Second Berlin patient has unusual immune response that seems to have removed his HIV

At the 20th European AIDS Conference (EACS 2025) in Paris last week, delegates received an update on a case of an apparent cure of HIV infection that was first presented at the 2024 International AIDS Conference in Munich.

The ‘second Berlin patient’ received a stem cell transplant in late 2015 that cured the acute myeloid leukaemia he was suffering from. It also appears to have cured his HIV infection, as he has now been off antiretroviral therapy (ART) for seven years without his HIV reappearing. Researchers have found no DNA in his cells capable of giving rise to new virus, and his antibody response to HIV is fading, indicating there’s no virus for the immune system to respond to.

Up until now, however, nothing has been presented on how his body’s response to the stem cell transplant and to his HIV somehow achieved this feat.

At EACS, a partial answer was provided: he had so-called natural killer cells from his innate immune system with an unusual genetic profile, which prompted the development of a set of antibodies that were exceptionally efficient in seeking out and destroying whatever HIV-infected cells were left in his body after the stem cell transplant.

Professor Michaela Müller-Trutwin of the Institut Pasteur in Paris, an expert on how the immune system responds to HIV, spoke about the case at EACS 2025.

“Although the antibodies generated by this patient were rather specific to his particular strain of HIV, they were very potent – better at neutralising infected cells than other broadly neutralising antibodies,” she said.

“If we could induce the innate immune response to HIV seen in this patient in others, it would broaden our repertoire of approaches towards a possible cure.”

Previous cases of cure

The second Berlin patient is now the seventh case of a person cured of HIV by means of a stem cell transplant. This number excludes two women who seem to be cases of spontaneous cure, and also some people who are in long-term remission from active infection following experimental immunotherapies.

One of these people, Johan Marais, received a single dose of two broadly neutralising antibodies (bnAbs) in the RIO study and spoke at another session at the conference. His HIV has not reappeared for four years now, without him having to take ART.

Other cases of HIV cure have been in people who needed stem cell transplants as a second-line therapy for cancer. Stem cell transplant is a complex and risky procedure as it involves essentially deleting much of a person’s immune system and replacing it with another, so it will never be a cure for all. But it has yielded valuable insights into how such a cure might be achieved.

The first ever cure was achieved when the doctors treating Timothy Ray Brown, an American then living in Berlin (and so the first ‘Berlin patient’) had a flash of inspiration: what if they replaced his stem cells with cells from a donor who had cells that were naturally immune to HIV?

About 1-2% of people with northern European ancestry carry cells that lack the CCR5 co-receptor that’s essential for HIV from another person to get into the cell. Such people are said to be ‘homozygous’ for a mutation called delta-32 which deletes the CCR5 gene; this means they have inherited the mutation from both their parents.

Although Brown’s transplant nearly killed him at the time, ultimately it enabled him to live for 13 years more without HIV. Since then, however, there have been three cases of people where a cure has been achieved using a stem cell transplant from people not naturally immune to HIV. In one case, the ‘Geneva patient’ announced in 2023, the stem cells came from a donor with no delta-32 mutation.

In two others, the ‘New York patient’ announced in 2022 and this second Berlin patient, the transplant was with cells partially resistant to HIV. In the New York case, cells from two donors, one with and one without delta-32, were combined.

In the present case, however, both donor and recipient had what’s known as ‘heterozygous’ stem cells – those inherited from one parent had the delta-32 mutation, but those from the other parent did not. People who are heterozygous form about 16% of the northern European population. Their single copy of delta-32 means they can still be infected with HIV, but they tend to have lower viral loads off therapy and their CD4 cell counts decline more slowly.

The second Berlin patient’s cure

This may have been a key factor in the second Berlin patient. He was diagnosed with HIV in 2010 and at the time had a viral load of about 13,000. Over the next four years, however, his viral load declined to about 1600 without him having to take ART.

His CD4 count, however, declined at the same time from 1000 to about 400, so in early 2015 he started ART. Less than six months later he developed leukaemia and underwent a stem cell transplant.

His doctors tried to find a donor that was homozygous for delta-32, but could not locate one, so the decision was made to use cells from a heterozygous donor. The patient remained on ART until September 2018. At that point, with assays failing to find any HIV DNA in his cells, the decision was taken to stop ART and he has now been off ART, with no sign of HIV, for seven years.

At the Munich conference last year, Professor Christian Gaebler reported that the patient achieved unusually rapid tropism – full replacement of all the old stem cells with the new ones within a month. But Gaebler could not find an antibody or CD4 cell response that explained how his ‘reservoir’ of HIV infected cells had been completely eliminated. More details from the Munich presentation can be found on the POZ website.

How did it happen?

Here we need to very briefly explain the three branches of the immune system. The cellular immune system, whose protagonists are the CD4 and CD8 cells or T-cells, are able to detect virally infected cells and destroy them. The humoral immune system, whose primary actors are the B-cells, generate huge amounts of the protein molecules called antibodies, which either physically block viruses and other pathogens from infecting cells, or alert the T-cells to destroy them. Both cellular and humoral immune cells are able to ‘remember’ the genetic hallmarks of pathogens so that subsequent attacks by the same pathogen can be quickly blocked (that’s how vaccines work).

The third branch, the innate immune system, is evolutionarily older, faster acting, and less specific than the other two branches. It does not (or so we thought) remember specific pathogens, but instead responds to general distress signals, speeding white blood cells to sites of tissue damage and infection, where they mount the classic inflammatory response.

Its three types of cells, neutrophils, monocytes and natural killer (NK) cells, either engulf pathogens or, in the case of NK cells, kill off infected cells in the same way that CD8 cells do.

At EACS 2025, Timo Trenkner, a researcher at the University Medical Centre Hamburg-Eppendorf, said that there were several reasons that might favour an HIV cure occurring in a stem cell recipient like this patient.

The first might be that both patient and donor might have HLA (human leukocyte antigen) genes that were particularly associated with sluggish HIV replication and spread, and NK cells that were especially responsive. HLA genes govern the signals that infected cells give out when they are infected – some are over-responsive and others only respond slowly (which is a good thing in HIV infection as it slows down the spread of viral infection through the immune system).

But neither the second Berlin patient or his donor had HLA genes or NK receptors typical of slow progression.

The second reason might be that the second Berlin patient’s NK cells might be of a subtype that was especially helpful in enabling a strong cellular immune response to HIV. Trenkner’s team was particularly looking for a signal that his NK cells had a particular combination of receptors called NKG6A⁺/CD57. The NKG6A⁺ receptor acts as a so-called immune checkpoint inhibitor, which means that it stops CD8 cells from committing ‘cellular suicide’ and prolongs their cell-killing abilities. CD57 moderates this activity; an uncontrolled CD8 response is harmful (and is what kills people in the case of some viral infections), but one that is ‘just right’ can defeat an infection.

But no, the second Berlin patient did not have NK cells with especially high levels of NKG6A⁺/CD57. Instead, they were high in another receptor called NKG2A⁺. The action of this receptor is less well understood. Michaela Müller-Trutwin says: “The data on NKG2A is mostly unpublished as yet. Normally, cells that develop the NKG2A receptor are inhibited from killing virus-infected cells. But in this case, they might be the ones that have killed this patient’s infected cells.”

The expression of NKG2A on NK cells acts as a director of a process called ADCC. This stands for antibody-dependent cellular cytotoxicity, and is the sort of thing a vaccine researcher would want to see; it means that the NK cells are stimulating the formation of antibodies to the pathogen they want to get rid of, in a kind of cross-talk between one department of the immune system and another.

This, it turns out, is what had happened. Trenkner and colleagues devised an assay which incubated the second Berlin patient’s NK cells with antibodies. It turned out that when antibodies were sensitised to the patient’s HIV by being exposed to his NK cells, they became extremely good at neutralising gp120, the envelope surface protein of HIV.

In fact, they were better at doing this than bnAbs that have been used in cure and prevention studies. They were also better at doing this than bnAbs from five different ‘elite controllers’ who control their HIV viral loads spontaneously off ART (but can’t be said to be cured).

Michaela Müller-Trutwin thinks that the fact that the patient both had, and received, cells that were CCR5-heterozygous, and therefore was already partially moderating his HIV viral load, may have been a key factor.

“It looks like a high viral load overwhelms innate immunity. But in people that may already have some, but not a lot, of virus in their blood, it may give the innate immune system a chance to mount an effective response.

“There’s still a lot we have to learn about innate immunity – it appears, for instance, that a subset of highly differentiated NK cells can, after all, remember viral antigens [components].

“In this case, they may have educated to kill.”

The role of NK cells in curing HIV is receiving a lot of attention at present. They are implicated, for instance, in ‘pruning’ the proviral DNA in reservoir cells so that, over time, the DNA ends up largely being located in ‘gene deserts’ where viral activation is much less likely. If the particular kinds of NK activity that govern these processes could be encouraged, we might be closer to developing a generalisable, non-toxic cure.