Science Interviews


Tue, 11th Mar 2014

Gene therapy makes cells HIV resistant

Bruce Levine, University of Pennsylvania

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This week scientists announced that they have used gene therapy to modify the immune cells of patients with HIV, to make them much harder for the HIV-1 particles assembling at the surface of an infected macrophage.virus destroy, which should keep patients healthier for longer. Bruce Levine, from the University of Pennsylvania, co-led the study. He explained to Chris Smith how it works...

Bruce - So, this story really begins with a medical mystery at the beginnings of the HIV epidemic and it was discovered that there was a very small percentage of people that were highly resistant to infection with HIV. It turned out that 1% of Caucasians possess a receptor mutation that makes them resistant to HIV infection. So then, you can begin to imagine what if we can recreate this mutation in people and if they're already infected with HIV, we could remove their immune cells and modify them. Now, you're maybe wondering how we do this and this began working with a company called Sangamo in California about a decade ago who developed a type of molecular scissors if you will. And this is a hybrid protein nuclease that can target this gene for CCR5, the receptor that HIV would otherwise use, induce a nick in DNA and then that gene cannot be translated into protein and expressed on the cell surface.

Chris - So, you were taking patients who currently are infected with HIV, taking out the kinds of white blood cells that HIV would normally attack or infect and then subjecting them to this manipulation that effectively cuts a small piece of their DNA away which removes from the cell a marker, this CCR5 marker that HIV would normally need to get into those white blood cells.

Bruce - That's exactly right. This is a type of cellular engineering and the patients on this study had their white blood cells collected in the laboratory that one normally uses for collecting stem cells for stem cell transplants. We get a bag of white cells, we take it to the lab, we add the DNA and coding for this protein nuclease to induce the mutation in this gene, grow the cells up, freeze them, test them, and then they're reinfused. I think what's really remarkable about this technology is that it is so specific. It can target the one gene. In fact, the part of the one gene out of the 25,000 genes and the entire human genome.

Chris - So, you're able to turn the cells that you manipulate into cells resembling someone who is hard to infect naturally with HIV. You then put the patient’s own cells back into them. What happens to those cells when they go back into the body? Do they survive in the long term?

Bruce - So, we think that they will. We have a limited time of follow up of a couple of years for the first patients treated in this trial. We can track the gene edited cells compared to the other cells, and under conditions of removing the patients from their anti-retroviral drug therapy under a supervision for 12 weeks, we can see a selective advantage for the gene edited cells that lack that receptor that HIV needs compared to the unmodified cells.

Chris - I see. So, you take patients off their treatment and see what happens, how their cells fair when they're not on any HIV drugs and these cells that you've modified appear to be less vulnerable to being attacked, which is what you would’ve expected to happen, isn’t it?

Bruce - That's exactly right and over the past 10 years that we’ve been working with Sangamo, we did a whole series of laboratory experiments and animal experiments to show that we could do this in the laboratory. And now that we’ve been able to demonstrate that we can do it for the first time in humans, it really bares out the original hypothesis which is that we could recreate this naturally occurring mutation and use it as a potential therapy for people already infected with HIV.

Chris - Why don't the viruses mutate to get around the adaptation that you've made?

Bruce - Well, that's a good question. It appears that this receptor CCR5 is by far the predominant receptor that HIV uses. There are a couple of other receptors that HIV can use, but it’s very uncommon for these other types of HIV to be transmitted. Now, the next part of the strategy then is to look at knocking out these other receptors and we have laboratory studies underway to do that.

Chris - How would you actually use this sort of approach? Would you take patients who have HIV, take some blood cells from them, give them this sort of treatment, and then every time the patient’s own cells drop a bit because the virus is attacking the cells and making them disappear, you would infuse some more?

Bruce - Well, we may only have a need to do a few infusions or maybe even one infusion because these gene-edited cells do have this selective advantage. Now, we need to do a lot more work and more patience to determine that, but we have data from other gene therapy studies that we’ve done in HIV that modified cells can persist for years. We’re hoping that that would be the case with this type of approach as well.

Chris - Is it safe?

Bruce - It appears to be safe so far. But again, this is a first in human study. We published the results of 12 patients. There are other ongoing clinical trials, but still, a small number of patients. I think in the long term, we have to see what the data will show but in this early studies, it does appear to be safe and feasible.


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This treatment was also discussed on TWiV 278 yellowcat, Thu, 3rd Apr 2014

This sounds very similar to the Timothy Ray Brown (Berlin Patient) who required a bone marrow transplant for leukemia. 

The doctors located a donor match who was CCR5 negative.  Now several years post-transplant, he has been considered "cured" of both Aids and Leukemia. 

So, the gene therapy has to be a subtractive gene therapy, essentially removing the CCR5 gene, or making it non functional. 

I suppose the question is how long the T cells live, and how new ones are formed.  If the body continues to make T-cells that are capable of being infected, then the infusion of a small number of disease free cells may help prevent symptoms, but may not actually cure the disease.

If a person had both CCR5 positive and negative cells in their body, would there be a risk of developing a mutation that ignores this receptor, and then spreading it into the general population? CliffordK, Thu, 3rd Apr 2014

Blood cells are formed from bone marrow - the excess of white blood cells in leukemia comes from mutated cells in the bone marrow.
Before doing a bone marrow transplant, the existing bone marrow is killed (eg with radiation), and then the donor's bone marrow is injected.
After that, the patient's T cells will have the same genetic expression as the donor's DNA (which resists HIV), not the recipient's DNA (which is susceptible to HIV). evan_au, Thu, 3rd Apr 2014

Yes, in a marrow transplant, one ablates the original cells and introduces all new cells.  However, a marrow transplant is a brutal, dangerous procedure. 

I think the idea in this experiment is to modify people's T-Cells ex-vivo to not express the CCR5 marker, then reintroduce those cells, without doing anything to one's existing T Cells, or the marrow where they are generated.

RBCs, of course, have a short lifespan, but I believe the WBCs have a much longer lifespan, perhaps years or decades. CliffordK, Fri, 4th Apr 2014

This treatment just treats a population of T4 cells not the cells in the bone marrow, I understand that T cells, when stimulated by antigen can divide and increase. New T4 cells will still me made in the bone marrow and these could still be infected by HIV.
I presume that this treatment would need to be repeated at intervals, or that bone marrow be treated, but that would be a much more difficult and risky procedure. yellowcat, Fri, 4th Apr 2014

The difference between the study discussed above and the patient in Berlin "cured" of HIV is that the Berlin patient underwent allogeneic (from another individual) bone marrow transplantion necessitated by a diagnosis of lymphoma. In his case all of his CD4 cells post-transplant were derived from the new donor marrow stem cells; as these were CCR5-delta-32, they were resistant to HIV infection.

In the present study, patients are receiving their own cells back in a manipulated state with the CCR5-delta-32 gene excised. The result is mixed clones of CD4 cells that lack CCR5, making them also HIV resistant. These cells co-exist alongside the native (unmodified) cells. As the study authors speculate, this may be all that is required for long term good health.

Chris chris, Mon, 7th Apr 2014

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