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In this study, we compared key steps in the replication cycle of three distinct PHEV isolates (VW572, Gent\/PS412, and Labadie) in mouse neuronal (N2a) cells. We found that PHEV-VW572 replicates more efficiently in these cells compared to the other two isolates. Interestingly, PHEV-VW572 showed high intracellular virus titers without efficient extracellular release. Further investigation revealed that PHEV-VW572, but not PHEV-Gent\/PS412, mainly uses multivesicular body (MVB)-derived exosomes for viral egress. Transmission electron microscopy confirmed the presence of complete PHEV-VW572 virions within intracellular vesicles and the release of fused PHEV-exosome structures near the plasma membrane. Finally, we showed that PHEV binding is restricted for all isolates. Still, we demonstrated that only PHEV-VW572 entry into cells is mediated by the tetraspanin CD81 receptor. Overall, these results suggest that PHEV-VW572 uses the MVB-derived exosomal pathway as a strategy to promote efficient infection and overcome the early restriction in neuronal cells. In addition, these findings highlight isolate-specific differences in PHEV neurotropism.<\/jats:p>\n                    <jats:sec>\n                      <jats:title>IMPORTANCE<\/jats:title>\n                      <jats:p>The neuropathogenesis of betacoronaviruses remains largely unclear despite the global impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. While these viruses are primarily known for their respiratory effects, mounting evidence suggests they can also cause significant neurological complications, ranging from mild symptoms such as headaches to severe outcomes, such as encephalitis and neurological diseases. The exact mechanisms by which coronaviruses affect the nervous system are still not fully understood, which hampers the development of adequate treatments and prevention strategies for these neurological disorders. In this study, we used the porcine hemagglutinating encephalomyelitis virus (PHEV) as a surrogate model for SARS-CoV-2 to further unravel the neuropathogenesis of betacoronaviruses.<\/jats:p>\n                    <\/jats:sec>\n                  <\/jats:sec>","DOI":"10.1128\/jvi.01171-25","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T12:28:41Z","timestamp":1759926521000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":4,"title":["Porcine hemagglutinating encephalomyelitis virus VW572 (not Gent\/PS412 and Labadie) uses the CD81 receptor and MVB-derived exosomal pathway for efficient entry and spread in neuronal 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