Herpes simplex virus type 1 (HSV-1) is a major cause of corneal blindness. In humans, corneal disease results from repeated reactivation of HSV-1 from a latent (quiescent) state that was established in the host sensory ganglia at the time of primary infection. Recent findings from several laboratories, including ours, challenge the general supposition that a lack of viral protein synthesis during HSV-1 latency precludes immune detection of latently infected neurons and immune modulation of the latent state. Rather, these findings give rise to a dynamic model of latency in which many reactivation attempts are aborted by a preemptive CD8+ T cell response in the latently infected ganglia. Our underlying hypothesis is that gene expression during latency allows ganglionic CD8+T cells to provide a 'just in time' mechanism to inhibit virus production in vivo. In this proposal, the concepts of antigen expression during latency and the enhancement of the immune-mediated maintenance of viral latency will be explored.
Specific Aim 1 will test the hypothesis that gene expression occurs in the TG during latency and induced reactivation without the production of infectious virus and 'true late' viral genes. We will derive recombinant HSV-1 that regulate two fluorescent proteins from different candidate viral promoters. Mice will be infected through the corneal route to establish latency. In conjunction with confocal imaging techniques, we will identify HSV-1 promoter activities in the TG of latently infected and reactivation-induced mice. Our model predicts that specific HSV-1 promoters are active during murine latency in the absence of late (gamma-2) genes and infectious virus.
In Specific Aim 2, we will test the hypothesis that immune infiltration of CD8+ T cells into the ganglia, and the protection they afford from reactivation, can be enhanced by persistent expression of viral epitopes in latently infected neurons. Viruses will be developed which express multimers of an immunodominant peptide under latency active promoters. Mice latently infected with such viruses will be assessed for CD8+ T cell infiltration and resistance to induced reactivation. Such studies will establish foundations for the design of vaccines to augment immune regulation of latency and reactivation.
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