Figure 1.
A) High CCR5 expression on a target cell allows the formation of the requisite gp120-CCR5 complexes for cell-cell fusion. B) Low CCR5 expression or C) the presence of a coreceptor antagonist reduces the surface density of gp120-CCR5 complexes and prevents fusion.
Figure 2.
Model predictions of cell-cell fusion in the absence of a coreceptor antagonist.
A) Distribution, f(C0), of the CCR5 expression level, C0, across cells, predicted using Eq. (12), for the mean expression, and different values of the standard deviation,
. Inset: Fraction of cells fused, F, is the (shaded) area under the f(C0) curve for
, the threshold CCR5 expression level for fusion. B) F as a function of GCT, the threshold surface density of gp120-CCR5 complexes necessary for fusion. Inset: The dependence of
on GCT computed using Eq. (11).
Figure 3.
Predictions of the ternary complex model.
Equilibrium surface densities of A) unbound gp120, G, B) unbound CCR5, C, C) gp120-CCR5 complexes, GC, D) CCR5-coreceptor antagonist complexes, AC and E) gp120-CCR5-coreceptor antagonist complexes, AGC, as functions of the concentration of the coreceptor antagonist, A0, for different values of the cooperativity factor, α, calculated by solving Eqs. (6)–(9).
Figure 4.
Model predictions of cell-cell fusion in the presence of a coreceptor antagonist.
The fraction of cells fused, F(A0), as a function of the concentration of the coreceptor antagonist for A) different values of GCT with α = 0.01 and B) different values of α with GCT = computed using Eqs (1)–(15). C) and D) The corresponding inhibition of fusion due to the coreceptor antagonist calculated using Eq. (16). The standard deviation of the CCR5 expression level,
.
Figure 5.
Comparisons of model predictions with experiments.
A) Fit of model predictions of F(A0) (line) to published experimental data [24] (symbols) of the fraction of cells fused as a function of vicriviroc concentration using ( = 5318 molecules/cell [24]) and with
,
, and
as adjustable parameters. The other parameters are mentioned in Methods. The dashed lines are 95% confidence limits on the predictions. Inset: Difference between model predictions and the experimental data; the mean error is 0.002 (in units of the percentage of cells fused) and is not significantly different from zero (P = 0.996 using a two-tailed t-test). B) Fits of model predictions of F(A0) (lines) to data [24] (symbols) of the fraction of cells fused as a function of vicriciroc concentration in the presence of different concentrations of rapamycin (RAPA) using
as an adjustable parameter. The other parameters are the same as in A). The best-fit parameter estimates are mentioned in the text.
Figure 6.
Robustness of model predictions.
Fits of model predictions (lines) of the relative extent of cell-cell fusion, 100−I(A0), as a function of maraviroc concentration to published experimental observations [28] (symbols) using nM−1 and with
and
as adjustable parameters. The other parameters are mentioned in Methods. The different panels represent data from experiments using different Env clones (legends). The best fits (solid lines) and the corresponding 95% confidence limits (dashed lines) are shown. The best-fit parameter estimates are mentioned in Table 1.
Table 1.
Threshold surface density of gp120-CCR5 complexes for different Env clones.
Table 2.
Summary of model parameters and their values employed.