Influence of an immunodominant herpes simplex virus type 1 CD8+ T cell epitope on the target hierarchy and function of subdominant CD8+ T cells

Herpes simplex virus type 1 (HSV-1) latency in sensory ganglia such as trigeminal ganglia (TG) is associated with a persistent immune infiltrate that includes effector memory CD8 + T cells that can influence HSV-1 reactivation. In C57BL/6 mice, HSV-1 induces a highly skewed CD8 + T cell repertoire, in which half of CD8 + T cells (gB-CD8s) recognize a single epitope on glycoprotein B (gB 498-505 ), while the remainder (non-gB-CD8s) recognize, in varying proportions, 19 subdominant epitopes on 12 viral proteins. The gB-CD8s remain functional in TG throughout latency, while non-gB-CD8s exhibit varying degrees of functional compromise. To understand how dominance hierarchies relate to CD8 + T cell function during latency, we characterized the TG-associated CD8 + T cells following corneal infection with a recombinant HSV-1 lacking the immunodominant gB 498-505 epitope (S1L). S1L induced a numerically equivalent CD8 + T cell infiltrate in the TG that was HSV-specific, but lacked specificity for gB 498-505 . Instead, there was a general increase of non-gB-CD8s with specific subdominant epitopes arising to codominance. In a latent S1L infection, non-gB-CD8s in the TG showed a hierarchy targeting different epitopes at latency compared to at acute times, and these cells retained an increased functionality at latency. In a latent S1L infection, these non-gB-CD8s also display an equivalent ability to block HSV reactivation in ex vivo ganglionic cultures compared to TG infected with wild type HSV-1. These data indicate that loss of the immunodominant gB 498-505 epitope alters the dominance hierarchy and reduces functional compromise of CD8 + T cells specific for subdominant HSV-1 epitopes during viral latency.