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Recent studies indicate that, prior to cell lysis, naked viruses are packaged and released inside extracellular vesicles (EVs). This has been considered a pro\u2010viral mechanism because EV membranes protect enclosed virions from neutralizing antibodies. Here, we explored whether immune cells can respond to picornavirus\u2010induced EVs. Using two different picornaviruses, we demonstrate that EVs from virus\u2010infected cells stimulate human immune cells to produce the antiviral cytokine type I IFN and chemotactic cytokine IP\u201010. Virus\u2010containing EVs trigger higher cytokine levels than similar amounts of naked virus. Monocytes are the predominant cell type to interact with and respond to virus\u2010induced EVs. By blocking virion\u2010receptor interactions we demonstrate that both EV\u2010enclosed virions and additional host\/virus components in EVs aid in immune cell stimulation. This EV\u2010induced response may provide protection prior to lytic virus release and development of the humoral immune response. We further demonstrate that EV\u2010enclosed viruses, in contrast to naked virus, cannot be opsonized by neutralizing antibodies. This prevents enhanced uptake of EV\u2010enclosed virus and ensuing pro\u2010inflammatory cytokine production by immune cells needed for viral clearance. This work underscores the role of virus\u2010induced EVs in host antiviral responses to picornavirus infections.\n                  <\/jats:p>","DOI":"10.1002\/jev2.70305","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:34:22Z","timestamp":1782275662000},"source":"Crossref","is-referenced-by-count":1,"title":["Extracellular Vesicles Released by Picornavirus\u2010Infected Cells Modify Antiviral Immune Cell Responses"],"prefix":"10.1002","volume":"15","author":[{"given":"Xinyi","family":"Pei","sequence":"first","affiliation":[{"name":"Infection Biology Section, Division Infectious Diseases &amp; Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janine T. A. T.","family":"Stienstra","sequence":"additional","affiliation":[{"name":"Infection Biology Section, Division Infectious Diseases &amp; Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6577-3520","authenticated-orcid":false,"given":"Margarida","family":"Viola","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Experimental Cardiology Laboratory  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renee G. C.","family":"Maas","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Experimental Cardiology Laboratory  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyra A. Y.","family":"Defourny","sequence":"additional","affiliation":[{"name":"Infection Biology Section, Division Infectious Diseases &amp; Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Mul","sequence":"additional","affiliation":[{"name":"Research Facilities, Sanquin Research and Landsteiner Laboratory Amsterdam UMC, University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saskia C. A.","family":"de Jager","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Experimental Cardiology Laboratory  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joost P. G.","family":"Sluijter","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Experimental Cardiology Laboratory  Utrecht The Netherlands"},{"name":"Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank J. M.","family":"van Kuppeveld","sequence":"additional","affiliation":[{"name":"Virology Section, Division Infectious Diseases &amp; Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine Utrecht University  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3172-9959","authenticated-orcid":false,"given":"Esther N. 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