PMID- 29206240 OWN - NLM STAT- MEDLINE DCOM- 20180109 LR - 20201214 IS - 1553-7374 (Electronic) IS - 1553-7366 (Print) IS - 1553-7366 (Linking) VI - 13 IP - 12 DP - 2017 Dec TI - Influence of an immunodominant herpes simplex virus type 1 CD8+ T cell epitope on the target hierarchy and function of subdominant CD8+ T cells. PG - e1006732 LID - 10.1371/journal.ppat.1006732 [doi] LID - e1006732 AB - Herpes simplex virus type 1 (HSV-1) latency in sensory ganglia such as trigeminal ganglia (TG) is associated with a persistent immune infiltrate that includes effector memory CD8+ T cells that can influence HSV-1 reactivation. In C57BL/6 mice, HSV-1 induces a highly skewed CD8+ T cell repertoire, in which half of CD8+ T cells (gB-CD8s) recognize a single epitope on glycoprotein B (gB498-505), while the remainder (non-gB-CD8s) recognize, in varying proportions, 19 subdominant epitopes on 12 viral proteins. The gB-CD8s remain functional in TG throughout latency, while non-gB-CD8s exhibit varying degrees of functional compromise. To understand how dominance hierarchies relate to CD8+ T cell function during latency, we characterized the TG-associated CD8+ T cells following corneal infection with a recombinant HSV-1 lacking the immunodominant gB498-505 epitope (S1L). S1L induced a numerically equivalent CD8+ T cell infiltrate in the TG that was HSV-specific, but lacked specificity for gB498-505. Instead, there was a general increase of non-gB-CD8s with specific subdominant epitopes arising to codominance. In a latent S1L infection, non-gB-CD8s in the TG showed a hierarchy targeting different epitopes at latency compared to at acute times, and these cells retained an increased functionality at latency. In a latent S1L infection, these non-gB-CD8s also display an equivalent ability to block HSV reactivation in ex vivo ganglionic cultures compared to TG infected with wild type HSV-1. These data indicate that loss of the immunodominant gB498-505 epitope alters the dominance hierarchy and reduces functional compromise of CD8+ T cells specific for subdominant HSV-1 epitopes during viral latency. FAU - Treat, Benjamin R AU - Treat BR AUID- ORCID: 0000-0002-3385-0250 AD - Molecular Virology and Microbiology Graduate Program, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. AD - Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. FAU - Bidula, Sarah M AU - Bidula SM AD - Molecular Virology and Microbiology Graduate Program, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. AD - Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. FAU - Ramachandran, Srividya AU - Ramachandran S AUID- ORCID: 0000-0001-7080-4942 AD - Molecular Virology and Microbiology Graduate Program, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. AD - Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. FAU - St Leger, Anthony J AU - St Leger AJ AUID- ORCID: 0000-0002-2547-200X AD - Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. AD - Immunology Graduate Program, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. FAU - Hendricks, Robert L AU - Hendricks RL AUID- ORCID: 0000-0001-7419-2912 AD - Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. AD - Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. AD - Department of Microbiology and Molecular Genetics, Pittsburgh, Pennsylvania, United States of America. FAU - Kinchington, Paul R AU - Kinchington PR AUID- ORCID: 0000-0002-1901-9970 AD - Molecular Virology and Microbiology Graduate Program, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. AD - Department of Ophthalmology, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America. AD - Department of Microbiology and Molecular Genetics, Pittsburgh, Pennsylvania, United States of America. LA - eng GR - R01 AI122640/AI/NIAID 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 - Comparative Study PT - Journal Article DEP - 20171204 PL - United States TA - PLoS Pathog JT - PLoS pathogens JID - 101238921 RN - 0 (DNA, Recombinant) RN - 0 (Immunodominant Epitopes) RN - 0 (Peptide Fragments) RN - 0 (Recombinant Fusion Proteins) RN - 0 (Viral Envelope Proteins) RN - 0 (glycoprotein B, human herpesvirus 1) SB - IM MH - Amino Acid Substitution MH - Animals MH - CD8-Positive T-Lymphocytes/immunology/pathology/*virology MH - Cell Line MH - Cells, Cultured MH - Chlorocebus aethiops MH - DNA, Recombinant/metabolism MH - Eye Infections, Viral/immunology/metabolism/pathology/virology MH - Female MH - Gene Deletion MH - Herpes Simplex/*immunology/metabolism/pathology/virology MH - Herpesvirus 1, Human/*immunology/physiology MH - Immunodominant Epitopes/*metabolism MH - Mice, Inbred C57BL MH - Peptide Fragments/chemistry/metabolism MH - Point Mutation MH - Recombinant Fusion Proteins/chemistry/metabolism MH - Trigeminal Ganglion/immunology/pathology/*virology MH - Vero Cells MH - Viral Envelope Proteins/chemistry/genetics/*metabolism MH - Virus Activation MH - Virus Latency PMC - PMC5736228 COIS- The authors have declared that no competing interests exist. EDAT- 2017/12/06 06:00 MHDA- 2018/01/10 06:00 PMCR- 2017/12/04 CRDT- 2017/12/06 06:00 PHST- 2017/04/26 00:00 [received] PHST- 2017/11/03 00:00 [accepted] PHST- 2017/12/19 00:00 [revised] PHST- 2017/12/06 06:00 [pubmed] PHST- 2018/01/10 06:00 [medline] PHST- 2017/12/06 06:00 [entrez] PHST- 2017/12/04 00:00 [pmc-release] AID - PPATHOGENS-D-17-00877 [pii] AID - 10.1371/journal.ppat.1006732 [doi] PST - epublish SO - PLoS Pathog. 2017 Dec 4;13(12):e1006732. doi: 10.1371/journal.ppat.1006732. eCollection 2017 Dec.