April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
A Compensatory CD8+T Cell Response In C57BL/6 Mice Trigeminal Ganglia Following Ocular Infection With HSV-1 Lacking The Immunodominant Epitope
Author Affiliations & Notes
  • Paul R. Kinchington
    Ophthalmology, Univ of Pittsburgh Eye & Ear Inst, Pittsburgh, Pennsylvania
  • Sarah M. Bidula
    Ophthalmology, Univ of Pittsburgh Eye & Ear Inst, Pittsburgh, Pennsylvania
  • Anthony J. St. Leger
    Ophthalmology, Univ of Pittsburgh Eye & Ear Inst, Pittsburgh, Pennsylvania
  • Srividya Ramachandran
    Ophthalmology, Univ of Pittsburgh Eye & Ear Inst, Pittsburgh, Pennsylvania
  • Bjoern Peters
    Center for Infectious Disease, Allergy & Asthma Research, La Jolla Institute for Allergy & Immunology, La Jolla, California
  • John Sidney
    Center for Infectious Disease, Allergy & Asthma Research, La Jolla Institute for Allergy & Immunology, La Jolla, California
  • Alessandro Sette
    Center for Infectious Disease, Allergy & Asthma Research, La Jolla Institute for Allergy & Immunology, La Jolla, California
  • Robert L. Hendricks
    Ophthalmology, Univ of Pittsburgh Eye & Ear Inst, Pittsburgh, Pennsylvania
  • Footnotes
    Commercial Relationships  Paul R. Kinchington, None; Sarah M. Bidula, None; Anthony J. St. Leger, None; Srividya Ramachandran, None; Bjoern Peters, None; John Sidney, None; Alessandro Sette, None; Robert L. Hendricks, None
  • Footnotes
    Support  NIH grants EY015291, EY005945, EY08098, HHSN272200700048C, Research to Prevent Blindness, Inc
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 3007. doi:https://doi.org/
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      Paul R. Kinchington, Sarah M. Bidula, Anthony J. St. Leger, Srividya Ramachandran, Bjoern Peters, John Sidney, Alessandro Sette, Robert L. Hendricks; A Compensatory CD8+T Cell Response In C57BL/6 Mice Trigeminal Ganglia Following Ocular Infection With HSV-1 Lacking The Immunodominant Epitope. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3007. doi: https://doi.org/.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Latent infection by herpes simplex virus type 1 (HSV-1) induces ganglionic infiltration by HSV-1-specific CD8+ T cells that can block HSV-1 reactivation from latency. Bolstering CD8+ T cell responses may reduce the incidence of recurrent HSV-1 disease including herpes keratitis. It is important to understand the viral antigens recognized by these CD8+ T cells and how mutations in viral proteins influence the dominance hierarchy of that response. Half of the CD8+ T cells in infected trigeminal ganglia (TG) of C57BL/6 mice recognize an immunodominant epitope on HSV-1 glycoprotein B (gB498-505): the other 50% recognize subdominant epitopes on 11 viral proteins. The goal of this study was to determine how mutating the immunodominant epitope would influence the specificity of CD8+ T cells in infected TG.

Methods: : We created HSV-1 mutated in the gB498-505 epitope and characterized their replication competence, recognition by gB498-505-specific CD8+ T cells, pathogenesis and latency establishment in vivo, and the size and specificity of the TG associated CD8+ T cell response. TG were removed 8 days after corneal infection with the mutant viruses, and the phenotype and function of the ganglion-resident CD8+ T cells was determined by immunofluorescence staining for surface markers and intracellular cytokines or with tetramers.

Results: : Two of 8 mutant HSV-1 altered in the gB498-505 epitope (F5L and L8A) exhibited wild type replication in vivo and in vitro, pathogenicity, and establishment of latency. They did not induce a gB498-505-specific CD8+ T cell response but induced CD8+ T cell TG infiltrates of comparable size to that induced by wild type HSV-1. The size of the infiltrate was maintained by a selective compensatory increase in CD8+ T cells specific for certain subdominant epitopes without apparent emergence of cryptic epitopes.

Conclusions: : We conclude that mutations that eliminate the strongly immunodominant HSV-1 gB498-505 epitope do not alter the size of the HSV-specific CD8+ T cell response, nor broaden the TCR repertoire through emergence of cryptic epitopes. Rather, a more even dominance hierarchy emerges with several formally subdominant epitopes rising to co-dominance. Whether this more balanced repertoire would provide more or less efficient protection remains to be determined.

Keywords: herpes simplex virus • protective mechanisms • immunomodulation/immunoregulation 
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