Broadening the Repertoire of Functional Herpes Simplex Virus Type 1–Specific CD8+ T Cells Reduces Viral Reactivation from Latency in Sensory Ganglia

Abstract

A large proportion of the world population harbors HSV type 1 (HSV-1) in a latent state in their trigeminal ganglia (TG). TG-resident CD8+ T cells appear important for preventing HSV-1 reactivation from latency and recurrent herpetic disease. In C57BL/6J mice, half of these cells are specific for an immunodominant epitope on HSV-1 glycoprotein B, whereas the other half are specific for 18 subdominant epitopes. In this study, we show that the CD8+ T cell dominance hierarchy in the TG established during acute infection is maintained during latency. However, CD8+ T cells specific for subdominant epitopes lose functionality, whereas those specific for the immunodominant epitope exhibit increased functionality in latently infected TG. Furthermore, we show that IL-10 produced by 16.4 ± 2.8% of TG-resident CD4+ T cells maintains the immunodominance hierarchy in part through selective inhibition of subdominant CD8+ T cell proliferation. Upon systemic anti–IL-10R Ab treatment, we observed a significant expansion of functional subdominant CD8+ T cells, resulting in significantly improved protection from viral reactivation. In fact, systemic anti–IL-10R Ab treatment prevented viral reactivation in up to 50% of treated mice. Our results not only demonstrate that HSV-1 reactivation from latency can be prevented by expanding the repertoire of functional TG-resident CD8+ T cells, but also that IL-10R blockade might have therapeutic potential to reduce or eliminate recurrent herpetic disease.