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bioRxiv · 10.64898/2026.06.01.729199

Differential Sensitivity of HSV-1 and PRV to IFN-{lambda} Reveals a Neuron-Specific Antiviral Role for RSAD2

Salazar, S.·Luong, K. T. Y.·Loaiza, A. D.·Cheng, D.·Drayman, N.·Koyuncu, O. O.
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Abstract

Alpha herpesviruses (-HV) initially infect mucosal epithelial cells and subsequently establish lifelong latency in the peripheral nervous system (PNS). 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 -HV, commonly used as a model -HV. Utilizing primary peripheral neuronal cultures, we previously showed that IFN-{lambda} pre-treatment significantly reduced PRV yield. In this paper, we further characterized the early and late neuronal responses to IFN-{lambda} by RNA-seq, and the antiviral potential of this response against HSV-1. Notably, HSV-1 exhibited neuron-specific resistance to IFN-{lambda} mediated antiviral responses both in murine primary neurons and human neuronal cells. An ICP34.5-deficient HSV-1 ({Delta}34.5) mutant showed IFN-{lambda} sensitivity in neurons, while replicating normally in untreated neurons showing that ICP34.5 is responsible for the neuron specific IFN-{lambda} resistance of HSV-1. Our results further demonstrate that RSAD2 is strongly induced by IFN-{lambda} in neurons, localizing to ER-associated membranes, and effectively restricting -HV protein synthesis in the absence of ICP34.5. siRNA-mediated RSAD2 knockdown in IFN-{lambda}-primed primary neurons largely restored replication of {Delta}34.5 HSV-1, highlighting the role of this IFN-{lambda} induced host factor in neuronal infections. Together, neuronal IFN-{lambda}-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.

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Salazar, S., Luong, K. T. Y., Loaiza, A. D., Cheng, D., Drayman, N., Koyuncu, O. O.. 2026-06-02. Differential Sensitivity of HSV-1 and PRV to IFN-{lambda} Reveals a Neuron-Specific Antiviral Role for RSAD2. https://doi.org/10.64898/2026.06.01.729199

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