Is a cure for HIV in sight?

Since the virus that causes AIDS was identified over 40 years ago, finding a cure has been the holy grail of HIV research and the army of scientists conducting it.

While antiretroviral (ARV) therapies are extending lives and keeping HIV at bay, and PrEP has the potential to effectively halt transmission of the virus, a cure has remained elusive. That’s because the HIV virus itself is elusive, both co-opting the immune system and hiding from it.

But new discoveries are putting the goal of a cure within reach, according to Dr. Luis Montaner, D.V.M., D.Phil, and the director of the HIV Cure and Viral Diseases Center at the Wistar Institute.

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Montaner doesn’t foresee a “magic bullet” for the job, but a combination of approaches, just like antiretroviral therapy. “One doesn’t work, but three do,” he says.

He spoke from the Wistar Institute’s offices in Philadelphia to explain.

LGBTQ Nation: I’m going to put you on the spot right out of the gate and ask: When will there be a cure for HIV?

Dr. Luis Montaner: I’m certainly confident that we’re going to have a breakthrough within my career, and I have a good 10 to 15 years left.

We’re really kind of landing this effort with the progress we’ve made to date. If you think about it like landing a plane and you’re going at 30,000 feet, and you’re then going down towards the runway, and you’re seeing the runway ahead, I think that we see the runway now much clearer than we did, say, five or 10 years ago, and it’s been because of the investment that’s been made.

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If you think about the cure-directed research activities that have been supported, both in the U.S. and internationally, over the last 15 years, they’ve really been an exponential investment, and that has resulted in a lot of activity in understanding the dynamics of persistence. Why does a cell persist without dying in the context of being infected by a virus? How does the immune system deal with clearance, and what are new strategies that have emerged that empower the immune system, when the immune system itself cannot deal with it to better clear it?

I think the only component where we need a clear breakthrough is with respect to how to expose an infected cell. I think that that still remains an area of active investigation by all of us, and by all of us, I mean independent groups that are looking into this question and specific approaches to try to accomplish that.

We have now a whole inventory of strategies to empower the immune system to clear an infected cell, but we still want to identify a strategy that can effectively expose a cell as infected. I’m quite confident that if we continue the investment, the outcome would be successful.

There have been about a dozen cases, by my estimate, where people with HIV have been declared virus-free. Is that an accurate description, and how did they get there?

Yes, you are correct. But in all these cases where individuals were viremic and therefore subsequently identified to be virus-free, all had included interventions that removed their immune system—their circulating immune system — and replaced it with a transplant with cells that are less fit to sustain infection.

That really proved a couple of important points. One, that tissue would not still be a source of virus in the blood. And second, the ability of a new immune system to not be compromised by mechanisms that we don’t yet understand. That did not happen either.

So that means that the dynamic of infection, as we understand it, holds true: that the virus needs certain steps to get in, and there’s nothing in the body that would sort of bypass that.

How does HIV work in the body, and what are the qualities of the virus that have made a cure so elusive?

Evolutionarily, the HIV virus gains from the same machinery that the immune system uses to respond against an infection. In the same manner that the immune system controls the virus, the virus uses it to persist. So, it’s sort of a central player in the cascade of activation that will follow an immune activation event.

You could think about it like material in a non-lending library. You have to make copies of it in the photocopier if you want to get the material out. As a retrovirus, HIV makes itself from a copy to an original. It goes backwards, and it does so in a very sloppy manner, and that has benefited it evolutionarily, because it means that if it can make a lot of mistakes, because of the nature of how it replicates, it can afford to survive as it gains from the immune activation event.

Because the immune activation event is going to home into a particular component of the virus to try to control it. And the virus needs that because it actually wants to replicate in the context of immune activation. So how does it gain from the activation, while at the same time not sign its death warrant?

Because, the way that it replicates, it goes back to an original, so it can always pressure itself to make a component that could be one step away from what the immune system is responding against. And because the viral replication is a day or less, and the immune system takes more than a day to respond, it’s always going to be days ahead of the immune system.

Now, the other component that it has, which we still don’t understand and is part of what drives this need to come up with strategies to reactivate it or expose it, has to do with immune memory. How does our immune system remember everything that we have been exposed to, and how do we regulate that whole system within ourselves to be sustainable for years on end? Meaning that, “I was exposed to this infection when I was 15, and I’m now 50, and I still have immunity against it.” We don’t really understand how that happens.

Somehow, HIV is able to persist in that same system. We refer to that as a reservoir, or an infected cell that can persist over time.

The old dogma was that if any T cell gets activated to divide, then it must make virus, and if it makes virus, it must die, or it must be detected by the immune system.

But all of a sudden it became clear that, no, there’s a subset of cells that appear to divide, not make a virus, and not die. How does that happen? Obviously, the cells that you have today are not the same cells that you had, say, two years ago, right? Just like it’s not the same cells in the top of your nail. Cells that you had two years ago, you replace them.

So, how do you retain memory from one year to the next if you have to generate new cells? There must be a system that we use naturally to divide without activation, and the virus appears to have hijacked that system because it can integrate and divide together with it.

So that’s the other component that it has. It has the component that I described earlier, which is how it can expand and yet survive as it infects initially, but once it gets through the door, then it has a secondary mechanism to persist by just becoming part of the immune system.

I think that answers part of my next question, which is that antiretroviral drugs, or ARVs, have been available for years for people with HIV, and they’re keeping them healthy. Why aren’t those drugs enough to produce a cure?

For the reasons that I just highlighted. All the drugs target the steps outside of the nucleus coming in. But the nuclear component, we don’t have any drugs for that.

So with all of that said, what are the most promising avenues to a “cure” for HIV? Do they take similar approaches? Are they radically different?

I think that the beauty is in the diversity of approaches, because I think everyone acknowledges that there’s not going to be a magic bullet, but a combination, just like antiviral therapy. One doesn’t work, but three do, because they all target potentially different components.

I think there’s several things that are really exciting.

The first is the discovery that there are antiretroviral regimens that could promote cell death of an infected cell, and that’s basically an intrinsic outcome of the drug and the infected cell.

Now, a lot of these drugs don’t kill 100% of the cells, so understanding what drives those that persist is going to be important. But still, it’s a process that we can build upon, because it doesn’t require immunological selection that the virus can escape from. So that’s one.

The second is lipid nanoparticles as a therapeutic strategy to deliver genetic information to cells.

That has opened up a lot of opportunities to identify an infected cell and deliver a cargo that may clear it, or identify cells that you want to empower with specific properties that then become antiviral. I told you that reactivating HIV to identify it was a major goal. So now there are lipid nanoparticles that you can actually package with a protein from the virus itself that can drive that.  

The third is gene therapy approaches as a whole. The expansion of gene therapy for cancer continues to open up new opportunities for HIV cure-directed research. For example, being able to empower certain T cells with enough viral detection strategies that the virus cannot mutate against them.

Another development, which is really exciting, is this acknowledgement that we can identify the virus that is not controlled by your own immune system.

And why is that important? Because if we can identify the virus that your immune system doesn’t yet control, we can try to empower the immune system while someone is on antiretroviral therapy to that virus, specifically, as opposed to the virus that you already control.

Because the virus has a one-day life cycle, and the immune system takes a lot longer, it’s like trying to catch a moving train. If you could actually stop the train with antiretroviral therapy and be able to design a strategy against the front end of the train, then by the time you get the train to restart, you would already be waiting for it with something that can control it.

If you have a million trains, and you don’t know which train you have to empower your immune system against, then you would be shooting blanks most of the time, right? But if you can identify the one train that you know has the probability to move forward and ignore the other ones because your immune system already controls them, then you would maybe have a better shot. And that has been a recent development as well.

So I think the future looks bright as far as a cure. I think we just need to not lose sight of the fact that we have invested so much.

It’s almost like being at a slot machine, and you’ve put all these quarters in, and you’re about to hit the jackpot, but there’s somebody saying, “All right, well, you’ve been at it long enough. Get out, and go to another machine,” and you’re like, “No, no, I’m staying at this one.”

I’m arguing we have to wait for the payout. We don’t get up from the chair until we finish the job.

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