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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.

SUBMITTER: van Velzen M

PROVIDER: S-EPMC3744444 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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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.

van Velzen Monique M Jing Lichen L Osterhaus Albert D M E AD Sette Alessandro A Koelle David M DM Verjans Georges M G M GM

PLoS pathogens 20130815 8

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 control ...[more]

PMID: 23966859

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Project description:Background The trigeminal ganglion contains neurons that relay sensations of pain, touch, pressure, and many other somatosensory modalities to the central nervous system. The ganglion is also a reservoir for latent herpes virus 1 infection. To gain a better understanding of molecular factors contributing to migraine and headache, transcriptome analyses were performed on postmortem human trigeminal ganglia. Methods RNA-Seq measurements of gene expression were conducted on small sub-regions of 16 human trigeminal ganglia. The samples were also characterized for transcripts derived from viral and microbial genomes. Herpes simplex virus 1 (HSV-1) antibodies in blood were measured using the luciferase immunoprecipitation assay. Results Observed molecular heterogeneity could be explained by sampling of anatomically distinct sub-regions of the excised ganglia consistent with neurally-enriched and non-neural, i.e. Schwann cell, enriched subregions. The levels of HSV-1 transcripts detected in trigeminal ganglia correlated with blood levels of HSV-1 antibodies. Multiple migraine susceptibility genes were strongly expressed in neurally-enriched trigeminal samples, while others were expressed in blood vessels. Conclusions These data provide a comprehensive human trigeminal transcriptome and a framework for evaluation of inhomogeneous post-mortem tissues through extensive quality control and refined downstream analyses for RNA-Seq methodologies. Expression profiling of migraine susceptibility genes identified by genetic association appears to emphasize the blood vessel component of the trigeminovascular system. Other genes displayed enriched expression in the trigeminal compared to dorsal root ganglion, and in-depth transcriptomic analysis of the KCNK18 gene underlying familial migraine shows selective neural expression within two specific populations of ganglionic neurons. These data suggest that expression profiling of migraine-associated genes can extend and amplify the underlying neurobiological insights obtained from genetic association studies.

Dataset Information

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.

Publications

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.

Similar Datasets

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