Gag-Pol Processing during HIV-1 Virion Maturation: A Systems Biology Approach
Figure 7
The effect of PR inhibitors on VMT.
(A) The dependence of VMT on the concentration of PI that binds to mature PR (red symbols) and on the concentration of a hypothetical PI that binds to full-length Gag-Pol dimers and inhibits auto-cleavage (blue symbols). The binding rate constants of both PIs were parameterized with data estimated for the PR binding of darunavir. A hyperbola-like function of the form y = a+b/(c−x)d could be fitted to the simulated VMT data, with a = 28.4 min, b = 8.75 min×mM, c = −0.91 mM, d = 1.53 for the inhibitor of PR, and with a = 29.4 min, b = 2.70 min×mM, c = −0.97 mM, d = 1.51 for the inhibitor of auto-cleavage. The vertical line indicates the theoretical maximum concentration of PR dimers at half of the initial concentration of Gag-Pol; the horizontal line indicates VMT in the absence of drug. (B) The effect of Gag-Pol content on critical drug concentration. Red dots indicate the theoretical maximum concentration of functional PR enzymes (half of Pol) at varied initial Gag-Pol content; black dots indicate the darunavir concentration required to delay virus maturation to VMT = 100 min in the model. (C) The dependence of VMT on the dissociation rate constant kd of an inhibitor of PR (red) and of an inhibitor of Gag-Pol (blue). The inhibitor of auto-cleavage requires greater binding affinity (lower log(kd)) to take effect. The vertical line indicates the estimated dissociation rate constant of darunavir. The horizontal line indicates VMT in the absence of drug; drug concentration was set to the possible maximal enzyme concentration (half of initial Gag-Pol) at 0.095 mM. (D) Isoclines of VMT = 30, in the plane of darunavir concentration against fold increase in the two catalytic parameters with the strongest effect on VMT. The same function as in (A) could be fitted with a = 0.57, b = 0.68 mM, c = −1.36 mM, d = 1.10 for the catalytic rate constant of CA/SP1 cleavage, and with a = 0.70, b = 0.66 mM, c = −1.18 mM, d = 0.94 for the catalytic rate constant of auto-cleavage. Vertical asymptotes (positioned by c values) show the limits on the compensation of drug effect by increased catalytic rates. In all panels, parameters were set as in Table 1 unless otherwise stated.