PROJECT SUMMARY Spread of neuroinvasive herpesviruses from sensory neurons to the eye, brain, or from mother to newborn, are significant causes of morbidity and mortality. Herpes simplex virus type 1 (HSV1) and pseudorabies virus (PRV) are representative members of the two genuses of mammalian neuroinvasive herpesviruses (simplexviruses & varicelloviruses). These viruses are dependent upon spread to the nervous system to establish life-long latent infections, yet very little is known regarding the neuroinvasive mechanism that underlies this remarkable trait. We propose to study the virus neuroinvasive machinery with the intent to: (i) decipher how these viruses invade the nervous system, (ii) understand the intrinsic barriers to neural infection that these viruses evade, and (iii) produce and characterize viruses lacking the neuroinvasive property as potential vaccines and recombinant vectors. These studies are designed to identify the virus-cellular interactions that promote virus genome delivery to the nuclei of non-neuronal and neuronal cells, and the corresponding intrinsic defenses that keep most pathogens at bay. We include preliminary data demonstrating that this path-breaking collaborative study has far-reaching medical and biological implications.