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ABSTRACT Infection by alphaherpesviruses invariably results in invasion of the peripheral nervous system (PNS) and establish-ment of either a latent or productive infection. Infection begins with long-distance retrograde transport of viral capsids and teg-ument proteins in axons toward the neuronal nuclei. Initial steps of axonal entry, retrograde transport, and replication in neuro-nal nuclei are poorly understood. To better understand how the mode of infection in the PNS is determined, we utilized a compartmented neuron culturing system where distal axons of PNS neurons are physically separated from cell bodies. We in-fected isolated axons with fluorescent-protein-tagged pseudorabies virus (PRV) particles andmonitored viral entry and trans-port in axons and replication in cell bodies during low and highmultiplicities of infection (MOIs of 0.01 to 100). We found a threshold for efficient retrograde transport in axons betweenMOIs of 1 and 10 and a threshold for productive infection in the neuronal cell bodies betweenMOIs of 1 and 0.1. Below anMOI of 0.1, the viral genomes that moved to neuronal nuclei were si-lenced. These genomes can be reactivated after superinfection by a nonreplicating virus, but not by a replicating virus. We fur-ther showed that viral particles at high-MOI infections compete for axonal proteins and that this competition determines the number of viral particles reaching the nuclei. Using mass spectrometry, we identified axonal proteins that are differentially regu-lated by PRV infection. Our results demonstrate the impact of the multiplicity of infection and the axonal milieu on the estab-lishment of neuronal infection initiated from axons. IMPORTANCE Alphaherpesvirus genomes may remain silent in peripheral nervous system (PNS) neurons for the lives of thei
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