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Anthony B Nesburn, Arif Khan, Ruchi Srivastava, Steven L Wechsler1, Lbachir BenMohamed; Identification of Herpes Simplex Virus Glycoprotein B Human Epitopes That Preferentially Recall Polyfunctional CD8+ T Cells from Seropositive Asymptomatic Individuals and Protect HLA Transgenic Mice Against Ocular Herpes. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6255.
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© ARVO (1962-2015); The Authors (2016-present)
A staggering number of individuals carry HSV-1 that cause a wide range of ocular diseases throughout their life. Evidence from B6 mice suggests that CD8+ T-cells, specific to the immunodominant HSV-1 glycoprotein B (gB) H2b-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, several immunological assays, T cell from HSV-1 seropositive asymptomatic (ASYMP) healthy individuals vs. symptomatic (SYMP) ocular patients, and a novel susceptible HLA-A*02:01 transgenic mouse model of ocular herpes to identify HLA-A*02:01-restricted CD8+ T cell epitopes from the HSV-1 gB amino acid sequence that will protect from ocular herpes infection and disease.
Six out of ten epitopes exhibited high affinity binding to HLA-A*02:01 molecules. In ten 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 ten 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 non-overlapping 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.
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