Therapeutic Immunization with a Mixture of Herpes Simplex Virus 1 Glycoprotein D-Derived “Asymptomatic” Human CD8 ⁺ T-Cell Epitopes Decreases Spontaneous Ocular Shedding in Latently Infected HLA Transgenic Rabbits: Association with Low Frequency of Local PD-1 ⁺ TIM-3 ⁺ CD8 ⁺ Exhausted T Cells

Abstract

Most blinding ocular herpetic disease is due to reactivation of herpes simplex virus 1 (HSV-1 IMPORTANCESeventy percent to 90% of adults harbor herpes simplex virus 1 (HSV-1), which establishes lifelong latency in sensory neurons of the trigeminal ganglia. This latent state sporadically switches to spontaneous reactivation, resulting in viral shedding in tears. Most blinding herpetic disease in humans is due to reactivation of HSV-1 from latency rather than to primary acute infection. To date, there is no licensed therapeutic vaccine that can effectively stop or reduce HSV-1 reactivation from latently infected sensory ganglia and the subsequent shedding in tears. In the present study, we demonstrated that topical ocular therapeutic vaccination of latently infected HLA transgenic rabbits with a lipopeptide vaccine that contains exclusively human "asymptomatic" CD8 ؉ T-cell epitopes successfully decreased spontaneous HSV-1 reactivation, as judged by a significant reduction in spontaneous shedding in tears. The findings should guide the clinical development of a safe and effective T-cell-based therapeutic herpes vaccine.

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

“…This was confirmed at the functional level by a decrease in the levels of CD107 a/b cytotoxic degranulation and by lower production of both IFN-␥ and tumor necrosis factor alpha (TNF-␣). These results are consistent with our recent finding of a significantly higher level of exhaustion of HSV-1 human epitope-specific CD8 ϩ T cells from TG of HLA Tg rabbits with higher virus reactivation compared to TG of HLA Tg rabbits with less virus reactivation (1,7,74). Because HSV-1 might coopt PD-1, TIM-3, 2B4, VISTA and/or TIGIT immune checkpoints as a strategy to evade CD8 ϩ T cell immune surveillance (70,75), a T cell-based immunotherapy will likely have to be combined with immune checkpoint blockade in order to reverse the dysfunction of antiviral CD8 ϩ T EM and CD8 ϩ T RM cells.…”

A Herpes Simplex Virus Type 1 Human Asymptomatic CD8+T-Cell Epitopes-Based Vaccine Protects Against Ocular Herpes in a “Humanized” HLA Transgenic Rabbit Model

“…4,5,25,26 Briefly, in 10 sequentially studied HLA-A*0201 positive, HSV-1 seropositive ASYMP individuals, the most frequent, robust, and polyfunctional gB-specific CD8 þ T-cell responses, as assessed by a combination of tetramer, IFN-cELISpot, CFSE proliferation, CD107 a/b cytotoxic degranulation, expression of GzmB, GzmK, PFN, were directed mainly against gB [17][18][19][20][21][22][23][24][25] , gB [342][343][344][345][346][347][348][349][350] , and gB 561-569 epitopes. Similarly, 3 of 10 potential VP11/12 peptides, VP11/12 66-74 , VP11/12 220-228 , and VP11/12 702-710 , were selected as being highly recognized by CD8 þ T cells from 10 HSV-1 seropositive ASYMP individuals, while CD8 þ T cells from ASYMP individuals significantly reacted to 3 of 10 VP13/14 epitopes (VP13/14 286-294 , VP13/14 504-512 , and VP13/14 544-552 ).…”

“…We selected 9 potential peptide epitopes from HSV-1: three from gB (gB [17][18][19][20][21][22][23][24][25] , gB [342][343][344][345][346][347][348][349][350] , and gB 561-569 ), three from VP11/12 (VP11/12 66-74 , VP11/12 220-228 , VP11/12 702-710 ), and three from VP13/14 (VP13/14 286-294 , VP13/14 504-512 , VP13/14 544-552 ; Table 1). Peptide epitopes were synthesized by 21st Century Biochemicals (Marlboro, MA, USA).…”

“…In the present study, based on the above observation in humans, we tested the hypotheses that: (1) an ocular herpes vaccine that exclusively includes ASYMP CD8 þ T-cell epitopes (while excluding SYMP T-cell epitopes) will be highly immunogenic and protective in the ''humanized'' HLA-A*02:01 transgenic rabbit (HLA-Tg rabbit) model of ocular herpes 17,18 and (2) immunization of HLA-Tg rabbits with a mixture of ASYMP human herpes T-cell epitopes selected from several HSV-1 Ags will generate multiepitopes and polyfunctional protective CD8 þ T-cell responses. To test these hypotheses, and to pave the way toward moving ASYMP multiepitopic peptide vaccines to clinical application, we used our recently developed HLA-Tg rabbit model.…”

Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44highCD62LlowCD8+TEMCells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Herpesvirus Infection

“…After primary (1°) ocular HSV-1 infection, the virus establishes latency in the sensory neurons of human trigeminal ganglia (TG), a state that lasts for the life of the host (1,(4)(5)(6). Sporadic reactivation of the virus from latently infected sensory neurons of TG produces virus shedding in tears, which can lead to either relatively harmless asymptomatic (ASYMP) secondary (2°) reinfection of the cornea (COR) or symptomatic (SYMP) recurrent corneal disease and potentially blinding herpetic stromal keratitis (HSK) (5)(6)(7)(8). The majority of HSVseropositive individuals are ASYMP (9-12).…”