ABSTRACT HSV-1 infection is a leading cause of eye disease and genital herpes but no HSV-1 vaccines have shown efficacy in humans. It elicits only a partially protective immune response and can establish persistent latent infections virus in neurons. Induction of type I interferons (IFNs) is an early, pivotal host response to most pathogenic viruses that limits viral replication, induces apoptosis/autophagy of infected cells, and mobilizes other immune responses. Although strategic circumvention of IFN responses is a hallmark of many viruses, it has not been fully defined in HSV-1 infections. Using recombinant viruses to dissect of the roles of individual cytokines in the context of the complex in vivo immune response environment, we have generated compelling preliminary data that indicate that circumvention of the type 1 IFN response plays a key role in both primary HSV-1 infection and subsequent induction of latency in mouse models of ocular infection and implicate the latency-associated transcript (LAT) of HSV-1 in modulation of the effects. IFN and IFN transcripts are significantly downregulated in the trigeminal ganglia (TG) of wild-type mice after ocular infection with LAT(+) virus as compared with LAT(-) virus. HSV-1 recombinant viruses expressing anti-apoptotic genes in place of LAT restore the LAT(+) survival phenotype to IFNAR1-/- infected mice, which are more susceptible to HSV-1 infection than wt mice. These activities of LAT map to an 811 bp region of LAT, which encodes small non- coding RNAs (sncRNAs). These and other data suggest a highly innovative hypothetical model in which HSV-1 LAT promotes HSV-1 evasion of clearance by the IFN system during both primary ocular infection and reactivation in the TG by: (i) Suppressing the production of IFN2 and/or IFN; and (ii) Limiting the apoptotic effects of IFN production. This hypothesis will be tested in mouse models by: (1) Determining if HSV-1 down- regulation of IFN2 and IFN, but not IFN, affects primary infection, establishment of latency, and reactivation in the TG after ocular HSV-1 infection; fine mapping of the regions of LAT involved in these processes; and analysis of the binding of the sncRNAs to IFN2 and IFN promoters in vitro; (2) Identification of the specific roles of LAT in protecting against infection in IFNAR1-/- mice through analysis of apoptosis induction and interference with replication together with fine-mapping of the regions of LAT that mediate these effects; and (3) Analysis of the differential and combinatorial roles of LAT-dependent IFN2 and IFN regulation in latency- reactivation and primary HSV-1 infection using IFN-/-, IFN2-/-, and IFN2-/-IFN-/- mice. The results generated will identify the primary mechanisms utilized by HSV-1 to evade the host IFN system and provide a basis for strategies that can be used to prevent infection and minimize recurrent disease.