biostudies-literatureUnknown11(1)Guillemet MBeneficial mutations drive the within-host adaptation of viral populations and can prolong the duration of host infection. Yet, most mutations are not adaptive and the increase of the mean fitness of viral populations is hampered by deleterious and lethal mutations. Because of this ambivalent role of mutations, it is unclear if a higher mutation rate boosts or slows down viral adaptation. Here, we study the interplay between selection, mutation, genetic drift and within-host dynamics of viral populations. We obtain good approximations for the transient evolutionary epidemiology of viral adaptation under the assumption that the mutation rate is high and the effects of nonlethal mutations remain small. We use measures of fitness effects of mutations for a range of viruses to predict the critical mutation rate required to drive viral extinction. This analysis questions the feasibility of lethal mutagenesis because the fold increase of viral mutation rates induced by available mutagenic drugs is not high enough to reach the critical mutation rate predicted by our model.Virus evolutionveaf084https://www.ebi.ac.uk/biostudies/studies/S-EPMC12640550biostudies-literatureLethal mutagenesis and the transient within-host dynamics of viral adaptation.PMC12640550Martin GGuillemet MGandon SRoze DHardy EfalseLethal mutagenesis and the transient within-host dynamics of viral adaptation.Beneficial mutations drive the within-host adaptation of viral populations and can prolong the duration of host infection. Yet, most mutations are not adaptive and the increase of the mean fitness of viral populations is hampered by deleterious and lethal mutations. Because of this ambivalent role of mutations, it is unclear if a higher mutation rate boosts or slows down viral adaptation. Here, we study the interplay between selection, mutation, genetic drift and within-host dynamics of viral populations. We obtain good approximations for the transient evolutionary epidemiology of viral adaptation under the assumption that the mutation rate is high and the effects of nonlethal mutations remain small. We use measures of fitness effects of mutations for a range of viruses to predict the critical mutation rate required to drive viral extinction. This analysis questions the feasibility of lethal mutagenesis because the fold increase of viral mutation rates induced by available mutagenic drugs is not high enough to reach the critical mutation rate predicted by our model.2025-01-01T00:00:00Z20252026-06-05T18:49:22.242Z2026-05-20T03:13:27.113ZS-EPMC126405504128763510.1093/ve/veaf084