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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.
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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.
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.
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.
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.
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