Cytotoxic Lymphocytes and HSV-1 Corneal Lesions

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): Recurrent herpes simplex virus type 1 (HSV-1) corneal disease, a leading cause of visual morbidity worldwide, results from reactivation of virus that is in a latent (quiescent) state in sensory neurons. During the past funding period we demonstrated that CD8+ T lymphocytes are selectively attracted to the ophthalmic branch of the trigeminal ganglion (TG), appear to form synaptic junctions with neurons, and become activated after the virus has established a latent infection. These findings refute the view that HSV-1 is invisible to the immune system during latency. Moreover, the HSV-1 specific CD8+ T cells were found to inhibit HSV-1 reactivation from latency in neurons, in part through the production of IFN-. In the next period we propose to use real-time fluorescence, and confocal imaging of whole TG and TG cultures, genetically modified mouse strains, and recombinant HSV-1 that express fluorescent proteins from a variety of viral promoters to directly explore the molecular interactions that maintain a pool of HSV-1 specific memory CD8+ T cells in the latently infected TG, and mediate their regulation of viral gene expression in neurons. In Specific Aim 1 we will identify the mechanisms by which CD8+ T cells can block HSV-1 reactivation from latency; in Specific Aim 2 we will identify factors that regulate differential expression of the functional program of CD8+ T cells in blocking HSV-1 reactivation from latency; and in Specific Aim 3 we will explore the factors that contribute to the maintenance of a pool of HSV-1 specific memory CD8+ T cells in the latently infected TG.