Figure 3.

Evolutionary trajectories of vRNAs in the viral quasispecies in a drug escape scenario. (A) Time evolution of vRNAs in the viral quasispecies under the conditions of a chronic infection and exposure to Daclatasvir at day 50. WT and mutants L31V, L31V Y93H, L31V Q54H Y93H are shown on an individual basis, and all other species are grouped together. L31V is on the pathway to the therapy-resistant triple mutant L31V Q54H Y93H, which is the dominant species from day 66; (B) time evolution of vRNAs in the viral quasispecies under a chronic infection treated with Sofosbuvir at day 50. WT, H479P, M289L, I293L and M289L I293L are shown on an individual basis, and all other species are grouped together. At day 50, the single mutant H479P is dominant, but has poor drug resistance, and is displaced as the dominant vRNA by the more resistant double mutant M289L I293L after day 55; (C) the time evolution of vRNAs in the viral quasispecies under chronic infection conditions and exposure to a PS-binding assembly-inhibitor at day 50. WT and the three emergent therapy-resistant vRNAs R1, R2 & R3 are shown individually, while WT-like vRNAs (characterised by having two high-affinity PSs at the 5’ end as in the WT) and R1/2/3-like vRNAs (containing only intermediate and low affinity PSs) are shown as groups. The dominant species following drug exposure is R1, which is then displaced by R2 after day 87. The sequence R3 is present at low frequencies at day 100, but becomes the dominant species from day 190.