Mutagenesis-Mediated Virus Extinction

One of the peculiarities of RNA viruses is their high mutation rate, which makes pathogens like HIV or Hepatitis C so elusive when it comes to vaccine design. A high mutation rate ensures that the virus can rapidly adapt to escape not only the host's immune response, but also antiretroviral treatments. Take HIV, for example: once inside the body, HIV evolves into numerous quasispecies -- new viral strains genetically distinct from the initial founder strain (the one that started the infection). That's why no single HIV strain can be used as a vaccine, as it wouldn't be protective against all possible strains. Furthermore, a cocktail of several drugs is needed in order to keep the viral load under control. When patients take one drug only the virus is able to rapidly find mutations that make it "immune" to the drug and hence make the treatment ineffective.

Last week I gave an introductory talk on both HIV and Hepatatis C and as I was describing the advantages of their high mutation rate, somebody in the audience asked, "Is there an upper limit on how high the mutation rate can be?"

The answer is: absolutely. You see, mutations happen at random. Some end up being advantageous, others will be deleterious. The advantageous one stay, the deleterious ones disappear because the viruses carrying them are non-viable. The population can tolerate a certain number of deleterious mutations, provided enough of advantageous ones appear at the same time in order to compensate for the loss. The effective mutation rate has to be high in order to ensure rapid adaptability, but if it ends up being too high deleterious mutations will prevail and the viral population will eventually go extinct.

So then the next natural question to ask is: can this be exploited as a new antiviral strategy?

This strategy exists and it's called "lethal mutagenesis" because its net effect is to decrease viral fitness by increasing the rate at which new mutations appear. By using mutagenic molecules, Moreno et al. [1] showed two possible outcomes in viral infections caused by the arenavirus lymphocytic choriomeningitis virus (LCMV): they either observed inhibition of progeny production and a decrease in viral infectivity, resulting in viral extinction, or a decrease in viral load. I found similar studies, spanning between 2001 and 2005, that used the same mutagen to attain extinction in the Foot-and-Mouth Disease Virus.

But how exactly do they increase the mutation rate? There are many kinds of mutagens. Ionizing radiations like X-rays, for example, are a familiar kind of mutagens: they cause mutations by damaging the DNA. However, here the task is subtler because we don't want to just damage the viral genome, we want to damage it in a way that it causes an increase in replication errors. The kind of mutagens used for this are called "base analogs", chemicals that can replace one of the usual nucleotides in the DNA, and when they do they cause copying errors to happen.

So, yes, a virus like HIV can use our own defenses to proliferate, since it attacks our immune system. But we can use its own defenses -- the high mutation rate -- to switch things around and try to defeat it.

[1] Moreno, H., Tejero, H., de la Torre, J., Domingo, E., & Martín, V. (2012). Mutagenesis-Mediated Virus Extinction: Virus-Dependent Effect of Viral Load on Sensitivity to Lethal Defection PLoS ONE, 7 (3) DOI: 10.1371/journal.pone.0032550