Think Out Loud

OHSU research sheds more light on possible cure for HIV

By Gemma DiCarlo (OPB)
June 6, 2023 5:30 p.m. Updated: June 14, 2023 9:57 p.m.

Broadcast: Wednesday, June 7

Scientists have documented five cases worldwide of people being cured of HIV through stem cell transplants. But researchers aren’t entirely clear on how the method works. New research from Oregon Health & Science University is helping to explain the mechanics behind the potential cure.

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A nonhuman primate study recently found that transplanted stem cells help kill HIV-infected cells by recognizing them as foreign invaders, much like they do for certain types of cancer. Researchers also found that HIV leaves the body in a series of stages, which could explain why some patients appear to be cured, but then experience a recurrence. OHSU professor Jonah Sacha led the study and joins us with more details on what the findings could mean for human patients.

The following transcript was created by a computer and edited by a volunteer:

Dave Miller: This is Think Out Loud on OPB. I’m Dave Miller. Scientists have documented five cases around the world of people being cured of HIV through stem cell transplants, but researchers haven’t been entirely clear how the method works. Now, new research on monkeys at OHSU provides more insight into the mechanics behind this potential cure. Jonah Sacha led the study, he’s a professor at OHSU and the chief of pathobiology and immunology at the Oregon National Primate Research Center, and he joins us now. It’s good to have you on the show.

Jonah Sacha: Thank you for having me.

Miller: I want to start with the big picture here, why you and others are doing this kind of research. How many people are living with HIV globally right now?

Sacha: That’s a great question. There’s currently the most people ever in human history living with HIV. It’s about 40 million people worldwide. And that’s a confluence of quite a few factors. Really, the COVID pandemic really interrupted the access to care that individuals were getting.

Miller: When you say access to care, I’m thinking about the revolutionary, now decades old antiretroviral medications. What have those meant for people who contract this virus?

Sacha: That’s correct, antiretroviral therapy has been amazing because it has prolonged the life of individuals. HIV infection is no longer a death sentence. You can live a relatively healthy and long life with this. And also when given to pregnant women, you could interrupt mother to child transmission.

Unfortunately, like so many things, if you’re in a developing country or you don’t have great access to health care, you can’t really access the antiretroviral therapy and you are able to transmit the virus. And we know for instance that Sub-Saharan Africa is the greatest location of mother to child transmission.

Miller: How did the COVID pandemic affect everything that you’re talking about?

Sacha: It massively interrupted supply chains and access to both care in terms of getting treatment when they’re already infected, and then preventative services.

Miller: But what we’re talking about here is a medication that, and correct me if I’m wrong, can lead to an undetectable viral load. But that’s not the same thing as being cured. But, a few people have been cured of HIV since the late 2000s. Can you tell us about those patients and how they came to be virus free?

Sacha: Absolutely. Currently, we know five individuals, we typically refer to them by the origin of where the cure happened. The first individual that was reported was Timothy Ray Brown, also known as the Berlin patient. He actually has a connection to the Pacific Northwest because he grew up in Seattle. He unfortunately died in 2020 due to relapse of his leukemia. But he was subsequently joined before his death by Adam Castilla, who’s the London patient. And then now more recently we have the New York patient whose identity is unknown, but is the first female who’s been cured of HIV. There’s the Dusseldorf patient in Germany, and then the City of Hope patient. And all of them were cured by a bone marrow transplant from an unrelated donor to treat a cancer.

Miller: So, the idea was not to treat HIV, that was a kind of a beneficial accident because they all contracted cancer after they’d become HIV positive?

Sacha: That’s correct. The physician that treated Timothy Ray Brown at the time he developed a blood cancer leukemia, and the treatment for that is a bone marrow transplant to cure the cancer, but his physician did something sort of unexpected at the time and said “I’m gonna actually try and cure him of HIV as well.” And the way he did this is he selected a donor who lacks a molecule called CCR5. And for some reason that we don’t quite yet understand, a small percentage of individuals of European descent simply lack CCR5. And what it is is it’s a molecule that sits on the surface of our white blood cells and it’s actually how HIV enters our body and infects us. And so individuals who don’t have CCR5 are naturally resistant.

Miller: Meaning if you don’t have that particular gene and you’re exposed to HIV through blood or something, you’re likely not going to contract HIV?

Sacha: That’s correct.

Miller: So this blood marrow transplant doctor said, hey, maybe we can do two things at once?

Sacha: Correct. And at the time, no one thought it was possible. When he first presented these results, no one could really even understand it. It got a poster, it wasn’t even a talk

Miller: That’s kind of an academic dis, right?

Sacha: Absolutely.

Miller: He was at a conference, but he didn’t present to a room of 300 fellow scientists. He was in more like a ballroom where, like a 7th grade science kid, he had a poster.

Sacha: That’s exactly right, tucked away in the corner. And since then we’ve now recognized that there was this absolute earthquake that showed us that yes, you can cure HIV.

Miller: But there’s a huge caveat to that, right? You can cure HIV, but it’s only happened four times since. If this were a true earthquake, why hasn’t it become much much more common?

Sacha: That’s a fantastic question, and that’s actually the purpose of our research. The stumbling block was that while, yes, this provided examples that you can cure HIV, we failed to understand the mechanisms of how. And that’s what our study set out to do.

Miller: Why is that important? I know I’m asking a scientist, I think what drives you is to understand the world, understand the particular corner of it that you’re studying. But if we know something does work, why do we care if we don’t quite know the mechanism?

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Sacha: The reason here is because bone marrow transplantation is a very dangerous procedure that we would never roll out to the general population of these 40 million people that have HIV. But if we understand the mechanisms, the why and the how, we can separate out the dangerous components of that procedure to the beneficial ones to make a safer, more widely applicable approach.

Miller: The dream here is to take advantage of what’s happening in a bone marrow transplant and provide some version of that without actually doing that procedure?

Sacha: That’s exactly correct.

Miller: So let’s turn back to what you did. I mentioned that you work with primates. Why did you choose a specific kind of macaque?

Sacha: It’s a great question. The real power of the animal model that we use is that human population, it’s very outbred, we’re all very different and you can do bone marrow transplants in a population of humans because we have the Be The Match registry, which I would recommend all listeners that haven’t already to participate in because you can save someone’s life. Monkeys are much the same way. They’re very difficult to match.

However, the population that we use, they come from the island of Mauritius, are descendants of what we call a population bottleneck event. About 500 years ago, Dutch spice traders or pirates were sailing in the Indian Ocean, and they actually shipwrecked on the island of Mauritius. And we know that it was one female and about four males on a beautiful desert island, no predators, lots of food. And here we are 500 years later, there’s 100,000 of these animals and they’re sort of inbred, for lack of a better term.

Miller: And so that they could all be donors for each other?

Sacha: For the most part, yes.

Miller: So in the end, you took eight macaques who were the monkey version of HIV positive. And with four of them, you provided a version of this treatment, and the four of them were controls. What happened with the four that had this stem cell transplant?

Sacha: It’s really fascinating. Because we’re able to experiment to control all the variables, we were able to document the stepwise fashion in which HIV, or our SIV, the Simian version of this virus, is cleared post transplant. And these are studies that you could not do in people because you would never be able to control the timing of it.

And what we found is that first HIV is cleared from the blood. And then secondly it’s cleared from lymph nodes, these are little nodules that you sometimes feel on your throat when you have a cold, those are just command centers of the immune system. And then finally, last of all, it was cleared from lymph nodes that drain our digestive tract.

Miller: But what I’ve read is that only two of those four monkeys were cured. So what happened to the two others?

Sacha: So the two others actually did not cure. And that also provided a very interesting example to us because it allowed us to understand that the CCR5 deficiency has to shield the donor cells that come in. The way a transplant works is you take a bone marrow transplant from an unrelated individual and you put that into your body. And that is essentially where the immune system comes from. The bone marrow is where the stem cells live to give rise to all your blood cells. So red blood cells that carry oxygen, and white blood cells, that’s your immune system. And so when you bring someone else’s immune system into your body, it actually can see your own cells as foreign invaders and attack it. And in cancer, that mediates an effect called graft-versus-leukemia. This is actually what cures people of cancer following a stem cell transplantation.

We documented that something similar happens in our setting of HIV, we call it graft-versus-reservoir. And what that is is that in-grafting immune system recognizing the cells that are harboring HIV as just foreign, and killing them. So that’s why those individuals are cured. And the two animals that actually did not become cured, we documented the virus transiting from the cells of the donor into that of the recipient. And that is why you have to have the CCR5 deficiency. We think of this effect of that graft-versus-leukemia, graft-versus-reservoirs as the sword, and the CCR5 not being there as the shield. You have to give your immune system both in order to have a chance to beat HIV and cure it.

Miller: So did this new study actually provide a potential road map for a different version of a therapy that would be easier for a body to handle than a transplant?

Sacha: Yes it does. As with all things in science, it’s going to be a long and winding road. But now that we understand the mechanisms of this, it sort of points us in a new direction, which is the cure is this way, and this is the road you have to walk. And so what we’re going to do now is begin to define what are the actual immune responses that cure people of HIV and cured these monkeys of the virus?

Miller: How long does a person or a monkey have to not exhibit a viral load before you can say as a clinician they are cured of HIV?

Sacha: This is a great question. This goes back to the old adage that absence of proof is not proof of absence. Trying to prove a negative is incredibly difficult.

The standard now is that you cannot detect the virus anywhere in the body in any tissues, that someone would stop antiretroviral therapy and the virus would not rebound for approximately two years, and then the third is that they lose their immune responses against the virus. And so in our study we met all of those.

Miller: So what’s next for you to study?

Sacha: Next, the question is what I was just talking about with the direction that we need to go in, and that is understanding what is special about this response of these grafted in donor cells from bone marrow that allow the virus to be cured. We’re going to use the power of our animal model to begin to understand that, and then we’re actually going to begin working with some of these cured HIV patients to really investigate in them as well, what are the immune responses and what do they look like?

Miller: When you say cured HIV patients, you mean the monkeys?

Sacha: No, in this case I actually mean, for instance, the London patient or the City of Hope patient.

Miller: It’s time to look more into humans themselves.

Sacha: Yes. This is the beauty of where we work, that interface between the pre-clinical and clinical, and they both inform the other. I will say the amazing thing about working with these people living with HIV is that they’re very motivated to participate in these studies to help find a cure.

Miller: Jonah Sacha, thanks very much.

Sacha: Thank you.

Miller: Jonah Sacha is a professor at OHSU and chief of pathobiology and immunology at the Oregon National Primate Research Center.

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