July 29, 2016
HIV is a particularly elusive virus, hiding inside yet-unmapped reservoirs within the body. Antiretroviral therapy has made it possible for patients to keep the virus at bay with lifelong treatment, but for decades the concept of a cure seemed out of reach.
However, in recent years, basic research scientists have made enormous strides and are now working to identify new molecules and treatment approaches that could one day be developed into a true cure. The Berlin patient was famously cured of HIV in 2008 after a stem cell transplant. And while others, such as the Mississippi child and the Boston patients, ultimately relapsed, all of these cases have provided valuable opportunities for scientists to learn more about the viral reservoir, bringing us one step closer to a cure.
Scientists gathered at the recent New York State 2016 HIV Cure Symposium were more hopeful than ever that a true cure is within sight. At the event, organized by Mount Sinai's Institute for Advanced Medicine, renowned scientists reviewed all the recent advancements in and lingering obstacles to HIV cure research.
At the Symposium Carl Dieffenbach, Ph.D., director of the Division of AIDS, National Institute of Allergy and Infection Diseases (NIAID), shared his thoughts on the challenges and opportunities ahead.
First of all, I really appreciated your talk. It really helped me, as a reporter and not a specialist, frame this conversation around the cure. So where are we now? What are the most promising approaches?
I think we have to put this in context, in that, as I said in my talk, it's not that we really have a clear path from where we are today to a universal cure that will work in everybody. I think that what we do know is that, for whatever reason, the [CCR5] co-receptor remains a target -- so, the gene therapy strategies, the University of Southern California and the group at the Fred Hutchinson Cancer Research Center are pursuing.
This idea about using strategies to activate the provirus, there are so many different cell types involved. It's not clear whether we know enough. We need to really understand what we're dealing with at the molecular level in a way that we just don't.
So I would say a combination of gene therapy; strategies for immune activation, for activating the latent reservoir; the CMV vaccine work is also really fascinating.
And then, the sort of wild card in all of this is the Gilead strategy with the TLR7 agonist. It's not clear to me why that works or how it works. Everything thus far has been in monkeys, and they're starting human studies. But that to me is one of the areas in which we are just beginning to try logically different strategies.
You had mentioned your experience with the Mississippi child [who was seemingly cured after very early treatment after birth], and remembering where you were when you found out about the rebound. I'm hoping that you can walk me through your reaction to that. Were you surprised? Were you disappointed? Can you explain where you were as a researcher?
Well, I was disappointed of course. I think everybody had aspirational goals for the child, that maybe early therapy meant that the reservoir didn't get formed or could be controlled. But the fact that the child had essentially no immune response against the virus -- in some ways it was as if the child had a ticking hand grenade within it. Because, essentially, if you think about immunity -- that's a resting cell -- something's going to come along and activate that cell at some point because it has an antigen process; it's going to go off.
It had to be. If you really are dispassionate about it, it had to be. There had to be a rebound at some point -- if there was a provirus that was replication confident, if that was made. And so that's also part of the complication with HIV. So much of the DNA that gets archived is defective. So one could have imagined and hoped that all of the provirus that was archived was defective.
It wasn't the case. The virus that rebounded was clonal, a clone virus sequence. It was identical to the mom's virus, as we expected it to be. The child fully suppressed back and is trucking along. But I think everybody was disappointed.
At the same time, it reminded all of us that if this were easy, we would be done. And I think it made us realize that we have to be in this for the long haul. People who say, "Just give me a hundred million dollars and we can make this problem go away" -- it's not easy.
We've been working on an HIV vaccine for 20 years. We're finally starting to see a signal. It may be that we're in that situation with a cure that it may be another five or six years, or more, before we really start getting someplace. But I think our level of sophistication has grown -- the quality of the questions we're asking and the definition of the targets. I'll keep coming back that: First define what are you targeting; go back to basic principles.
With antiretrovirals, we go in and we specifically target reverse transcriptase, or protease, or integrase. What is the target? Well, CCR5 is a defined target. Are there other defined targets that are a combination of a cellular factor and a viral factor that come together, that we can figure out how to target, that will be unique?
If we inhibit some cellular function, you always worry about toxicity. CCR5 is unique because we knew you can live without it. So it really is about keeping the goal on high-quality, basic research that's defining mechanisms, as well as continuing to do experiments in people. This is a disease of people. We ought to be able to figure out how to ethically do this kind of research and not require a significant amount of work in animals. Because it's not exactly the same. Ultimately, we want to do it in people.
There was a question raised at the end of your talk about identifying targets to spur the involvement of industry. I'm hoping you can elaborate on that a little bit more, both specifically the targets that you think could prompt industry to get involved, but then also just kind of the economic milieu around that question.
Industry is really good about taking a concept and putting it into practice. Can we make a protease that has better PK? Better pharmacokinetics, pharmacodynamics and better activity? We've got the core structure. Build it better.
Industry really doesn't have the resources. Given the way the drug industry, the pharmaceutical industry, has evolved, they don't have the luxury to go out and do the years of basic research that they did some of in the past. Largely, that's a role of academia and then of the National Institutes of Health (NIH) -- to get at fundamental mechanisms of disease. Once you understand the fundamental mechanism of the disease, then a smart chemist can go in and say, "That is a druggable target. We can make a molecule that selectively inhibits -- or activates -- that protein or that RNA and then have an effect." That's how drugs are discovered. It's a classic model.
I just think for industry right now, there's no target there. Some industry, like -- I talk about the TLR7 agonist with Gilead; they're making a bet on that. That's a good -- that's an interesting bet. We'll see. But that's the fundamental issue.
I think it's unreasonable to ask industry to jump in. They can't. They don't have anything to jump in on.
So they're shooting in the dark right now?
Yeah, they're shooting in the dark.
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