The long-term objectives of the Program Project are to identify the viral and cellular factors involved in the establishment, maintenance and reactivation of herpes simplex virus type 1 (HSV-1)/ latency and to determine the roles of these factors in the latency process To achieve these objectives, the following four projects are proposed. Project 5 (Knipe) will define the mariner in which the host immediate response induced by specific viral antigens affects latent infection by HSV-1. Special emphasis will be placed on the duration of cytokine expression and the T cell response following immunization. The identity of the viral functions required for long-term effects on neuronal gene expression will be determined using mutant viral strains. The mechanisms by which the LATs down-regulate productive-cycle gene expression and ICP8 stimulates accumulation of viral DNA in neurons will also be investigated. Project 6 (Coen) will investigate the mechanisms by which various recognized blocks to viral gene expression, including the LATs, are involved in maintaining HSV-1 latency. The molecular and genetic basis for the ability of an ACVr, TK- clinical isolate to establish and reactivate from latency will be investigated to identify viral functions able to compensate for TK in latency. Changes in host cell gene expression and factors affecting these changes during HSV-1 latency in mice will also be examined. Project 4 (Schaffer) will determine the kinetics and order of viral gene expression relative to the initiation of viral DNA replication in reactivating mouse TG. The roles of oriL and oriS, and specifically the 0BP and GR binding sites in these origins, in the initiation of DNA replication during reactivation in mouse TG and in rabbits will be investigated. The identity of cdks required for reactivation of HSV-1 from latency and the effects of cdks on the transactivating activity and post- translational modification of lCP0 will be identified. Project 7 (M. Greenberg) will characterize the neurotrophins, cytokines and neuropeptides in TG neurons that support HSV replication and determine whether these molecules can regulate HSV-1 latency and reactivation in TG cell cultures. The intracellular signaling pathways activated by stimuli that induce HSV-1 reactivation, and that mediate NGF withdrawal induced reactivation in sympathetic neurons will also be investigated. Collectively, the results of these studies will provide new insights into the mechanisms by which HSV-1 latency in established, maintained and reactivated in neurons. In turn, these insights will reveal novel strategies for intervening in this poorly understood aspect of HSV-1 pathogenesis.
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