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

Tissue-resident CD8⁺ T cells (T_rm) can rapidly eliminate virally infected cells, but their heterogeneous spatial distribution may leave gaps in protection within tissues. Although T_rm 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 Homo sapiens and predict that infection does not induce enough T_rm 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_rm 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_rm rather than spatial reassortment of these cells. The fixed spatial structure of T_rm induced by HSV-2 is sufficient for rapid elimination of infected cells but only in a portion of genital tract microregions.