The one and only
Most people tend to agree that multi-drug approaches, hitting the virus from several directions at once, is the way forward but as Elizabeth Tanner explains to Chris Smith, if you choose your target wisely, one drug may well be enough.
Elizabeth - One of the major challenges in using drugs to treat viral infections is that drug resistance tends to emerge very rapidly, sometimes within days, and one of the best ways of circumventing this problem is to use multiple drugs, usually three at a time to prevent resistance. However, there are many viral infections for which we don't even have a single drug, let alone multiple. Finding multiple takes a lot of money and many years, and so we wanted to figure out if there was a way to use just a single drug to simultaneously stop the growth of the virus, cure the infection, and prevent the emergence of drug resistance.
Chris - Why do some viruses - and particularly things like HIV - why do they have such a high tendency to become resistant to these drugs?
Elizabeth - So, the replication of the virus genome, especially when it's an RNA virus - not a DNA virus - is very error prone, there is a lot of mistakes.
Chris - Is it possible to exploit that fact and come up with drugs that, rather than be hampered and hindered by the fact there are so many variants - one of which could be resistant to the agent - is there a way of exploiting that to make a drug that works very well in that setting?
Elizabeth - Yes. So, there are some virus proteins, that as part of their function, must form a complex. So, there's something called the capsid on the virus and that's sort of the outer shell of the virus and it's made up of 60 different copies of a protein. So, you can imagine those 60 different copies can come from 60 different variants. If one of those proteins or even maybe a handful of them come from a drug resistant variant, only a small fraction of proteins in the actual structure will be drug resistant. The majority will be drug susceptible and will still bind the drug and they won't function. So, overall, that entire complex is likely to be non-functional, even though there are drug resistant proteins in there.
Chris - In other words, it should be possible to use your strategy and make a single drug which despite the fact you will get some resistance, it should nonetheless - if chosen carefully in terms of its target on the virus - should be able to bring down the entire shooting match.
Elizabeth - Exactly!
Chris - How have you modelled this, and how have you tested it to see whether or not the theory does play out and it does deliver?
Elizabeth - We set up an infection model like would be in a patient - only we used mice - in this case, they're transgenic for the human polio virus receptor. And we infected them with polio virus and then we treated them with a drug, actually, the drug that's currently in human clinical trials for polio virus. And it inhibits the capsid which has a number of proteins in this structure, and when we treated them with the drug, we were looking to see if over a number of days we could see drug resistant virus emerging from the infection. With the capsid inhibitor, even up to 7 days, drug resistant virus never emerged, compared to a control drug that we didn't think would work in this way. In that case, by 4 days, we could see a significant increase in the amount of virus that's resistant to that other drug.
Chris - Do you nonetheless think that there's a risk of getting some kind of compensatory mutations where, given enough time, the virus will evolve some kind of novel effector mechanism which would, in some way, thwart the blockade of your drug?
Elizabeth - Yes. It's theoretically very possible. For example, if there was a way for the drug resistant variant to only form a complex with other proteins from its own types. So, drug resistant proteins only associate with other drug resistant proteins then yes, it can escape. But that would have to happen independent of the mutation to also make it resistant. So, it's sort of like having multiple drug therapy because the virus will have to simultaneously gain two new abilities. One, it will have to become resistant to the drug, and two, it will have to be able to identify only other proteins like it.
Chris - Are these results therefore, generalizable more broadly, not just polio but many other agents. Could we extrapolate this and take the modus operandi that you have disclosed, showing that this is achievable and say, "Right. If we know what the sort of target is in the virus that we're looking for, we can go and find something similar across the board in different agents and that's the one to go for and we can have mono-drug therapy."
Elizabeth - Yes. Other people in the Kirkegaard lab are actually working on other viruses and actually totally different targets. Someone's working on Hepatitis C, and someone else is working on DNA virus, and they have very, very promising results that you can extrapolate to those viruses.