Figure 8. Mathematical models inclusive of multiple paracrine cytokine functions leading to realistic distributions of HSV-2 shedding episode severity.

(A) Mathematical model schematic: possible cytokine effects including enhanced killing of infected cells, lowering viral replication rate in infected cells, lowering HSV-2 infectivity to uninfected cells, and activating other bystander Trm cells to proliferate and secrete cytokines; models including at minimum enhanced killing of infected cells and activation of other bystander Trm cells to proliferate and secrete cytokines provided best fit to the data (Supplemental Figure 1). (B) Three simulated episodes starting at different E:T ratios; log₁₀ HSV-2 DNA (red) and relative cytokine concentration (blue). (C and D) 1000 Simulated episodes with starting E:T ratio densities (inclusive of CD4⁺ and CD8⁺ T cells) randomly selected from Figure 2D; inverse correlation of the ratio of Trm cells to epithelial cells within (C) the entire model grid of 15,625 cells and (D) the 49 cells surrounding the first infected cell to peak viral load. E:T ratio of greater than 0.2 immediately surrounding the first infected cell is most predictive of low peak viral load.