Gene therapy for HIV

01 October 2019

Interview with 

Ravi Gupta, Cambridge University; Michael Pepper, University of Pretoria

HIV

HIV viruses in green budding from a lymphocyte

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Around the world, almost 40 million people are living with HIV. It grows in and progressively destroys the immune system, leaving victims highly susceptible to what would normally be trivial infections. Now, after decades of effort, scientists are finally beginning to cautiously use the C word: “cure” - and gene therapy is likely to be central to the approach they’re taking. Infectious diseases specialist Ravi Gupta from Cambridge University and University of Pretoria physician and molecular cell biologist Michael Pepper told Chris Smith and Katie Haylor about their research in this area. First up, Katie asked Ravi, what does HIV actually target when it gets into the body...

Ravi - So HIV is what we call a retrovirus which means that it infects cells, as many other viruses do, except this time rather than just making copies of itself, it actually integrates into the genes or chromosomes of the individual so it's there permanently.

So this is why HIV is a disease that doesn't go away and could not be cured until recently because of this latent phase that we refer to. Now this happens primarily in white blood cells that are there to protect you. They're called lymphocytes and they have a protein called CD4 and this is a protein that HIV absolutely requires to gain entry to a cell. So that's why it's only able to infect a CD4 positive T cell.

Chris - And by growing in those cells and destroying them in the process, it's going to leave that person with a dwindling population of the cells that are a lynchpin part of the immune system?

Ravi - That's right, CD4 cells orchestrate the entire immune system and so once they start disappearing you get susceptibility to not only infections but cancers.

Chris - And how did you cure, in inverted commas, your patient?

Ravi - We were able to identify an individual who unfortunately due to advanced HIV infection developed Hodgkin's lymphoma which is a recognized complication, because our immune systems defend us against cancer in our everyday lives.

And so this individual had end-stage cancer that was not responsive to any chemotherapy that we used and the only option left for him was a transplant using cells from a donor who was already immune to HIV. And we know that certain individuals are immune.

Chris - Why was that person immune to HIV, the donor person?

Ravi - Around two decades ago, we identified a second receptor or protein that HIV absolutely requires. This is called CCR5. So you need both CCR5 and CD4 for the virus to enter cells.

Chris - So that's sitting on the outside of the cell. It's almost like a stepping stone for the virus to be able to grab hold of and then get into the cell and if that's not there the virus can't invade.

Ravi - Absolutely. And so we realized that around 1 percent of individuals have two mutated copies of CCR5 in their genes and therefore they cannot be infected.

Chris - And hence if you put that bone marrow into your patient and they then build a new immune system from that person's HIV resistant cells, they can't then mount an ongoing HIV infection.

Ravi - Absolutely.

Chris - And that's what you believe has occurred in this patient?

Ravi - That's right. There was a patient who needed a transplant from a donor and for that to work you need to give high doses of chemotherapy to clear the patient's own cells, to allow the incoming cells that are resistant to HIV to then take hold and to populate the blood.

Chris - I suppose Michael that the problem with the strategy that Ravi is outlined here, is that, as he says, only a tiny minority of people naturally have a bone marrow with that particular genetic configuration that's resistant to HIV. So this wouldn't be a practical solution for the 40 million or so people who are currently infected with HIV.

Michael - Absolutely Chris. The problem is amplified here in sub-Saharan Africa where we have a huge genetic diversity. And to find somebody who has an adequate match and is also deficient in CCR5 is really very very difficult. So our approach is to try and engineer cells that we're going to give to patients in order to make them resistant to the virus.

Chris - So it's a similar sort of strategy in the sense that Ravi is putting into a patient a set of cells that are resistant to HIV, albeit from a donor. You're saying “can I take a person's own cells or even get donor cells and change them in some way to make them resistant, so when they go in that person's immune system can be rebuilt from those cells and their own virus can attack them.”

Michael - The idea is to take the person's own cells, engineer them outside of the body so that they don't express CCR5, and then create space in the bone marrow so that when you give them back to the patient they can take up residence and start producing an immune system which is resistant to HIV.

There are many techniques that are being used to do this. One of probably the most topical at the moment is gene editing, to edit out CCR5 from the cells that you're going to give back to the patient. And then there are other techniques, such as the one that we're using, which is to try and prevent the protein from being expressed and therefore the docking element on the surface of the cell would be absent.

Chris - So you're saying you manipulate the cells in a dish, having collected them from the patient. So you've got HIV uninfected cells and you manipulate them to remove from the cell that lynchpin protein that Ravi was talking about, the CCR5 that the virus would normally need to get in, and then you can put those cells back into the person and they then become the source of their immune system?

Michael - That's correct Chris. I think that's the technique that everybody is working on at the moment all over the world. In sub-Saharan Africa the question is going to be one of capacity and of course cost. So it was very exciting to hear Sue and Steve speaking earlier about their approach, which is to directly introduce the material that is going to do the gene therapy into the patient's bloodstream and that either the virus or the DNA would then have its effect on the target cells. And the hope is that in the long run, particularly in this part of the world, that we'll be able to do away with engineering the cells outside of the patient's body, and simply add the virus which is carrying the machinery necessary to engineer the cells or the DNA directly into the bloodstream of the patient.

Chris - Have you got evidence that this will actually work in a patient yet though?

Michael - So we have evidence in mice that have a human immune system, and we can achieve a functional cure in these mice. There are people working in other parts of the world that have done the same thing and there have recently been some publications from other people who've showed that gene engineered cells do persist in the body of people in whom CCR5 has been removed from the target cells.

Chris - Ravi what do you think? Does this sound plausible to you?

Ravi - Certainly I think that the theory is there. The problem that is going to emerge is that without use of chemotherapy to essentially remove existing cells, it's a question of a relatively small number of engineered cells being introduced or being modified. The problem is that HIV can then just go into the cells that have not been modified. And so that's the big problem we have.

Chris - So I guess what you're alluding to is what Michael was saying about making space in the bone marrow. So Michael presumably you've got to give patients bone marrow toxic drugs to wipe out some of their normal bone marrow, to make space for your modified cells to come in. And I should say it's probably a bit of an ethical dilemma isn't it? Because we're quite good at treating HIV with drugs at the moment. And you're saying give people more poisonous drugs and a risky procedure, when they're not actually ill at the moment.

Michael - Hopefully there are agents other than toxic chemotherapeutic agents that will be useful in the future, to open up a niche in the bone marrow. There is work going on in several areas around the world.
But there is an alternative. And that is to use T cells. So you may have heard about CAR  T cells which have been used very successfully for the treatment of leukemia and lymphoma. And people are now moving in the direction of creating CAR T cells that would be used for HIV.

Chris - This is the Chimeric Antigen Receptor T cells it isn't. It's where we modify the cells to endow them with a very specific, targeted, receptor that recognizes one thing we've programmed them to go after.

Michael - That's correct. Should this be successful, it would no longer be necessary to open up a niche in the bone marrow. One would simply remove the T cells from the patient, engineer them and give them back. And these cells are pretty long lasting.

Chris - Ravi? Your thoughts?

Ravi - Yes I think there is huge amounts of effort going into different approaches for modification and of course knocking out various populations of cells. So I think it is a very exciting field at the moment. I think what's incredible is that infectious diseases and cancer, for example, are sharing a lot of technologies and there are more similarities than we ever really appreciated in the past. I think that's a wonderful thing.

Chris - Ravi, we've talked a lot about deleting this CCR5 gene that HIV uses to clamber inside the cells it wants to hit. If you take that away, does that not render a person at any kind of disadvantage or less healthy than people who have that gene? Presumably it's there for a reason.

Ravi - That's a really good question. I think that it's been uncertain for a long time. We postulate that this mutation emerged as a natural or a process of natural selection, potentially because of infectious diseases such as smallpox or one of the other postulated things was the plague.

But for whatever reason this mutation has persisted in the population without apparent deleterious or harmful effects. On the other hand, a recent study published in Nature Medicine suggested that people with the double deletion in both copies of the gene lived on average a year and a half less than those who didn't have it. Which throws into question whether it's going to be safe or not.

Chris - And Michael, returning to the therapies that you're alluding to, both doing these genetic manipulations and putting stem cells in, and also using these CAR T cells, these modified T cells to go after HIV. It sounds wonderful and we know that we can do this for certain diseases, but can we afford it? Because there are 40 million people with HIV. They're not rich people. They're not in rich countries.

Michael - Chris that's the key question for this part of the world, where a large part of health budgets go towards providing antiretrovirals for the 7 million or so people in South Africa that are affected.

Gene therapy is expensive. If you do a health economics analysis though, the cost of HIV is enormous. And I'm not including the cost of the antiretrovirals, I’m including the cost of the complications that arise such as cancer and infectious diseases. The cost to society where we have child-headed households in South Africa, and all of the social complications that come as a result of that.

I think as the procedures become refined, and as we can move to cheaper alternatives, such as for example not having to engineer cells but giving vectors or DNA directly to patients, the cost will come down. And of course the more we do, there'll be economies of scale. And so hopefully that this will bring the cost down.

But I think a case can be made for a once off, fairly costly, form of treatment as opposed to the lifelong cost of someone who is HIV positive.

Ravi - Yes I would echo those opinions because there was a time when people thought antiretrovirals were too expensive for Africa. And things change. So I think that not pursuing certain things in medical science, because of cost, is a mistake. We need to do the best science, to show we can do it, and then deal with the cost.

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