To Norway now, where a 63-year-old man – known as the “Oslo patient” – has become one of only a tiny number of patients to be considered “cured” of HIV. The patient received a bone marrow transplant from his brother who, serendipitously, also carried a genetic mutation – called CCR5 delta 32 – that made his immune cells resistant to HIV infection. The study – published in Nature Microbiology – showed that – 2 years after stopping anti-HIV therapy – the man remains free from the infection. The results, as well as similar findings in several other patients around the world since, are actually making clinicians re-evaluate how we think these sorts of transplants might be curing patients. Historically, we believed that it was the genetic mutation that protected the new immune system. And while that might be a contributory factor, as Marius Troseid, infectious diseases doctor at Oslo University Hospital and part of the team behind the new study, explains to Chris Smith, it’s more likely that the new incoming bone marrow-derived cells attack the existing virus-infected immune system and wipe out the HIV reservoir…

Marius – So the Oslo patient is a man now in his 60s. He was admitted to our hospital because, not because of HIV actually, but because of a bone marrow disease, so a pre-stage to blood cancer, haematological cancer, and he needed treatment for this bone marrow disease. The first line treatment with, you know, cytotoxic or immunotherapy didn’t work, so he needed a bone marrow transplant. So in a bone marrow transplant, you need to get a new immune system from a donor. And when our blood specialists were planning to do this procedure, they also looked for a suitable donor in an attempt to also cure his HIV.

Chris – Tell us more about that, because why would a bone marrow transplant cure HIV?

Marius – So, when the Oslo patient was transplanted back in 2019, there were two cases worldwide having been potentially cured for HIV. These two patients had both received bone marrow transplant with a certain mutation, a certain genetic variant, that alters the surface on the immune cells, and the fascinating thing about this, is this alteration makes it impossible for the HIV virus to enter the immune cells. So there was a search for a donor with this kind of mutation also for the Oslo patient, but it was impossible to find in the registries in Europe. It was decided that he should get a transplant from a suitable donor for his bone marrow disease, and it turned out to be his brother who was compatible with the patient. And on the day of the transplant, it was actually found out quite coincidentally that his brother actually carried this genetic variant, this mutation that locks out the virus from the immune cells.

Chris – So you take someone with HIV, you destroy the immune system they have, and this is also to treat the blood cancer problem. And then you give them back a new immune system using cells taken from a donor, but that donor patient also, in this case, happened to have the genetic change that makes the immune cells impossible for HIV to infect.

Marius – Right. So we believe it’s the new immune system and replacing the old one that is actually, you know, knocking down the virus in the body because HIV, it hides in your DNA. So it really becomes part of your DNA, part of yourself. So you need to kill the immune cells that carries HIV and then replace it with a new immune system. So probably it’s this process that drives down the virus and kicks it out, and then you have this genetic variant or this special structure on the immune cells that also makes it impossible for the virus to enter the new immune system. So it’s like an extra safety belt that keeps the virus out.

Chris – So is that what happened in your patient, that after the graft, after the new immune system comes in, the virus disappears from the bloodstream and has stayed away?

Marius – Yeah. So after the transplant, he was still on antivirus medication for two years. But after two years, there was no detectable virus in blood. We also looked for a virus integrated in the DNA and it seemed to be away. The immune system was restored to normal blood cell counts. So it was decided then to try to stop his antiviral medication and see if the virus rebounded. And after following him two years without any drugs, we did very thorough analysis to really search for any rests of the virus or if his immune system seemed to recognise the virus. It’s not possible to detect any viable virus, so we believe he’s effectively cured.

Chris – And you think then it is the treatment to destroy the existing immune cells that helps, but the incoming immune system, you’re arguing, turns on any vestige of the old immune system, and that also helps to just wipe the slate clean and get rid of any possible reservoir of virus.

Marius – Right. When we started out, we thought there was this genetic mutation that would be key to cure. But after we started working with the Oslo patient, they have in two cases now been cured without this mutation. So we believe it’s actually the new immune system replacing the old one that is key to cure in these cases. We also did very thorough workup on the Oslo patient, doing analysis to see if the new immune system had completely replaced the old one in different organs. I mean, this has been shown in blood and bone marrow previously, but the main harbour for hidden viruses is in the immune system in the guts. The gut really carries the largest number of immune cells in the body, and also there we could show that the new immune system had completely erased the old one.

Chris – It’s obviously impractical to treat 30 million people, the current reservoir in the population of HIV infection, with a bone marrow transplant. It’s also extremely dangerous as an intervention. You have to have some other major life-threatening disorder to balance the risk up, don’t you?

Marius – Right.

Chris – But what does this teach us about the plausibility of using a strategy like this? Or does it give us clues as to how we might be able to cure people of HIV in the future?

Marius – I think first of all, it’s a stepstone together with other cure patients that it’s possible to cure HIV. I think that’s important. I think we have also, with these cure cases, shown that there are probably different mechanisms that could lead to cure. You have this mutation that I talked about. There are probably also the immune reactions against the viral reservoir, which we can try to mimic in different ways. And third, I think we and other cases have also tried to find blood tests that you could take to make it most likely that you’re actually cured for HIV. So it’s everything from measuring the amount of hidden virus in different places in the body, but also to measure the immune reaction towards the virus.