Herpesviruses are ubiquitous and are responsible for significant human mortality and suffering both in terms of initial infections and (even more so) recurrences. In addition, with increasing occurrences of immunosuppressive disorders, a corresponding increase in the frequency of clinically significant initial and latent herpesvirus infections arise. Therefore, the long-term objective of this project is to gain a functional understanding of the herpesvinis-encoded genes involved in latency and reactivation - knowledge that is fundamental to the rational design of interventive therapies. We have identified a region of the genome termed the """"""""reactivation critical region"""""""" (rcr) that is required for epinephrine-induced reactivation. The primary focus of this proposal is to characterize the functional role sequence elements in the rcr of the Herpes simplex virus type 1 (HSV- 1) genome play in reactivation of infections latent in sensory ganglia neurons. The overriding hypothesis of this study is that the HSV rcr facilitates reactivation by regulating gene expression from the latent genome allowing the initiation of acute gene expression during reactivation. Using a molecular genetic approach involving specifically engineered viral recombinants, we will follow the transcriptional and replicative processes of HSV- 1 reactivation in the rabbit cornea-epinephrine model to link viral genetics with processes in animals. Specifically, the proposed studies will test three potential mechanisms by which the rcr functions to facilitate reactivation: a) the rcr acts as a modulator of transcription which facilitates reactivation by regulating the expression of LAT, ICPO and/or ICP4, b) the rcr is a target of methylation and/or cellular factors that regulate transcription during latency and reactivation, and c) the rcr acts as a non-coding functional RNA that regulates gene expression via a dosage compensation-like mechanism. These three mechanisms are not mutually exclusive and it is likely an interplay between these regulatory elements is necessary for the maintenance of and reactivation from latency. This work will lead to the identification of viral target(s) of host factors that communicate stress stimuli leading to reactivation.
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