Viral infection leads to the dysregulation and reprogramming of various cellular processes and pathways to establish a host environment that is suitable for its survival. Published data by our lab show the critical role of heparanase (HPSE), an endoglycosidase, that participates in the degradation and remodeling of the extracellular matrix (ECM) through cleavage of heparan sulfate (HS), a proteoglycan expressed on cell surfaces, during the course of viral infection. Our lab has shown that HPSE expression and activity is upregulated in response to HSV-1 infection, via NF-kB pathway and, in turn, HPSE facilitates HS shedding from plasma membrane helping the release of newly generated virions. However, HPSE exhibits non-enzymatic activity as well, and the involvement of HPSE in the regulation of downstream cellular processes and signal transduction pathways remains inconclusive. Recent findings by our lab suggest the involvement of both enzymatic and non-enzymatic HPSE in mediating the activity of β-catenin during viral replication and pathogenesis. Accumulating data reveals the importance of the β-catenin signal transduction in viral replication, pathogenesis and latency. β- catenin is an evolutionarily conserved and multifunctional protein involved in the transduction of Wnt signals as well as intercellular adhesion. The dysregulation of this pathway has been implicated in various pathological conditions. We have discovered that herpes simplex virus-1 (HSV-1) infection results in wnt-independent activation, nuclear translocation and signal transduction of β-catenin. Interestingly, inhibiting the binding of β- catenin with transcriptional coactivators, cAMP response element-binding protein CREB (CBP) and TCF4, results in robust inhibition of viral replication. However, the differential contributions of β-catenin signal transduction in primary viral infection and disease progression remains unknown. Given these findings, we hypothesize that β-catenin-dependent signaling increases viral replication and disease progression and that this activity is potentiated by HPSE. These hypotheses will be addressed under the following Specific Aims: (1) To identify the role of HPSE in potentiating β-catenin dependent transcription during HSV-1 infection and (2) To characterize the role of β-catenin in HSV-1 infection and disease progression. With results gathered from these studies, we aim to elucidate the differential contributions made by latent and active HPSE in potentiating the activity of β-catenin during HSV-1 infection, identify key pathways that β-catenin signal transduction may influence and expose key therapeutic targets in the treatment of ocular HSV-1.