A Fixed Spatial Structure of CD8+ T Cells in Tissue during Chronic HSV-2 Infection

Abstract

Tissue-resident CD8 T cells (T) can rapidly eliminate virally infected cells, but their heterogeneous spatial distribution may leave gaps in protection within tissues. Although T patrol prior sites of viral replication, murine studies suggest they do not redistribute to adjacent uninfected sites to provide wider protection. We perform mathematical modeling of HSV-2 shedding in and predict that infection does not induce enough T in many genital tract regions to eliminate shedding; a strict spatial distribution pattern of mucosal CD8 T cell density is maintained throughout chronic infection, and trafficking of T across wide genital tract areas is unlikely. These predictions are confirmed with spatial analysis of CD8 T cell distribution in histopathologic specimens from human genital biopsies. Further simulations predict that the key mechanistic correlate of protection following therapeutic HSV-2 vaccination would be an increase in total T rather than spatial reassortment of these cells. The fixed spatial structure of T induced by HSV-2 is sufficient for rapid elimination of infected cells but only in a portion of genital tract microregions.

Increased oral Epstein-Barr virus shedding with HIV-1 co-infection is due to a combination of B cell activation and impaired cellular immune control

“…We then fit this model to participant 308 data, seeking to determine the drivers of these differences. [45][46][47]. These previous models all captured the stochastic patterns 323 of HSV-2 shedding well, which appear similar to the patterns of oral EBV shedding.…”

Elimination of HSV-2 infected cells is mediated predominantly by paracrine effects of tissue-resident T cell derived cytokines

“…During chronic infection, genital tissue contains HSV-2 specific and bystander TRM months after local elimination of infected cells (9). The release of HSV-2 from latently infected ganglia via sensory neurons into genital tissues is temporally and spatially stochastic, resulting in seeding of low and high density TRM regions (19,20,50). Within micro-regions, the spatial heterogeneity of TRM results in highly variable amounts of viral replication and subsequent TRM-mediated expansion (21).…”

“…HSV-2 reactivates in specific micro-environments throughout the human genital tract because of random travelling of virions along highly arborized branches of peripheral neurons (37). We observed a fixed spatial meta-structure of CD8+ T-cell density in infected tissue, defined by dense clusters in some regions and low numbers in others (20). To characterize tissue micro-environments, we summarized TRM densities observed in 19 genital biopsy specimens ( Fig.…”

“…During HSV-2 infection in humans, cells with TRM characteristics cluster at the dermal-epidermal junction where neuron endings release HSV-2 into the mucosa (9,10,16). The heterogeneous spatial aggregation of TRM in genital skin explains the considerable variability of HSV-2 severity, including episodes which are contained after a few hours of viral replication and those that persist for many days and cause symptomatic lesions (17)(18)(19)(20)(21).…”

“…Analysis of human biopsy specimens of HSV-2 infected tissues reveals high-density clusters of TRM in certain micro-regions, with low densities of TRM in others (20). Yet, a majority of HSV-2 shedding episodes are eliminated within 6-24 hours (19,21,30).…”