PMID- 25878105 OWN - NLM STAT- MEDLINE DCOM- 20150824 LR - 20181113 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 89 IP - 13 DP - 2015 Jul TI - 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. PG - 6619-32 AB - 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 Nepsilon-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. IMPORTANCE: 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. FAU - Khan, Arif A AU - Khan AA FAU - Srivastava, Ruchi AU - Srivastava R FAU - Chentoufi, Aziz A AU - Chentoufi AA FAU - Geertsema, Roger AU - Geertsema R FAU - Thai, Nhi Thi Uyen AU - Thai NT FAU - Dasgupta, Gargi AU - Dasgupta G FAU - Osorio, Nelson AU - Osorio N FAU - Kalantari, Mina AU - Kalantari M FAU - Nesburn, Anthony B AU - Nesburn AB FAU - Wechsler, Steven L AU - Wechsler SL FAU - BenMohamed, Lbachir AU - BenMohamed L LA - eng GR - EY14900/EY/NEI NIH HHS/United States GR - EY019896/EY/NEI NIH HHS/United States GR - R01 EY019896/EY/NEI NIH HHS/United States GR - EY024618/EY/NEI NIH HHS/United States GR - UL1 TR001414/TR/NCATS NIH HHS/United States GR - R01 EY014900/EY/NEI NIH HHS/United States GR - R01 EY024618/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (HAVCR2 protein, human) RN - 0 (Hepatitis A Virus Cellular Receptor 2) RN - 0 (Herpes Simplex Virus Vaccines) RN - 0 (La protein, human) RN - 0 (Membrane Proteins) RN - 0 (PDCD1 protein, human) RN - 0 (Phosphoproteins) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Vaccines, Synthetic) RN - 0 (Viral Envelope Proteins) RN - 0 (glycoprotein D, Human herpesvirus 1) SB - IM MH - Animals MH - Animals, Genetically Modified MH - CD8-Positive T-Lymphocytes/chemistry/*immunology MH - Clonal Anergy MH - Disease Models, Animal MH - Epitopes, T-Lymphocyte/genetics/*immunology MH - Female MH - Hepatitis A Virus Cellular Receptor 2 MH - Herpes Simplex Virus Vaccines/administration & dosage/genetics/*immunology MH - Herpesvirus 1, Human/genetics/*immunology MH - Humans MH - Immunization/*methods MH - Keratitis, Herpetic/immunology/*prevention & control MH - Lymphocyte Subsets/chemistry/immunology MH - Membrane Proteins/analysis MH - Phosphoproteins MH - Programmed Cell Death 1 Receptor/analysis MH - Rabbits MH - Recombinant Fusion Proteins/genetics/immunology MH - Vaccines, Synthetic/administration & dosage/genetics/immunology MH - Viral Envelope Proteins/genetics/immunology MH - *Virus Shedding PMC - PMC4468472 EDAT- 2015/04/17 06:00 MHDA- 2015/08/25 06:00 PMCR- 2016/01/01 CRDT- 2015/04/17 06:00 PHST- 2015/04/17 06:00 [entrez] PHST- 2015/04/17 06:00 [pubmed] PHST- 2015/08/25 06:00 [medline] PHST- 2016/01/01 00:00 [pmc-release] AID - JVI.00788-15 [pii] AID - 00788-15 [pii] AID - 10.1128/JVI.00788-15 [doi] PST - ppublish SO - J Virol. 2015 Jul;89(13):6619-32. doi: 10.1128/JVI.00788-15.