Figure 5. Mathematical model simulation of a prolonged HSV-2 shedding episode.

(A) Cartoon of mathematical model including susceptible cells, infected cells, cell-associated virus, cell-free virus and CD8+ T cells (T_RM). These equations are simulated stochastically in 200 regions concurrently as shown in (C) & (D). (B) Simulated HSV-2 shedding episode notable for multiple peaks. The thick red line represents total viral load that would be detected with a clinical swab, while the thin lines represent viral load generated within single-microregions of infection. Simulated T_RM structure and degree of protection (C) before and (D) following clearance of the shedding episode in (B). The left column represents the density of T_RM within each micro-region before and after the episode. The circumscribed black regions had viral replication during the episode (thin lines in (B)). Regions which generated high viral loads transitioned from low to high T_RM density as a large amount of local T_RM proliferation was required to contain infection. The middle column demonstrates the log10 effective reproductive number (R_e) of each region at the two timepoints. This number is inversely correlated with T_RM density and denotes the potential for persistent cell-to-cell spread of virus prior to elimination. Green scale regions have R_e>1 (log10 R_e>0) indicating the need for T_RM proliferation prior to elimination of all infected cells. Grey scale regions have R_e<1 indicating no need for T_RM proliferation prior to very rapid elimination of only a few infected cells. The right column plots the rank of each region according to T_RM regional density. The shape of the distribution is stable before and after the episode, in keeping with the stable long-term détente established between HSV-2 and its host, despite dynamic reshuffling of individual region’s rank due to localized T_RM proliferation events.