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Herpes simplex virus-1 (HSV-1), a human pathogen persisting in the majority of the adult population, shares neuroinvasive properties with Pseudorabies virus (PRV), a swine \u03b1-HV, commonly used as a model \u03b1-HV. Utilizing primary peripheral neuronal cultures, we previously showed that IFN-\u03bb pre-treatment significantly reduced PRV yield. In this paper, we further characterized the early and late neuronal responses to IFN-\u03bb by RNA-seq, and the antiviral potential of this response against HSV-1. Notably, HSV-1 exhibited neuron-specific resistance to IFN-\u03bb mediated antiviral responses both in murine primary neurons and human neuronal cells. An ICP34.5-deficient HSV-1 (\u039434.5) mutant showed IFN-\u03bb sensitivity in neurons, while replicating normally in untreated neurons showing that ICP34.5 is responsible for the neuron specific IFN-\u03bb resistance of HSV-1. Our results further demonstrate that RSAD2 is strongly induced by IFN-\u03bb in neurons, localizing to ER-associated membranes, and effectively restricting \u03b1-HV protein synthesis in the absence of ICP34.5. siRNA-mediated RSAD2 knockdown in IFN-\u03bb-primed primary neurons largely restored replication of \u039434.5 HSV-1, highlighting the role of this IFN-\u03bb induced host factor in neuronal infections. Together, neuronal IFN-\u03bb-induced RSAD2 and HSV-1 ICP34.5 define a neuron-specific antagonistic mechanism that collectively determines the replication efficiency of HSV-1 in the PNS.<\/jats:p>","DOI":"10.64898\/2026.06.01.729199","type":"posted-content","created":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T05:30:14Z","timestamp":1780464614000},"source":"Crossref","is-referenced-by-count":0,"title":["Differential Sensitivity of HSV-1 and PRV to IFN-\u03bb Reveals a Neuron-Specific Antiviral Role for RSAD2"],"prefix":"10.64898","author":[{"given":"Stephanie","family":"Salazar","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, CA 92697"},{"name":"The Center for Virus Research, University of California, Irvine, CA 92697"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khanh T. 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