Herpes simplex virus‐2 dynamics as a probe to measure the extremely rapid and spatially localized tissue‐resident T‐cell response

Summary Herpes simplex virus‐2 infection is characterized by frequent episodic shedding in the genital tract. Expansion in HSV ‐2 viral load early during episodes is extremely rapid. However, the virus invariably peaks within 18 hours and is eliminated nearly as quickly. A critical feature of HSV ‐2 shedding episodes is their heterogeneity. Some episodes peak at 10 8 HSV DNA copies, last for weeks due to frequent viral re‐expansion, and lead to painful ulcers, while others only reach 10 3 HSV DNA copies and are eliminated within hours and without symptoms. Within single micro‐environments of infection, tissue‐resident CD 8+ T cells ( T RM ) appear to contain infection within a few days. Here, we review components of T RM biology relevant to immune surveillance between HSV ‐2 shedding episodes and containment of infection upon detection of HSV ‐2 cognate antigen. We then describe the use of mathematical models to correlate large spatial gradients in T RM density with the heterogeneity of observed shedding within a single person. We describe how models have been leveraged for clinical trial simulation, as well as future plans to model the interactions of multiple cellular subtypes within mucosa, predict the mechanism of action of therapeutic vaccines, and describe the dynamics of 3‐dimensional infection environment during the natural evolution of an HSV ‐2 lesion.