Evidence from C57BL/6 mice suggests that CD8(+) T cells, specific to the immunodominant
HSV-1 glycoprotein B (gB) H-2(b)-restricted
epitope (gB498-505), protect against ocular herpes
infection and disease. However, the possible role of CD8(+) T cells, specific to HLA-restricted gB
epitopes, in protective immunity seen in HSV-1-seropositive asymptomatic (ASYMP) healthy individuals (who have never had clinical herpes) remains to be determined. In this study, we used multiple prediction algorithms to identify 10 potential
HLA-A*02:01-restricted CD8(+)
T cell epitopes from the HSV-1 gB amino acid sequence. Six of these
epitopes exhibited high-affinity binding to
HLA-A*02:01 molecules. In 10 sequentially studied
HLA-A*02:01-positive, HSV-1-seropositive ASYMP individuals, the most frequent, robust, and polyfunctional CD8(+) T cell responses, as assessed by a combination of tetramer, IFN-γ-ELISPOT,
CFSE proliferation, CD107a/b cytotoxic degranulation, and multiplex
cytokine assays, were directed mainly against
epitopes gB342-350 and gB561-569. In contrast, in 10
HLA-A*02:01-positive, HSV-1-seropositive symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent clinical herpes disease) frequent, but less robust, CD8(+) T cell responses were directed mainly against nonoverlapping
epitopes (gB183-191 and gB441-449). ASYMP individuals had a significantly higher proportion of HSV-gB-specific CD8(+) T cells expressing CD107a/b degranulation marker and producing effector
cytokines IL-2, IFN-γ, and TNF-α than did SYMP individuals. Moreover, immunization of a novel herpes-susceptible
HLA-A*02:01 transgenic mouse model with ASYMP
epitopes, but not with SYMP
epitopes, induced strong CD8(+) T cell-dependent protective immunity against ocular herpes
infection and disease. These findings should guide the development of a safe and effective T cell-based herpes
vaccine.