Tissue-resident T cell–derived cytokines eliminate herpes simplex virus-2–infected cells

The mechanisms underlying rapid elimination of herpes simplex virus-2 (HSV-2) in the human genital tract despite low CD8(+) and CD4(+) tissue-resident T cell (Trm cell) density are unknown. We analyzed shedding episodes during chronic HSV-2 infection; viral clearance always predominated within 24 hours of detection even when viral load exceeded 1 × 10(7) HSV DNA copies, and surges in granzyme B and IFN-γ occurred within the early hours after reactivation and correlated with local viral load. We next developed an agent-based mathematical model of an HSV-2 genital ulcer to integrate mechanistic observations of Trm cells in in situ proliferation, trafficking, cytolytic effects, and cytokine alarm signaling from murine studies with viral kinetics, histopathology, and lesion size data from humans. A sufficiently high density of HSV-2–specific Trm cells predicted rapid elimination of infected cells, but our data suggest that such Trm cell densities are relatively uncommon in infected tissues. At lower, more commonly observed Trm cell densities, Trm cells must initiate a rapidly diffusing, polyfunctional cytokine response with activation of bystander T cells in order to eliminate a majority of infected cells and eradicate briskly spreading HSV-2 infection.