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HTLV\u20101\u2010encoded proteins, like the transactivator and oncoprotein Tax\u20101, are loaded into EVs but their precise impact on EV cargos is not yet known. Here, we report a comprehensive interaction map between Tax\u20101 and the human PDZ (PSD95\/DLG\/ZO\u20101) proteins that regulate EVs formation and composition. We show that Tax\u20101 interacts with more than one\u2010third of hPDZome components, including proteins involved in cell cycle, cell\u2013cell junctions, cytoskeleton organization and membrane complex assembly. We extensively characterized Tax\u20101 interaction with syntenin\u20101, an evolutionary conserved PDZ hub that controls EV biogenesis. Using nuclear magnetic resonance (NMR) spectroscopy, we have determined the structural basis of the interaction between the\n                    <jats:italic>C<\/jats:italic>\n                    \u2010terminal PDZ binding motif of Tax\u20101, and two PDZ domains of syntenin\u20101. Importantly, we show that a small molecule able to inhibit HTLV\u20101 cell\u2010to\u2010cell transmission breaks the Tax\u20101\/syntenin\u20101 interaction, impacts the levels of syntenin\u20101 and viral proteins in EVs, and shifts the EV composition toward cellular antiviral proteins and microRNAs, including the miR\u2010320 family. Consequently, we demonstrate that mimics of miR\u2010320c, encapsulated into EVs, have antiviral activities with a potential to be used against HTLV\u20101 induced diseases.\n                  <\/jats:p>","DOI":"10.1002\/jev2.70137","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T09:55:22Z","timestamp":1754474122000},"source":"Crossref","is-referenced-by-count":6,"title":["Inhibitors of Tax1\u2010PDZ Interactions Block HTLV\u20101 Viral Transmission by Changing EV Composition"],"prefix":"10.1002","volume":"14","author":[{"given":"Jedidja","family":"Puttemans","sequence":"first","affiliation":[{"name":"Laboratory of Viral Interactomes, Unit of Molecular Biology of Diseases, GIGA Institute University of Liege  Li\u00e8ge Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmine","family":"Brammerloo","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Interactomes, Unit of Molecular Biology of Diseases, GIGA Institute University of Liege  Li\u00e8ge Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karim","family":"Blibek","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Interactomes, Unit of Molecular Biology of Diseases, GIGA Institute University of Liege  Li\u00e8ge Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy","family":"Blavier","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Interactomes, Unit of Molecular Biology of Diseases, GIGA Institute University of Liege  Li\u00e8ge Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thandokuhle","family":"Ntombela","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Interactomes, Unit of Molecular Biology of Diseases, GIGA Institute University of Liege  Li\u00e8ge Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inge","family":"Van Molle","sequence":"additional","affiliation":[{"name":"VIB\u2010VUB Center for Structural Biology Flemish Institute of Biotechnology (VIB), Pleinlaan 2  Brussels Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Joseph","sequence":"additional","affiliation":[{"name":"Department of Microbiology &amp; Immunology Drexel University College of Medicine  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Olivet","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Interactomes, Unit of Molecular Biology of Diseases, GIGA Institute University of Liege  Li\u00e8ge Belgium"},{"name":"Structural Biology Lab, Molecular Structural &amp; Translational Virology Group, Rega Institute for Medical Research and Department of Microbiology, Immunology and Transplantation KU Leuven  Leuven Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deeya","family":"Saha","sequence":"additional","affiliation":[{"name":"Laboratory of Viral Interactomes, Unit of Molecular Biology of Diseases, GIGA Institute University of Liege  Li\u00e8ge Belgium"},{"name":"Dept. 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