Drug Discovery Opinion

The concept of ‘lethal mutagenesis’ has been developed as a means of curing viral infections and has also been used to explain the action of some antiviral drugs. Although mutation is the basis for adaptation and survival, especially in the presence of antiviral drugs, most mutations are detrimental and the theory of lethal mutagenesis holds that an infecting population can be pushed to extinction by an overwhelmingly high mutation rate. Chemical mutagens have been used to increase error rates in a number of RNA viruses including HIV-1 and HCV and have been found to significantly reduce viral titres and, in some cases, achieve extinction. For example, the antiviral activity of the ribonucleoside analogue 5-azacytidine (5-AZC) against HIV-1 has been attributed primarily to an increase in mutant frequency consistent with lethal mutagenesis caused by incorporation of 5-AZC into viral DNA.

A team of researchers from the University of Texas at Austin have now raised serious concerns about the strategy of inducing lethal mutations, suggesting that it could cause viruses to become more virulent. The team predicted that growing the DNA bacteriophage T7 in the presence of a mutagen would lead to a substantial decline in viral fitness but found instead that, after 200 generations, fitness had increased despite a mutation rate two to three orders of magnitude above baseline. Although the researchers agree that extremely high mutation rates will mostly lead to viral extinction, they caution that forcing viruses to undergo rapid mutation could, if the mutation rate is not high enough, lead to well adapted ‘superviruses’.

The study is published in the journal Genetics.