Herpes simplex virus tegument protein VP11/12-derived epitopes preferentially recall polyfunctional effector memory CD8+ T cells from seropositive asymptomatic individuals and protect “humanized” HLA-A*02:01 transgenic mice against ocular herpes (VIR6P.1172)

Abstract

Abstract In this study, we used multiple prediction computer-assisted algorithms to identify 10 potential HLA-A*02:01-restricted CD8+ T cell epitopes from the 716 amino acids sequence of Herpes Simplex Virus type 1 virion tegument phosphoprotein 11/12 (HSV-1 VP11/12). Three out of ten epitopes exhibited high to moderate binding affinity to HLA-A*02:01 molecules. In ten sequentially studied HLA-A*02:01 positive, HSV seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease), the most frequent, robust and polyfunctional effector CD8+ T-cell responses, as assessed by a combination of tetramer frequency, granzyme B, granzyme K, perforin, CD107a/b cytotoxic degranulation, IFN-g and multiplex cytokines assays, were predominantly directed against three epitopes: VP11/1266-74, VP11/12220-228 and VP11/12702-710. Interestingly, ASYMP individuals had significantly higher proportion of CD45RAlowCCR7lowCD44highCD62LlowCD27lowCD28lowCD8+ effector memory T cells (TEM) specific to the three epitopes, compared to symptomatic (SYMP) individuals (with a history of numerous episodes of recurrent ocular herpetic disease). Moreover, immunization of HLA-A*02:01 transgenic mice with the three ASYMP CD8+ TEM cell epitopes induced a strong protective immunity against ocular herpes infection and disease. Our findings outline the features of protective HSV-specific CD8+ T cells that should guide the development of an effective T-cell-based herpes vaccine.