Herpes simplex virus type-1 (HSV-1) is the prototypic member of the Herpesviridae, with ~90% seroprevalence in adults. HSV causes cold sores, genital sores, and is the leading cause of viral encephalitis. HSV also causes ocular diseases ranging from self-limiting dendritic epithelial keratitis, conjunctivitis, and blepharitis to necrotizing stromal keratitis. The ability of HSV to establish latency renders it resistant to cure and represents a major hurdle in the prevention of herpetic diseases, the majority of which result from recrudescence of the virus from this latent state. In accordance with this significant clinical problem and this proposal, the NEI's August 2012 Strategic Plan seeks to elucidate innate and adaptive immune responses in the cornea, and to develop vaccines and treatments for HSV-induced keratitis. The over-arching goal of this project, now in its 24th year, is to study innate and adaptive immunity to HSV during all stages of pathogenesis. Our central hypothesis is that innate immunity, and the autophagy pathway (which acts in both innate and adaptive immunity) act in a compartment-specific fashion to control HSV replication and disease. We further hypothesize that pharmacological modulation of innate immunity and autophagy will result in significant clinical benefit and improved resolution of infection and disease. In this competing continuation we will continue to study the interplay of host immunity and viral immunomodulatory genes in the determination of the outcome of HSV acute and latent infections. Our overall approach will be to examine acute infection, establishment, and reactivation of latency of HSV in a murine corneal model. We will use mouse strains deficient in selected pathways of host immunity in combination with HSV recombinants lacking selected immunomodulatory genes. On the virus side we will focus on HSV γ34.5 and ICP0 which are critical and versatile virulence determinants that counter many aspects of the innate response. On the host side we will focus on the tissue-specific IFN responses that serve to control virus infection. Using mouse and HSV genetics simultaneously provides a synergistic approach to address our hypotheses, advance our understanding of HSV pathogenesis and develop novel therapies. If successful, this project will elucidate the molecular and cellular basis of a complex and clinically significant host-pathogen interface, and also test 2 new candidate therapeutic approaches that were identified during the previous funding cycle. The impact of this project will therefore stem from identification of novel therapeutic paths for treatment of HSV, and from performance of proof-of-principle experiments for novel therapies against HSV ocular disease. More generally, this work will impact our overall understanding of fundamental mechanisms that promote the lifelong persistence of this ubiquitous and significant ocular pathogen.