David Harrich of the Queensland Institute of Medical Research in Australia says he and his team have created a mutant protein that inhibits multiple steps in the life cycle of HIV.
Dubbed Nullbasic, "potent" inhibitor was created by modifying a protein in the Human Immunodeficiency Virus (HIV) that usually lets the virus spread. David Harrich's experiments have a way to go yet - initial experiments have been limited to a lab dish, so the next step will be animal testing in the lab, and only much later can human trials begin. But it's an exciting development - and it comes soon after reports that researchers at the University of Western Ontario in Canada, under Professor Chil-Yong Kang, had successfully completed Phase 1 clinical trials on humans for a HIV vaccine.
DW: Why did you decide to target this particular protein in HIV?
David Harrich: Well, the reason is that it's an essential viral protein, so HIV requires this particular protein for a number of different jobs. So, I think what we didn't know back in the late 80s and early 90s was just how important this protein was and how many different roles it had inside the cell to help HIV grow. And so we started mutating this protein until we got one that interfered with different jobs that this protein normally has to achieve. So, really, the idea was that the way to target HIV is to stop the virus life cycle at multiple points - you just can't target a single enzyme or a single viral enzyme or a single step in replication - that turns out not to be very effective. What has proven to be effective - and this is just based on anti-retroviral therapy - is that you need to target at least a couple of different enzymes or a couple of different proteins and if you can do that, you can often achieve very low levels of virus replication. So that was the model we used and we started understanding that our mutant protein was actually having this effect, that it was inhibiting multiple steps of the virus life cycle.
Give us an idea of how effective it is because what we're reading is that this inhibitor is stopping the replication by about eight to ten-fold. What exactly does that mean? Is there room for error?
It actually could be more than that - that was a suboptimal experiment. We're still learning on this and how to deliver it and how to express the protein. So we used a system that we really weren't happy with but we wanted to get the information out into the public domain so we decided to go with it anyway.
Early days yet
But does that mean that there is still room for it not actually working? How effective is it at that level or at the levels you think you can achieve?
There is absolutely room for this protein to not work on a number of different levels. Not just because it may not be a good enough inhibitor, but also because once you express a protein inside a cell you can have other effects. So while our preliminary studies show that we cannot find any very serious detrimental effects imparted by this protein on the cell - so, very low toxicity - it doesn't mean that as you progress that something doesn't pop up, that you don't find something. So, toxicity is going to be an issue, I think immunological responses are going to be an issue because if you express a foreign protein inside a cell, there's a chance that those cells will be targeted by the immune system and eliminated. So on a number of different levels there are hurdles that we're going to have to cross. But I think we started down this road because the initial gene therapy trials showed that some of those things weren't really a problem. So we thought: as long as we have a good inhibitor, we'll push it as far as we can. So, so far, all we've done is preclinical trials, laboratory experiments in human cells obtained from blood and we've protected them very, very well.
It's a very real job that you have here - to find a cure for a very real virus - but at the same time, sex is sex, and people do seem to make decisions about whether they protect themselves or not and if they can say, Well, you know, in a few years we will have a cure so who cares now - I won't wear a condom, I won't protect myself! Is that a problem for you when you do your research?
It's not a problem for us doing the research because I think it's certainly an important job in public health to continue the message that the best way to prevent HIV infection is preventative action - so, not sharing needles, using condoms when having sex and so on - it's still the most important public health message that has to get out there. Now, what we're trying to do is say that if it's too late, if you've already become HIV infected, we're working on a therapy that hopefully would improve quality of life. And what I mean by that is that, if it works to our expectations, a patient would no longer have to take anti-retroviral drugs - that's really our goal.
And also, I suppose, a proper cure could lead to stamping out the virus entirely rather more effectively than a vaccine, is that right?
There are two aspects to a cure. I like to think that a true cure means that the body is no longer infected by HIV, that there's no detectable HIV present anywhere in the body. This will not accomplish that. This is really a therapy to try to prevent disease progression. This is actually really intended - if it's successful - to be a replacement for anti-retroviral therapy.
Associate Professor David Harrich is group leader in the department of HIV Molecular Virology at the Queensland Institute of Medical Research in Australia and a Fellow of the Australian Research Council (ARC).
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