering the cells. Castillejo has been without antiretroviral treatment and free of the virus for five years.
The case of the new Düsseldorf patient is very similar to that of his predecessors: he was diagnosed with HIV infection in 2008 and started antiretroviral therapy; However, in 2012 he was suffering from acute myeloid leukemia and had to undergo a bone marrow transplant, so they looked for a compatible stem cell donor who also had the CCR5Δ32 mutation. About six years after the transplant, when the hematological disease had stabilized, the antiretroviral treatment was discontinued and since then (four years) there has been no trace of the virus.
A key mutation
In all three cases there is a confluence of HIV infection and blood cancer. Due to the hematological disease and after exhausting all therapeutic options, doctors decide to have a bone marrow transplant from a compatible donor. To kill two birds with one stone, the donor not only has the compatibility, but also this strange mutation, found in only 1% of the European population, that prevents the virus from entering cells. “There’s a protein, CCR5, that’s normally expressed in the body’s cells, but it’s not expressed in people with the mutation. In order to enter cells, the virus has to open two doors, the CD4 molecule and the CCR5. If CCR5 is not expressed, the virus cannot open this door and enter the cells,” explains Martínez-Picado.
With the transplantation itself, the recipient’s entire immune system is also wiped out and completely regenerated with the donor’s cells. “As a result, the virus reservoir of the patient disappears. It’s not that it’s not there, we don’t see it,” said the IrsiCaixa researcher. There is also a phenomenon that occurs in this type of transplant that could favor the success of HIV elimination: graft-versus-host syndrome, explains Martínez-Picado. “Pre-chemotherapy to eliminate diseased lymphocytes kills almost everything, although some cells are difficult to eliminate. But when the transplant is complete, the donor’s cells “destroy the remaining blood cells of the recipient,” knocking out any cells still hidden that are infected with the virus. “Whenever there is this reaction, we see a good prognosis. This is called the graft-versus-reservoir reaction,” says the scientist.
By adding the mutation to the equation of this transplant, when the immune system is regenerated, the cells are resistant to the virus. Patients could actually be reinfected, but the chances are very slim. “It is virtually impossible for them to become infected with a virus that uses CCR5 [como puerta de entrada]. There is a part of the virus that sometimes, instead of opening this door, uses another one, CXCR4, and it is possible that they will be re-infected by viruses that use this door,” emphasizes Martínez-Picado. But the chances are slim.
In the case of the Düsseldorf patient, researchers were able to use increasingly sensitive techniques to examine the presence of the virus in the blood, lymph nodes and intestines. And they found some traces of HIV, but in very small amounts and which they believe does not have the ability to replicate, agrees Martínez-Picado: “We can continue to detect the presence of the virus in some nodes, but I think they can not replicate. Because we know from thousands of antiviral treatment interruptions that the virus comes back a few days after stopping it, and we’ve been here for four years without the virus reappearing in the blood.
Another indirect evidence that no competent virus is around is that specific antibodies and specific immune cells to fight HIV, which are normally activated when the virus circulates, have not been detected. However, the scientists add in the study that “the presence of replication-competent viruses could not be completely ruled out”. Caution is never superfluous, explains Martínez-Picado: “You have to be careful in the scientific field and outside it, because this article will also be read by people living with HIV. We don’t want to send big messages. In addition, we cannot make a transplant scalable for all patients with HIV because it carries a very high risk.”
A transplant is not for everyone
Not everyone who is infected with HIV can receive a bone marrow transplant. In the case of hematological tumors, this procedure is only indicated if other therapy alternatives fail. The technique is very risky and it is unethical to subject patients to these aggressive treatments to get rid of the virus when there are effective and less dangerous antiretroviral drugs available to keep HIV at bay. However, the fact that this method is not directly applicable does not mean that the strategy is not scalable.
Martínez-Picado points out that gene therapy is being studied to modify the cells of people living with HIV: it would involve manipulating a specific population of cells from the person (not from a donor) in the laboratory and reintroducing them into the patient that he had enough cells with this mutation to make it impossible for the virus to replicate.
The investigation continues and the scientific community continues to add cases to the list of patients in remission. Using a similar approach to these three cases described, another one patient in New York and one-fifth of another person from City of Hope Hospital in Duarte, California are about to be released.
Beatriz Mothe, a researcher at the Fundación Lucha contra las Infecciones and a member of the AIDS Study Group (Gesida) of the Spanish Society for Infectious Diseases, emphasizes that the relevance of the Düsseldorf patient study is that “the viral reservoirs and how to lose the immune response”, when the virus goes away. Mothe, who did not take part in the study, acknowledges that the transplant technique cannot be translated into clinical practice, but he is committed to developing strategies that simulate the effect of the procedure. “There are gene therapy strategies that try, but the challenge and difficulty is getting to all the cells in the body and making sure 100% of the cells convert with that mutation” so the virus can’t enter them.
José Alcamí, Director of the Carlos III Health Institute’s AIDS Immunopathology Unit, celebrates the “merit” of the Düsseldorf patient’s study, but stresses that it will have no impact on daily practice: “Like all cases of eradication or cure the we publish are exceptional cases that cannot be extended to practically all patients. It is unethical to perform a bone marrow transplant when it is not indicated by a hematological disease, since the mortality rate of the procedure is very high (more than 40%),” warns the medical specialist, who was not involved in the research, in comments to Media Center Science. And gene therapy to eliminate the CCR5 gene in the cells of HIV patients, as the authors suggest, is still “a distant goal,” Alcamí says.
In this sense, Pere Domingo, head of the infectious diseases department at the Sant Pau Hospital in Barcelona, who also did not intervene in the research, insists that while the study “has value and follows in the wake of the other two patients” and , Indeed, “it is very spectacular, attractive and inspiring”, gene therapy is very complex and “barely applicable for the majority of patients”.
Elite Driver
Aside from the case of these three patients who were cured after the transplant, the scientific community is also following two other profiles of patients who managed to self-control the virus without medical intervention. They are, for example, the so-called elite controllers, a handful of people in the world who have contracted the infection but, because of their particular immunological properties, are able to control the infection themselves without the need for antiretroviral treatment or clinical mediation. There is also another group, known as post-treatment controllers, who after a period of antiviral treatment stopped their medication and the virus did not come back.
Martínez-Picado explains the differences: “These are different things, but everything helps us to understand antiviral persistence: the transplant cases are people with standard diseases that we cure with an intervention; Elite Controllers are individuals who have been monitored for more than 20 years, with no treatment or virus, but whom we have done nothing to control for HIV; Post-treatment controllers are people who have had the virus in their blood for a while, been treated for a while and don’t come back after stopping it.”
All of them will definitely continue to be carefully studied. And the Düsseldorf patient’s confirmation serves as a shock to fuel the search for a cure for HIV. The man, who maintains anonymity, has celebrated his story through a statement released by University Hospital Utrecht: “I was diagnosed with HIV in 2008. I still remember what my doctor said: ‘Don’t take it to your chest like that. Let’s experience together that HIV can be cured!’ At the time, I dismissed the claim as an alibi. Today I am even more proud of my global medical team who managed to cure me of HIV and of course leukemia at the same time. On Valentine’s Day this year, I celebrated the 10th anniversary of my bone marrow transplant: my donor was the guest of honor.”
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