An Interview With David Harrich, Ph.D.
Gene therapy is one of several avenues being explored by researchers hunting for a way to beat HIV once and for all. But to many of us, even within the health care community, the science being conducted in this area is a black box: We periodically read about study results, be they encouraging or discouraging, without understanding much of the effort behind them.
Let's see if we can peel back the lid on this black box a little bit.
At CROI 2014, a major HIV research conference that recently took place in Boston, I met David Harrich, Ph.D., an associate professor at the QIMR Berghofer Medical Research Institute in Queensland, Australia. He was at CROI to present a poster on a potential form of HIV gene therapy that has been in development for the better part of two decades. It goes by the name of Nullbasic.
Before we get deeply into the study, take me back to the beginnings of Nullbasic. How was it discovered? How did you all realize what it was capable of?
David Harrich, Ph.D.
This project began about 1987. I was a research assistant working for Professor Richard Gaynor at UCLA [the University of California-Los Angeles]. He had the idea that you could make some mutations in a virus protein, and that [it would have] a dominant effect, or be able to inhibit, the wild-type protein. An idea of fighting fire with fire, as some people like to describe it.
It works. But when we started those studies, we didn't have all the tools. We didn't exactly know all the things that we know today.
By "works," I assume you're referring to within lab cultures, right?
Yeah. In an in vitro laboratory setting, we could show some inhibition. But that got put onto a back burner.
I kept working on it over the years. About 10 years later, I made some discoveries that a protein had additional activities to help the virus grow. And I thought, "Can we do the same trick? Can we mutate the protein and inhibit the virus?"
It turned out to be the same mutant that my mentor discovered, only we changed the protein in other ways, made it more stable so that there was more of the protein around. In a nutshell: We took these Tat mutants, and we call this Nullbasic -- "null" in that it doesn't have a basic domain; they're the mutations in this part of the protein that is called the "basic" region. It lacks the basic domain.
Lo and behold, when we put this protein into human T cells, we find that HIV will no longer grow.
What's the significance of the Tat mutant?
The significance is that normally, this Tat protein is critical for the virus to replicate. What Tat has to do is interact with other cellular or viral proteins. It's sort of like a helper: It goes around in the cells, says, "OK. We need this to grow." It grabs it and uses these cellular proteins.
What this mutant [Nullbasic] does is, it's able to grab onto these cellular proteins that HIV requires, but it can't complete the job. In other words, it squanders all the things that HIV would normally require and therefore HIV stops growing. In addition, this protein actually targets one of the virus's own proteins; this is called reverse transcriptase. It targets reverse transcriptase and it stops that enzyme from doing its job.
You guys are looking into developing this as a potential gene therapy.
Why not an antiretroviral?
Well, we think investigation of some of these roles that it has, some of these mechanisms that it uses to inhibit HIV, could lead to new drug discovery. And we are pursuing that. But as an antiviral, this is a very dominant phenotype. In our hands, it seems to work each time.
By each time, you mean ... ?
I mean, it doesn't matter. Each experiment we try: We introduce this protein to human T cells; the virus no longer grows in those cells. We cannot detect virus replication, virus production. Normally, HIV gets into a cell and it produces virus. When HIV gets into one of these changed cells, protected cells, we can actually not detect virus being made.
No RNA shows up?
We see no virus particles. There's probably some virus RNA in the cells. We're still looking at that. We haven't finished those studies. But we know the virus particles are no longer produced.
How do you tie this in to the generalized research that's going on right now when it comes to gene therapy?
I think this is at a much earlier stage than some of the things that you've heard at CROI, which are further developed. It fits along the same lines; it fits into the avenue that treating a patient with Nullbasic gene could lead to a functional cure for AIDS. In other words, a person would still be infected by HIV, but they would have a repertoire of T cells that were no longer susceptible to infection, or would die from HIV infection.
This is the thing that fascinates me: the last sentence of your conclusion. You're saying here, "Our data suggest that Nullbasic can protect cells from infection as well as suppress the reactivation of latent HIV," which is the opposite of what several paths of the research toward a cure are trying to do -- which is activate and then destroy the latent HIV.
Absolutely. This is the flip side of the coin. And it's not the only one: There's another group in Australia, led by Tony Kelleher, that has another method of gene therapy that can essentially achieve the same thing, by silencing HIV directly in infected cells.
These are strategies that if -- once you have these cells -- should they see HIV, and HIV gets into the cells and integrates, it simply won't be able to produce any more virus.
Could this therapy get into reservoirs that already exist? I'm thinking about this in the context of a person who is already infected with HIV, who is maybe chronically infected. So HIV is already hiding out somewhere.
The difficulty is targeting this kind of a therapy to those cells. It's difficult to go in with a laser beam and, say, only into latent reservoir cells, and shunt the virus to there. I don't know that we have that technology, to go in with that fine-toothed comb.
The gene therapy being explored by other researchers in early human trials: That's all systemic, right?
It's all systemic. And the idea: Most of the gene therapy that is being proposed is to produce HIV-resistant cells. This is along the same line.
You've heard about CCR5-delta 32 mutations, and the gene editing to make CCR5-negative cells? [Nullbasic] does it in a different way. Instead of making them not infectable by HIV, these cells could become infected -- but then the HIV could do nothing. It would get into these cells and take up knitting. That's about it.
This is supposed to be the "towards-a-cure" section [of the poster exhibition hall]. Did you know that?
I did not. Based on the title hanging from the ceiling, "HIV Persistence," it suggests it's not precisely toward a cure.
If you look at where we're at, from here down to the end [of this row], these posters are about "towards-a-cure." Many of them are about reducing the reservoirs, and how hopefully you can then eliminate them. I'm the only one that's [on] the other side [of the issue].
If HIV gets in and can't do anything, can't make any virus, who cares? The whole idea is to stop making virus. That's the idea. And you either do that by eliminating the reservoirs so you can stop making virus, or you just create cells that are resistant to virus. [Nullbasic-treated] cells will not make virus.