The presence of latent virus influences the maintenance and phenotype of the HSV-specific CD8 memory population

HSV-1 establishes latency in sensory neurons of the trigeminal ganglia (TG) following corneal infection. The concept that latently infected neurons are ignored by the host immune response has given way to the notion that CD8 T cells maintained in the TG monitor infected neurons thereby subverting reactivation. The tendency of HSV-1 to periodically reactivate in humans and mediate recurrent disease is associated with significant morbidity. A desire to understand the complex interactions of this pathogen, the neurons that harbor it, and the immune system that monitors latency define this study. Two populations of CD8 T cells rapidly infiltrate the TG coincident with resolution of replicating virus and juxtapose with neurons for the life of the mouse. One population recognizes the immunodominant glycoprotein B (gB) epitope while the other does not (gB-nonspecific). We establish that the homeostatic cytokine IL-15 does not contribute to the maintenance of gB-specific or gB-nonspecific CD8 T cells within the TG during latency. However, IL-15 is crucial for the regulation of gB-specific memory CD8 T cells in noninfected tissues. These findings led us to question whether gB-nonspecific CD8 T cells are important in the HSV-1 response. We demonstrate that gB-nonspecific CD8 T cells upregulate the effector molecule granzyme B, and produce IFNã and proliferate in response to HSV-1-infected but not gB-transfected targets. This data conclusively shows that gB-nonspecific CD8 T cells in the infected TG are HSV-1 specific. This population is also capable of preventing reactivation following explant of latent TG. Contrary to their gB-specific CD8 counterparts, gB-nonspecific CD8 T cells have a reduced capacity to produce IFNã during latency and this reduction in function is associated with increased expression of PD-1. Surprisingly, blockade of PD-L1 did not rescue effector function yet increased the viral burden during latency. We show that a population of neurons expressing PD-L1 contains an enriched reservoir of HSV-1 latency that is highly prone to reactivate