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.