An Interview With David Harrich, Ph.D.
I realize this is all based on lab study -- everything in this section. But is this not a potential path to a vaccine?
Well, it's a type of intracellular vaccine. You've heard of innate immunity? You hear all these restriction factors: APOBEC; TRIM5alpha; tetherin; SAMHD1. This is an artificial restriction factor. This is inside a cell. A cell makes those factors; it makes those proteins. The whole idea of those proteins is to stop virus infection.
[With Nullbasic,] we've now made an HIV protein that's a restriction factor. It stops the cells from making virus.
APOBEC mucks with reverse transcription. This mucks with reverse transcription. This is [also] the only factor I know of that also has effects on gene expression: It downregulates gene expression, and it downregulates the production of RNAs that make the envelope and the capsid protein. So cells don't make new particles.
So it hits from multiple angles, making it more likely to work successfully?
It is like three drugs. In other words, cART, combined antiretroviral therapy, uses drugs that target more than one enzyme, or more than one molecule: a receptor on the cell surface, or reverse transcriptase, or integrase. This targets three viral targets: reverse transcriptase, Rev and Tat.
Consequently, we've not been able to grow a virus that's resistant.
To what extent do you feel it's even theoretically possible that HIV could mutate around this?
Well, we've tried, and we haven't generated one. We've tried for months and months, co-culturing and growing, taking these cells that we knew were HIV infected and hitting them with drugs to induce some virus, then taking those and doing it over and over again.
Have you tried with different strains of virus?
That's on the card; we have all the clades now. This, of course, is only done with laboratory virus. But those experiments are with a Ph.D. student in Australia.
I assume that, in a case like this, tropism isn't going to have too much of an effect?
No. We have tried it with CXCR4. We've tried it with T-tropic and M-tropic viruses. Those are the two that people like to talk about -- which is kind of a misnomer; you know: It's R5 or X4 viruses. We've tried it with both; it works on both.
The mechanism of inhibition isn't based on the receptor; it's based on the viral enzymes. There could be some differences in reverse transcriptase, or differences in Tat, or even differences in Rev -- and in amino acid level -- that can be slightly different, in which this may not work as well. We'll just have to wait and see.
Where will this research head next?
We're going to humanize mice, is the next step. With these mice, we can do experiments out to six months to a year, if we're lucky, to see whether or not we can keep HIV from growing.
The problem with this protein [on which Nullbasic is based] is it has a bad reputation.
How do you mean?
The wild-type protein is associated with cytotoxicity. We've looked for cytotoxic effects of this protein as best we can, with the assays that we have available. We haven't seen any. So we think that particular mutations [found in Nullbasic] have downregulated, or negated, these cytotoxic effects that are associated with wild-type Tat.
Will you be more able to tease out any possible risk with these mice studies?
That's why we do these short-term mouse studies: The whole idea is that, in primary cells, we can only do an experiment for two or three weeks in a test tube. That's it; the cells die. Using those same cells, you can go into a mouse and go about eight or 10 weeks, if you're lucky. We've taken it out five weeks [in our poster], because I wanted data for the conference. And the cells are fine.
As for the humanized mouse: Now we're not going into the CD4 cells; we're going to go with CD34 cells -- a completely different cell type. We've done an experiment with CD34s. We've introduced the protein into them. We've induced them to grow in vitro, and they look fine. We don't see any cell death. We don't see any changes in their cell proliferation, the way they divide. We don't see anything yet.
What we have to do now is transduce CD34s and put them into a mouse, see if they engraft, and see if those cells develop immune cells. Can it change the way the immune cells grow, or the way they develop? Does this have any effects on developmental biology? There's a lot of very fundamental questions that have to be addressed.
How hopeful are you overall that this type of approach can result in something that ultimately -- I'm not saying, one year, five years or even 10 -- but that ultimately can find its way into humans and be a viable treatment option?
Some people say this will never work. I get that all the time.
I'm guessing you would not have been researching this for the past 18 years if you felt it couldn't work.
It's got a chance, right?
I keep doing experiments to see if this will fail. I don't do experiments to see if it works; I do experiments to see if this protein fails. As soon as I see that it's toxic or has detrimental effects, why bother? Then I'll stop. That was the whole point of that last panel [in my poster]: What happens in a mouse? Do these cells live? Are they healthy? Do they look OK?
The answer so far has been OK. When we'll go into CD34s, if we try it a few times and we find out those cells die, the project's over. So far it's crossed every hurdle. If I get to CD34s and it works, then I'm going to be more hopeful.
Every time you jump one of these hurdles, you become a little more hopeful; but also maintain your skepticism. You can't get sucked into your own science. The job of a scientist is to see if something holds true.
The hypothesis is that Nullbasic can protect human cells from HIV and cause no detrimental effects. We're testing that hypothesis. As soon as we show that the answer to that is, "It's not true," then the project will stop. I'm hopeful.
I'd wish you luck, but the answer's already out there; we just don't know what it is yet.
The answer is out there. I know. We just need people and money to do the work.
This transcript has been edited for clarity.
Myles Helfand is the editorial director of TheBody.com and TheBodyPRO.com.
Follow Myles on Twitter: @MylesatTheBody.
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