PMID- 31826989 OWN - NLM STAT- MEDLINE DCOM- 20200821 LR - 20220720 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 94 IP - 5 DP - 2020 Feb 14 TI - Herpes Simplex Virus 1-Specific CD8(+) T Cell Priming and Latent Ganglionic Retention Are Shaped by Viral Epitope Promoter Kinetics. LID - 10.1128/JVI.01193-19 [doi] LID - e01193-19 AB - Reactivation of herpes simplex virus 1 (HSV-1) from neurons in sensory ganglia such as the trigeminal ganglia (TG) is influenced by virus-specific CD8(+) T cells that infiltrate the ganglia at the onset of latency and contract to a stable activated tissue-resident memory population. In C57BL/6 mice, half of HSV-specific CD8(+) T cells (gB-CD8s) recognize one dominant epitope (residues 498 to 505) on glycoprotein B (gB(498-505)), while the remainder (non-gB-CD8s) recognize 19 subdominant epitopes from 12 viral proteins. To address how expression by HSV-1 influences the formation and ganglionic retention of CD8(+) T cell populations, we developed recombinant HSV-1 with the native immunodominant gB epitope disrupted but then expressed ectopically from different viral promoters. In mice, the epitope expressed from the gB promoter restored full gB-CD8 immunodominance to 50%. Intriguingly, earlier expression from constitutive, immediate-early, and early promoters did not significantly increase immunodominance, indicating that these promoters cannot elicit more than half of the CD8 compartment. Epitope expressed from candidate viral promoters of "true late" HSV-1 genes either delayed or reduced the priming efficiency of gB-CD8s and their levels in the TG at early times. HSV expressing the epitope from the full latency-associated transcript promoter did not efficiently prime gB-CD8s; however, gB-CD8s primed by a concurrent wild-type flank infection infiltrated the TG and were retained long term, suggesting that latent epitope expression is sufficient to retain gB-CD8s. Taken together, the data indicate that viral promoters shape latent HSV-1-specific CD8(+) T cell populations and should be an important consideration in future vaccine design.IMPORTANCE Latency of HSV-1 in host neurons enables long-term persistence from which reactivation may occur to cause recurrent diseases, such as blinding herpetic stromal keratitis. Latency is not antigenically silent, and viral proteins are sporadically expressed at low levels without full virion production. This protein expression is recognized by ganglion-resident HSV-1-specific CD8(+) T cells that maintain a protective resident population. Since these T cells can influence lytic/latent decisions in reactivating neurons, we argue that improving their ganglionic retention and function may offer a strategy in vaccine design to reduce reactivation and recurrent disease. To understand factors driving the infiltration and retention of ganglionic CD8s, we examined several HSV recombinants that have different viral promoters driving expression of the immunodominant gB epitope. We show that the selection of epitope promoter influences CD8(+) T cell population hierarchies and their function. CI - Copyright (c) 2020 American Society for Microbiology. FAU - Treat, Benjamin R AU - Treat BR AD - Graduate Program in Microbiology and Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. FAU - Bidula, Sarah M AU - Bidula SM AD - Graduate Program in Molecular Virology and Microbiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. FAU - St Leger, Anthony J AU - St Leger AJ AUID- ORCID: 0000-0002-2547-200X AD - Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. AD - Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. FAU - Hendricks, Robert L AU - Hendricks RL AD - Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. AD - Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. AD - Department of Molecular Microbiology and Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. FAU - Kinchington, Paul R AU - Kinchington PR AUID- ORCID: 0000-0002-1901-9970 AD - Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA kinchingtonp@upmc.edu. AD - Department of Molecular Microbiology and Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. LA - eng GR - R00 EY025761/EY/NEI NIH HHS/United States GR - R01 EY026891/EY/NEI NIH HHS/United States GR - T32 AI049820/AI/NIAID NIH HHS/United States GR - P30 EY008098/EY/NEI NIH HHS/United States GR - R01 EY005945/EY/NEI NIH HHS/United States GR - R01 EY015291/EY/NEI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200214 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Immunodominant Epitopes) RN - 0 (Viral Envelope Proteins) RN - 0 (glycoprotein B, Simplexvirus) SB - IM MH - Animals MH - CD8-Positive T-Lymphocytes/*immunology MH - Chlorocebus aethiops MH - Disease Models, Animal MH - Female MH - Ganglia/*immunology MH - Ganglia, Sensory/immunology MH - Herpes Simplex/*immunology/virology MH - Herpesvirus 1, Human/genetics/*immunology MH - Immunodominant Epitopes/*immunology MH - Keratitis, Herpetic/immunology MH - Kinetics MH - Mice MH - Mice, Inbred C57BL MH - Trigeminal Ganglion/virology MH - Vero Cells MH - Viral Envelope Proteins/genetics PMC - PMC7022356 OTO - NOTNLM OT - CD8 T cell OT - HSV-1 OT - immunodominance OT - latency EDAT- 2019/12/13 06:00 MHDA- 2020/08/22 06:00 PMCR- 2020/08/14 CRDT- 2019/12/13 06:00 PHST- 2019/07/26 00:00 [received] PHST- 2019/12/02 00:00 [accepted] PHST- 2019/12/13 06:00 [pubmed] PHST- 2020/08/22 06:00 [medline] PHST- 2019/12/13 06:00 [entrez] PHST- 2020/08/14 00:00 [pmc-release] AID - JVI.01193-19 [pii] AID - 01193-19 [pii] AID - 10.1128/JVI.01193-19 [doi] PST - epublish SO - J Virol. 2020 Feb 14;94(5):e01193-19. doi: 10.1128/JVI.01193-19. Print 2020 Feb 14.