Figure 5. Access to the Peripheral Circulation Is Required for Viral Persistence in the Simulation.

(A) The virtual virus does not persist when latently infected virtual B cells (B_Lat) are denied access to the peripheral circulation. The graph shows the level of B_Lats over time for a simulation run with the default parameter set allowing (red line) or denying (brown line) access of the B_Lats to the peripheral circulation Note that only the first 60 d of virtual infection are shown. A characteristic series of spikes in B_Lats is observed that was lost after approximately 30–40 d. These spikes arise because normally B_Lats spend time in the circulation, and the time they spend there does not advance them towards the lytic state. By denying them access to the blood, both the mean time to burst and the standard deviation of this statistic decrease. This causes the virtual viral bursts and infection of new virtual B cells to arrive synchronously as narrow spikes, one spike per generation of infected virtual cells.

(B) Increasing the initial infectious dose does not allow persistence in the absence of a peripheral blood compartment. The simulation was run without a peripheral blood compartment as described in (A), except the initial infectious dose was increased in increments as shown. The initial infectious dose is the average number of Vir deposited at each mesh point (node) on the surface of the virtual lymphoepithelium. To obtain the total infectious dose, this value is multiplied by the number of surface nodes (16,205). The figure shows runs with infectious dose of 7/mesh point (pink line) and 70/mesh point (green line). The default value for initial infectious dose is 0.7/mesh point.

(C) Increasing the Vir burst size does not allow persistence in the absence of a peripheral blood compartment. The simulation was run without a peripheral blood compartment as described in (A), except the number of Virs released when a B_Lyt bursts was doubled (default average burst size = 800 Virs).

(D) Decreasing the efficiency of the immune response does not allow persistence in the absence of a peripheral blood compartment. The simulation was run without a peripheral blood compartment as described in (A), except the efficiency with which CTLs are activated and kill their targets was reduced incrementally. With this approach it was possible to find a level of virtual immunosuppression (50% brown line) that produced an infection that lasted for the length of the simulation (880 virtual days). However, this looks nothing like EBV persistence in a real infection. Rather, the virtual infection involves wild oscillations in the number of latently infected virtual B cells (B_Lat) and it appears that the average level is trending upwards to overwhelm the B cell compartment, a condition we refer to as virtual death. Small incremental increases above 50% immunosuppression (e.g., 75% blue line) resulted in the B cell compartment being rapidly overwhelmed with latently infected virtual B cells (B_Lat). Small incremental decreases below 50% immunosuppression resulted in clearance of Vir similar to that seen in Figure 5A.