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Life cycle synchronization is a viral drug resistance mechanism

Fig 6

Modified basic reproductive ratio , unlike the time-averaged , accurately predicts infection outcome under a periodic drug treatment.

(A) Time course of infection levels (concentration of mature infected cells, y(t)) for an unsynchronized strain (T = 2 days and τ = 5 days). The maturation time is fixed and drug levels are modeled as a periodic step function. Unsynchronized strains are more exposed to the drug effects, as they overlap less with the off-windows of the drug treatment. (B) Synchronized strains (τ = 2) are less exposed to the drug effects, as they overlap with the off-windows of the drug treatment. The off-windows in the drug treatment are represented by blue shading. In this example, we use drug period T = 2 days and drug efficacy f = 0.75. (C) The time-averaged basic reproductive ratio minus one () is plotted versus the maturation time (τ) for a fixed drug efficacy and the simple on-off model of drug levels (black line). is independent of maturation time when immature cells do not die (d_w = 0 here) and weakly dependent for d_w ≪ m. versus is unable to explain the observed persistence versus extinction of viral strains (e.g. Fig 2). We derived a new quantity, (blue line), which works in the presence of synchronization to describe the observed behavior. was obtained via numerical solution of Equation (S.99) for and substitution of into Equation (S.100). The equilibrium infection level for a single strain (red line) is scaled to match at τ = 1.8. The drug efficacy is set to f = 0.9, and the death rate of immature infected cells is zero (d_w = 0). (D) Same as (C), except the drug efficacy is set to f = 0.5, and the death rate of immature infected cells is non-zero (d_w = 0.1). The equilibrium infection level is scaled to match at τ = 0. Connecting lines between points are drawn as a guide for the eye.

doi: https://doi.org/10.1371/journal.pcbi.1005947.g006