HSV type 1 (HSV-1) expresses its genes sequentially as immediate early (α), early (β), leaky late (γ1), and true late (γ2), where viral DNA synthesis is an absolute prerequisite only for γ2 gene expression. The γ1 protein glycoprotein B (gB) contains a strongly immunodominant CD8⁺ T cell epitope (gB_498–505) that is recognized by 50% of both the CD8⁺ effector T cells in acutely infected trigeminal ganglia (TG) and the CD8⁺ memory T cells in latently infected TG. Of 376 predicted HSV-1 CD8⁺ T cell epitopes in C57BL/6 mice, 19 (gB_498–505 and 18 subdominant epitopes) stimulated CD8⁺ T cells in the spleens and TG of HSV-1 acutely infected mice. These 19 epitopes identified virtually all CD8⁺ T cells in the infected TG that represent all or the vast majority of the HSV-specific CD8⁺ TCR repertoire. Only 11 of ∼84 HSV-1 proteins are recognized by CD8⁺ T cells, and most (∼80%) are expressed before viral DNA synthesis. Neither the immunodominance of gB_498–505 nor the dominance hierarchy of the subdominant epitopes is due solely to MHC or TCR affinity. We conclude that the vast majority of CD8⁺ T cells in HSV-1 acutely infected TG are HSV specific, that HSV-1 β and γ1 proteins that are expressed before viral DNA synthesis are favored targets of CD8⁺ T cells, and that dominance within the TCR repertoire is likely due to the frequency or expansion and survival characteristics of CD8⁺ T cell precursors.

Human alphaherpesviruses including herpes simplex viruses (HSV-1, HSV-2) and varicella zoster virus (VZV) establish persistent latent infection in sensory neurons for the life of the host. All three viruses have the potential to reactivate causing recurrent disease. Regardless of the homology between the different virus strains, the three viruses are characterized by varying pathologies. This review will highlight the differences in infection pattern, immune response, and pathogenesis associated with HSV-1 and VZV.