Fig 1.
Plasma viral load measurements, in copies (cp) per ml, in rhesus macaques inoculated subcutaneously with the indicated dose of Brazilian (BR, green triangles) or Puerto Rican (PR, purple circles) ZIKV.
The limit of detection of the experimental assay is 100 RNA cp /ml, and when ZIKV was undetectable in a sample it is shown here at the limit of detection for illustrative purposes.
Fig 2.
Viral load (VL) characteristics (from measured data, Fig 1) by inoculum dose (log10 PFU, x-axis) and viral strain (indicated by markers, BR: green triangles, PR: purple circles).
Correlations between inoculum dose and VL characteristics are tested by Pearson correlation for each strain separately, and where this is found to be significant at the α = 0.05 level after Bonferroni correction for multiple testing (m = 6) the linear regression line is shown in the panel, and the p-value and correlation coefficient are shown in the legend. Differences in VL characteristics between viral strains for each inoculum group are tested with the Mann-Whitney U test, and none are found to be significant at the α = 0.05 level after Bonferroni correction for multiple testing (m = 6). The day 1 VL, time of peak VL and value of peak VL are the observed measurements. The area under the curve (AUC) of the log10 plasma VL and the downslope of the log10 plasma VL are calculated as described in the methods. Animals with VL data only to day 7 or which do not have any undetectable VLs after the peak are excluded from the analysis of “time of first undetectable plasma VL”.
Table 1.
Estimated population parameters from fitting the indicated models to viral load data from all animals using a non-linear mixed effects model.
An explicit covariate relationship between inoculum dose and initial viral load V0 is incorporated, with the median population estimate for log10 V0 at each inoculum dose shown in italics. Relative standard errors are shown in parentheses. Fixed parameters used in the model fits are: k = 8 d-1, c = 10 d-1, s = 1 d-1, α = 2 d-1, K = 103, n = 0.25, T(0) = 105 ml-1, each with no variability.
Fig 3.
Individual viral load predictions from population model fits.
For each animal the observed plasma viral loads (markers), the predicted viral load from the immune response model with viral interference (Eq 3, Table 1) are shown. The horizontal grey dotted line represents the limit of detection of the assay, and samples in which virus is not detected are shown with open markers at this value. Viral strain is indicated by marker and color (BR: green triangles, PR: purple circles) and both inoculum dose and viral strain are indicated in the top right corner of each panel.
Fig 4.
Predicted dynamics for the immune response model with viral interference (Eqs 2 and 3, Table 1).
Each inoculum dose is indicated by color, with the mean predicted dynamics within an inoculum group shown. The solid line shows the model dynamics with the estimated parameters. The dotted line shows the model dynamics with estimated parameters but with g(V) fixed at 0, such that viral interference has no effect on immune response.
Fig 5.
Estimated parameter distributions for the three model fits: immune response model with viral interference (Eq 3, Table 1, solid line), the innate immune response model including a dose dependency in the timing of the immune response (Eq 2, S6 Table, dashed line) and the target cell limited model (Eq 1, Table 1, dotted line). Where inoculum dose is explicitly included as a covariate in the model, the distributions for each dose are indicated by color.