Recurrences of herpes simplex virus infections afflict millions of Americans. Recurrent infections also serve as an important source of communicable virus. Clinical disease is especially important in the immunocompromised patients and in recurrences during childbirth. The applicant proposes to use a mouse foot pad model to study significant molecular events in the establishment, maintenance and reactivation phases of the herpes simplex virus cycle. The in vivo studies focus on the LAT cap region and LAT promoter, which is the only promoter active in latent infection. These studies include the specific mechanism for neuronal specific transcription in mouse neural tissues as well as the mechanism responsible for keeping the LAT promoter active during latency when all other promoters are shut off. Studies on the LAT intron will further document the molecular nature of this RNA including additional proofs that it is an intron by mutation of the splicing signals. Other experiments may provide some insight into why it is so stable. A fundamental switch in the virus life cycle between productive and latent infections may occur at the immediate-early stage of infection. Several studies are proposed to determine if there is site specific repression or inactivation of those genes in latently infected neurons.
