title: 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) from latency rather than to primary acute infection. No herpes simplex vaccine is currently available for use in humans. In this study, we used the HLA-A*02:01 transgenic (HLA Tg) rabbit model of ocular herpes to assess the efficacy of a therapeutic vaccine based on HSV-1 gD epitopes that are recognized mainly by CD8(+) T cells from "naturally" protected HLA-A*02:01-positive, HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease). Three ASYMP CD8(+) T-cell epitopes (gD(53-61), gD(70-78), and gD(278-286)) were linked with a promiscuous CD4(+) T-cell epitope (gD(287-317)) to create 3 separate pairs of CD4-CD8 peptides, which were then each covalently coupled to an Nε-palmitoyl-lysine moiety, a Toll-like receptor 2 (TLR-2) ligand. This resulted in the construction of 3 CD4-CD8 lipopeptide vaccines. Latently infected HLA Tg rabbits were immunized with a mixture of these 3 ASYMP lipopeptide vaccines, delivered as eye drops in sterile phosphate-buffered saline (PBS). The ASYMP therapeutic vaccination (i) induced HSV-specific CD8(+) T cells that prevent HSV-1 reactivation ex vivo from latently infected explanted trigeminal ganglia (TG), (ii) significantly reduced HSV-1 shedding detected in tears, (iii) boosted the number and function of HSV-1 gD epitope-specific CD8(+) T cells in draining lymph nodes (DLN), conjunctiva, and TG, and (iv) was associated with fewer exhausted HSV-1 gD-specific PD-1(+) TIM-3+ CD8(+) T cells. The results underscore the potential of an ASYMP CD8(+) T-cell epitope-based therapeutic vaccine strategy against recurrent ocular herpes.
  
  
  OBJECTIVE
  Seventy 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.
authors: Arif A
authors: AA
authors: Khan
authors: Ruchi
authors: R
authors: Srivastava
authors: Aziz A
authors: AA
authors: Chentoufi
authors: Roger
authors: R
authors: Geertsema
authors: Nhi Thi Uyen
authors: NT
authors: Thai
authors: Gargi
authors: G
authors: Dasgupta
authors: Nelson
authors: N
authors: Osorio
authors: Mina
authors: M
authors: Kalantari
authors: Anthony B
authors: AB
authors: Nesburn
authors: Steven L
authors: SL
authors: Wechsler
authors: Lbachir
authors: L
authors: BenMohamed
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D017635:Clonal Anergy; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2; D022301:Herpes Simplex Virus Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007114:Immunization / Q000379:methods*; D016849:Keratitis, Herpetic / Q000276:immunology / Q000517:prevention & control*; D016131:Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology; D008565:Membrane Proteins / Q000032:analysis; D010750:Phosphoproteins; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis; D011817:Rabbits; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology; D017201:Virus Shedding
chemical_list: D018984:Epitopes, T-Lymphocyte; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D022301:Herpes Simplex Virus Vaccines; C574674:La protein, human; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D010750:Phosphoproteins; D061026:Programmed Cell Death 1 Receptor; D011993:Recombinant Fusion Proteins; D014614:Vaccines, Synthetic; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1