title: Local CD4 and CD8 T-cell reactivity to HSV-1 antigens documents broad viral protein expression and immune competence in latently infected human trigeminal ganglia.
abstract: Herpes simplex virus type 1 (HSV-1) infection results in lifelong chronic infection of trigeminal ganglion (TG) neurons, also referred to as neuronal HSV-1 latency, with periodic reactivation leading to recrudescent herpetic disease in some persons. HSV-1 proteins are expressed in a temporally coordinated fashion during lytic infection, but their expression pattern during latent infection is largely unknown. Selective retention of HSV-1 reactive T-cells in human TG suggests their role in controlling reactivation by recognizing locally expressed HSV-1 proteins. We characterized the HSV-1 proteins recognized by virus-specific CD4 and CD8 T-cells recovered from human HSV-1-infected TG. T-cell clusters, consisting of both CD4 and CD8 T-cells, surrounded neurons and expressed mRNAs and proteins consistent with in situ antigen recognition and antiviral function. HSV-1 proteome-wide scans revealed that intra-TG T-cell responses included both CD4 and CD8 T-cells directed to one to three HSV-1 proteins per person. HSV-1 protein ICP6 was targeted by CD8 T-cells in 4 of 8 HLA-discordant donors. In situ tetramer staining demonstrated HSV-1-specific CD8 T-cells juxtaposed to TG neurons. Intra-TG retention of virus-specific CD4 T-cells, validated to the HSV-1 peptide level, implies trafficking of viral proteins from neurons to HLA class II-expressing non-neuronal cells for antigen presentation. The diversity of viral proteins targeted by TG T-cells across all kinetic and functional classes of viral proteins suggests broad HSV-1 protein expression, and viral antigen processing and presentation, in latently infected human TG. Collectively, the human TG represents an immunocompetent environment for both CD4 and CD8 T-cell recognition of HSV-1 proteins expressed during latent infection. HSV-1 proteins recognized by TG-resident T-cells, particularly ICP6 and VP16, are potential HSV-1 vaccine candidates.
authors: Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
authors: Monique
authors: M
authors: van Velzen
authors: Lichen
authors: L
authors: Jing
authors: Albert D M E
authors: AD
authors: Osterhaus
authors: Alessandro
authors: A
authors: Sette
authors: David M
authors: DM
authors: Koelle
authors: Georges M G M
authors: GM
authors: Verjans
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000956:Antigens, Viral / Q000276:immunology* / Q000378:metabolism; D001344:Autopsy; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D016207:Cytokines / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics; D005455:Fluorescent Antibody Technique; D006561:Herpes Simplex / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D008875:Middle Aged; D009474:Neurons / Q000276:immunology / Q000378:metabolism / Q000821:virology; D012668:Trigeminal Ganglion / Q000166:cytology / Q000276:immunology / Q000821:virology*; D014764:Viral Proteins / Q000276:immunology / Q000378:metabolism*; D017735:Virus Latency / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D016207:Cytokines; D004279:DNA, Viral; D014764:Viral Proteins
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