Descriptive Transcript
music // Title card reads Back to Basic Toronto, 2014. Brad Jones. Are we close to cure(s) or remission of HIV? Brad Jones stands alone on the main stage at the Back to Basic conference. An on-screen graphic identifies him as an OHTN investigator and Banting Fellow, Ragon Institute of Massachusetts General Hospital, the Massachusetts Institute of Technology, and Harvard University.
Brad Jones: So, are we closer to a cure or remission of HIV? So, I’ve been asked to give, kind of, an overview from 30,000 feet on this topic. I have to admit, I’m kind of more used to looking under a microscope, but I’ll see what I can do. So, this is, kind of, my perspective has a basic scientist who’s managed to get out of the lab for a day.
So, first of all, why is it hard to cure HIV infection? This is a very complicated question, with a complicated answer, but part of the reason certainly is this issue of latency.
Jones displays a slide containing artist renderings of HIV-infected activated Cd4 T-cells. On the left hand side of the image, is a cluster of live cells. On the right hand side of the image is a cluster of dead cells.
So, when HIV infects normally activated cells, the fate of these cells is that most of them die. Either because the virus kills them, or because the immune system can see them and kill them.
The image on Jones’ slide expands so that a single latently-infected CD4 T-cell peels away from the living cells and avoids the path toward death.
But some of these cells escape this killing, and they go to this latent — this kind of quiescent state, where they can stay in this stasis for decades, and the virus persists. As Dr. Cochran pointed out, it can be reawakened later to receive this infection. So, how are we going to cure HIV?
So, first of all, let’s define cure a little bit.
There’s, kind of, two types of cures that people talk about. First of all, there’s a sterilizing cure. This is where we manage to completely get rid of the virus from the body. So, to do this, we have to purge those latent reservoirs. And this approach, I would say, it’s safe to say, has maximum potential for full restoration of health. If you completely get rid of the virus, it gives your immune system the best chance to fully recover to it’s the best of its ability. And, if the virus is gone, there’s obviously no potential to transmit to partners. There’s no concerns with that. And it’s not clear whether or not that person would then be protected from reinfection with HIV.
On the other side, we have this functional cure, or remission. And the idea here is that we can’t get rid of all of the virus, maybe. But maybe we can teach the immune system to control the little bit of virus that’s left, and people can come off of their antiretroviral drugs. Some of the complications that are involved in this, though, is that the virus, you know, potentially could come back. So there’d be ongoing monitoring of health, ongoing viral load tests, and, you know, people — there’d still be some issues in terms of potential risk to partners, and some of the social issues that you’re all very aware of may still be very important.
So, the path forward, from a basic scientist perspective — okay, this is kind of what the sterilizing cure looks like. It’s not a very easy path to walk.
Jones displays a slide containing two images. The image that represents the sterilizing cure depicts a person climbing the sheer side of a mountain. The peak towers in the distance and the climber is barely able to stand upright using ropes. The image representing a functional cure or remission is a moderate incline through a wooded area. The path is long but looks less daunting.
This is “the chief” in Squamish. My sister’s climbed that, but I haven’t. And then the functional cure might be a bit of an easier path, here. So I think, if, kind of, left to our own devices, as scientists and funding agencies, I think we’re, kind of, going to naturally drift a little bit towards, kind of, the functional cure and remission side, which, you know, might be okay. Maybe that’s where we can really make some progress. But we really want to hear from the community, from the people who are going to benefit from these cures, and, if you think, in particular, that the sterilizing cure, for example, has much, much more value, then I think, you know, you need to, kind of, keep pushing us in that direction. And there are people who are willing to, of course, try to make that that climb for you. We’re always up for challenges.
Okay. So, precedents for a cure. I think many people are aware of these. I’m going to go through them very fairly quickly. You’re all probably familiar with Timothy Ray Brown’s case. So, the Berlin participant, where we had basically wiped out the immune system, and the doctor had the foresight to replace the immune system with cells that had a mutation in CCR5. So, just known to be a resistant mutation that stops a cell from getting infected with HIV.
There’s then the Boston participants that are, kind of, painted as a bit of a setback in the cure field, recently. So, this had some ingredients of the Berlin patient, so these individuals had types of cancers, so they needed to have their immune system wiped out by radiation, and to get a stem cell transplant, but, in this case, the donor cells did not have this resistant mutation. And, what we found is, with this treatment set-up, we were able to get rid of the virus to the point that our most sensitive assays couldn’t pick it up. But, when you took these people off of therapy, the virus still came back, even though, in some cases, it took up to 32 weeks, which is much, much longer than it would normally take. So, the virus can hide out and it’s, you know, it can be, kind of, there even though we can’t necessarily see it. So, that’s, kind of, on the sterilizing side.
On the functional side, some very encouraging data from this Visconti Cohort, which are participants who were infected with HIV and went on to therapy very early with antiretroviral therapy, and then, a few years later, they were taken off of therapy and we were pleasantly surprised to see that about 15% of these people controlled their virus. It’s been several years now without therapy. So, this is compared to about 1% of, you know, just in the general population that is actually controllers. So, the idea is, by controlling the virus early, we can give the immune system a chance to, kind of, keep the virus in check. And this is a nice, I think, precedent for what we’re trying to do with functional cures.
Jones displays a slide containing several line graphs extracted from a paper by Hansen et al. in 2011. The details of the graphs are unintelligible from the audience. The two graphs on the left hand side contain several black lines and a smaller number of red lines. The graphs on the right hand side are overwhelmed by black lines.
Another, I think, very exciting area that I’ll mention is, you know, the Portland monkeys. I don’t know if other people call it that, but I’m going to call it that. Which is this animal experiment where these monkeys are given a vaccine — and this is based on a CMV vector, so it elicits very strong immune responses to SIV, the monkey equivalent of HIV — I’m not sure if I have a pointer here, but, basically, let’s see — no pointer. Okay. So, there’s basically just a few different vaccine regimens and some control monkeys.
The take-home message here is that, if the monkeys didn’t receive a vaccine, you’d have the black lines on the far right panel, here, and the monkeys that the did receive the vaccine are in the other panels. In some cases you can see monkeys that control their viral load completely. It’s basically not detectable, and they go on to actually, it seems, to cure themselves out this infection. So, this is obviously being followed-up on. T-cell responses can cure a retroviral infection, it looks like, under these circumstances, which is, I think, very encouraging. But, in this case, the vaccine is given before the monkeys were infected. So, an important question that’s being asked now is, if the monkeys are infected first and then put on therapy, and then given the vaccine, can that prevent the virus from rebounding when they come off of therapy? Also, is this vaccine safe? It uses a live CMV virus. This is an important issue and, you know, will it work in humans the same way that it works in monkeys?
So, with those precedents moving into some of the, kind of, strategies for cure. You’ve heard a bit about this “shock and kill,” “kick and kill,” — I kind of prefer this “flush and kill;” it’s a little bit less violent — towards these sterilizing or functional cures.
Jones displays a slide containing an artist’s rendering of infected cells, which he describes below. In the image, a latently infected cell becomes productively infected cell, showing HIV on its surface.
And the idea is you use latently-infected cells that are hiding from the immune system. You hit them with something that we call a latency-reversing drug. This gets them to show parts of the virus on their surface — and you’ve seen some nice introduction to how the immune system presents these pathogens like viruses earlier today —
The image expands as a large, HIV-specific cytotoxic T-lymphocyte (CTL) appears and reaches toward the HIV presenting on the infected cell’s surface.
— and this then lets armor the immune system. So, I’m a bit cytotoxic T-cell-centric, but there could be other immune effectors that can then kill these.
The image changes a second time as the infected cell explodes.
Other ways that we can go about trying to cure people is through gene editing. So, can we take CD4 cells out of someone, do something to them so that they’re resistant to HIV — for example, delete this CCR5 gene — put them back into patients, and then they’ll have this, kind of, protected population that could allow for resistance from HIV. And vaccines and other immune enhancers. Can we get people’s immune systems to control the virus on their own, like we see with the Visconti Cohort? And like we see with these Portland monkeys?
Okay. So, some of the main questions in cure research. I don’t time to go through these in a lot of detail, but what I want to do is just highlight some of the speakers who will be presenting at the breakout sessions, and how these relate to some of these key questions.
Some of these questions, though, is: what are the locations of all the HIV reservoirs in the body? What types of cells, what types of tissue compartments, which therapeutic agents can drive the virus out of latency? How can we use the immune system to kill this virus once it’s exposed? How do we measure the HIV reservoir? This is something that’s actually very difficult to know. Not all of the viral DNA we can find could result in actual viruses, so, some of it, we may not have to worry about so much. How much of an impact do we have to have on the reservoir so that the person actually has a clinical benefit? And, also, what kind of innovative, out-of-the-box ideas might we bring to bear on this challenge?
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