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While the role of CD8 + T cells in the control of herpes simplex virus 1 (HSV-1) infection and disease is gaining wider acceptance, a direct involvement of effector CD4 + T cells in this protection and the phenotype and function of HSV-specific human CD4 + T cell epitopes remain to be fully elucidated. In the present study, we report that several epitopes from the HSV-1 virion tegument protein (VP11/12) encoded by UL46 are targeted by CD4 + T cells from HSV-seropositive asymptomatic individuals (who, despite being infected, never develop any recurrent herpetic disease). Among these, we identified two immunodominant effector memory CD4 + T EM cell epitopes, amino acids (aa) 129 to 143 of VP11/12 (VP11/12 129-143 ) and VP11/12 483-497 , using in silico , in vitro , and in vivo approaches based on the following: (i) a combination of the TEPITOPE algorithm and PepScan library scanning of the entire 718 aa of HSV-1 VP11/12 sequence; (ii) an in silico peptide-protein docking analysis and in vitro binding assay that identify epitopes with high affinity to soluble HLA-DRB1 molecules; and (iii) an ELISpot assay and intracellular detection of gamma interferon (IFN-γ), CD107 a/b degranulation, and CD4 + T cell carboxyfluorescein succinimidyl ester (CFSE) proliferation assays. We demonstrated that native VP11/12 129-143 and VP11/12 483-497 epitopes presented by HSV-1-infected HLA-DR-positive target cells were recognized mainly by effector memory CD4 + T EM cells while being less targeted by FOXP3 + CD4 + CD25 + regulatory T cells. Furthermore, immunization of HLA-DR transgenic mice with a mixture of the two immunodominant human VP11/12 CD4 + T EM cell epitopes, but not with cryptic epitopes, induced HSV-specific polyfunctional IFN-γ-producing CD107 ab+ CD4 + T cells associated with protective immunity against ocular herpes infection and disease. IMPORTANCE We report that naturally protected HSV-1-seropositive asymptomatic individuals develop a higher frequency of antiviral effector memory CD4 + T EM cells specific to two immunodominant epitopes derived from the HSV-1 tegument protein VP11/12. Immunization of HLA-DR transgenic mice with a mixture of these two immunodominant CD4 + T cell epitopes induced a robust antiviral CD4 + T cell response in the cornea that was associated with protective immunity against ocular herpes. The emerging concept of developing an asymptomatic herpes vaccine that would boost effector memory CD4 + and CD8 + T EM cell responses is discussed.

journal of virology

Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4<sup>+</sup>T<sub>EM</sub>Cells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in “Humanized” HLA-DR Transgenic Mice

Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4+TEMCells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in “Humanized” HLA-DR Transgenic Mice

Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4⁺T_EMCells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in “Humanized” HLA-DR Transgenic Mice