Fig 1.
Immunological and virological data from Lin et al. (2012).
Each color represents measurements from one of seven macaques (corresponding identification codes in panel A) infected with wild-type MV and monitored up to 71 days post infection. (A) Infectious viral load was determined by cocultivation of peripheral blood mononuclear cells with susceptible cells and then translated to tissue culture 50% infectious doses (TCID50) [40]. (B) The total number of lymphocytes per microliter of blood was measured using an automated cell counter. (C) MV-specific T cell activity was determined by the number of IFN-γ spot-forming cells per microliter of blood using enzyme-linked immunospot (ELISpot) assays. (D) MV-specific IgG titers were quantified using enzyme immunoassays (EIAs) and IgG avidity was measured by disruption of antibody binding [41]. Overall antibody response is expressed as IgG titer × avidity. Further details of the data and experimental methods are given in the S1 Appendix.
Fig 2.
Schematic of the three main model structures: (i) target cell limited; (ii) target cells and T cells; and (iii) target cells, T cells, and antibodies.
Virion shapes (V) represent infectious virus and circles represent distinct cell populations i.e. general susceptible lymphocytes (S), infected lymphocytes (I), and MV-specific activated T lymphocytes (A). Typical transitions of virion and cell dynamics are depicted by arrows and the constant biological parameters governing each transition are described by the corresponding text. The basic structure of model (i) is captured by the thin black arrows connecting all virion and cell populations. Model (ii) is obtained by the addition of T cell killing (red lightning bolt), and model (iii) is obtained by the addition of T cell killing and antibody killing (yellow lightning bolt). Additional functions governing the temporal evolution of T-cell activation and lymphocyte proliferation are discussed in the main text.
Table 1.
Model comparisons using Akaike Information Criterion corrected for small sample sizes (AICc).
Fig 3.
The target and T cell model calibrated with data from Lin et al. (2012).
Points indicate data for (A) total lymphocytes, (B) MV-specific T cells, and (C) viral load; solid lines indicate the corresponding model predictions determined by maximum likelihood optimization. The activated T cell predictions are depicted before scaling for comparison with the MV-specific T cell data. Each row corresponds to an individual macaque (with identification codes inset in panel C), and panels B and C are shown on the log scale.
Table 2.
Parameter estimates from the best-fitting model combining target cells and T cells.
Fig 4.
Predictions of the best-fitting target cell and T cell model.
Solid lines indicate predictions for (A) susceptible lymphocytes, (B) infected lymphocytes, (C) activated T cells, and (D) viral load. Each color represents an individual macaque (with identification codes inset in panel D) and red shaded regions indicate the approximate window of peak viral load. Activated T cell numbers reflect absolute model predictions by incorporating the data scaling factor, ψ.
Fig 5.
Investigating drivers of viral clearance.
Solid lines indicate the effect of T cell depletion (A) or target cell addition (B) on viral load; dashed lines indicate the corresponding control simulations. Grey shaded regions in panel A represent the period of T cell depletion and the dashed grey vertical lines in panel B represent the timing of target cell addition. Each color represents an individual macaque (with identification codes inset in panel B).
Fig 6.
Comparing the dominant driver of viral clearance across individuals.
For each macaque, the impacts of T cell depletion and target cell addition on viral load were calculated as the difference in the area under curve (AUC) between the experimental and control simulations, normalized by the AUC of the control simulation. Results for each individual are indicated by the corresponding identification code and the dashed line signifies the y = x boundary where experimental effects are equal. Simulations were conducted for (A) MV (by using best-fit parameters from the original target cell and T cell model); and (B) a virus with increased fitness (by doubling each individual’s viral replication rate, p). All axes are depicted on the log scale.
Table 3.
Parameters included in all model structures.