Abstract
Following acute infection of mucosal surfaces, herpes simplex virus 1 (HSV-1) establishes life-long latent infections within neurons, including sensory neurons in trigeminal ganglia (TG). Periodically, reactivation from latency occurs resulting in virus transmission and recurrent disease. In the absence of lytic cycle viral transcriptional proteins, host factors are predicted to mediate early stages of reactivation from latency. Previous studies suggested the canonical Wnt/β-catenin signaling pathway promotes productive infection. To further examine how the Wnt/β-catenin signaling pathway enhances productive infection, we examined two antagonists of the Wnt-signaling pathway. KYA1797K enhances formation of the β-catenin destruction complex, resulting in β-catenin degradation. Conversely, iCRT14 inhibits β-catenin dependent transcription by interfering with β-catenin interactions with T-cell factor/lymphoid enhancer factor (TCF)/Lef family of cellular transcription factors and interferes with TCF/Lef binding to DNA. iCRT14 and KYA1797K significantly inhibited HSV-1 productive infection in human and mouse neuronal cells and monkey kidney cells (VERO). Although iCRT14 was only effective when present throughout infection, delayed addition or early removal of KYA1797K did not significantly reduce its antiviral properties. KYA1797K had no effect on virus entry or penetration indicating it impairs certain aspects of viral replication. These studies demonstrated β-catenin promotes HSV-1 productive infection and indicate antagonists of the canonical Wnt/β-catenin signaling pathway may be effective anti-HSV therapeutic agents.