The model equations were solved stochastically with a Tau-leap approximation algorithm that draws a random number of events of each transition type from a Poisson distribution (binomial for the infectivity term) to occur in a fixed time step based on the rates of each transition. by HSV-2 is sufficient for rapid elimination of infected cells but only in a portion of genital tract micro-regions. Introduction Tissue-resident Agnuside T-cells (Trm) are a population of memory cells which exist at mucosal sites, serve as a first point of contact between pathogenic viruses and the adaptive host immune system, and can rapidly recall canonical effector functions including cytolysis and secretion of inflammatory cytokines (1C3). Trm rapidly recognize viral target antigens that are expressed on infected cells, and initiate a generalized antiviral state consisting of both innate and acquired responses (4, 5). Both mouse studies (6C8), and mathematical modeling of human data (9C11), suggest that sufficiently large numbers of Trm induce a rapid enough local proliferative response to prevent widespread viral spread and tissue destruction (12, 13). During chronic human herpes simplex virus-2 (HSV-2) infection, both CD4+ and CD8+ T-cells persist at prior sites of viral reactivation in genital mucosa (14, 15). At the single cell level, Agnuside CD8+ T-cells demonstrate activated gene expression profiles many months after clearance of HSV-2 replication consistent with a Trm profile, suggesting that they play an immunosurveillance role (16). We recently developed mathematical models to link observed variability in HSV-2 shedding patterns in humans over short, and long, time intervals, with our observation of profound spatial heterogeneity in T-cell density across the genital tract (11). HSV-2 shedding consists of frequent episodes that vary enormously in terms of viral production, duration and clinical consequence (17). Our models predict that the density of CD8+ T-cells at the precise spatial location of an HSV-2 reactivation is an imprint of prior infection events, and is randomly determined based on the complex branching pattern of neuron Arnt endings, which release virus from latency into genital mucosa (10). A high density of CD8+ T-cells at the site where the first genital tract keratinocyte is infected, predicts rapid containment of HSV-2 spread to surrounding cells, whereas a low density is associated with symptomatic ulcers and prolonged shedding over many days (9). The heterogeneous imprint of HSV specific T-cells is a fundamental feature of chronic infection and is dynamic over space and time. HSV-2 replication at low Trm density sites Agnuside is a likely explanation for breakthrough shedding on high doses of available antiviral therapies (18C20). A recent observation in murine systems of infection is that Trm are highly mobile and actively patrol for infected cells. Patrolling Agnuside consists of generalized migration between keratinocytes, extension of dendritic arms to contact a maximal number of possible infected cells, and possible chemo-attraction towards infected cells within local microenvironments (21C23). Importantly, Trm movement is limited to a surface area within one mm of prior microscopic sites of infection due to the slow, random nature of migration (23). Upon encountering Agnuside an infected cell, Trm transform into a round morphology and proliferate locally (12, 13), cease further movement, and release interferon-gamma and other soluble factors to induce a broad antiviral program in susceptible target cells (21). Single CD8+ T-cells are then capable of eliminating multiple infected cells concurrently in a synergistic fashion with other T-cells (24). We observed slow linear decline in regional CD8+ T-cell density over months following herpetic.