Exosome mimicry by a HAVCR1-NPC1 pathway of endosomal fusion mediates hepatitis A virus infection.

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Cell-to-cell communication by exosomes controls normal and pathogenic processes1,2. Viruses can spread in exosomes and thereby avoid immune recognition3. While biogenesis, binding, and uptake of exosomes are well-characterized4,5, delivery of exosome cargo into the cytoplasm is poorly understood3. We report that phosphatidylserine receptor HAVCR16,7 and cholesterol transporter NPC18 participate in cargo delivery from exosomes of hepatitis A virus (HAV)-infected cells (exo-HAV) by clathrin-mediated endocytosis. Using CRISPR/Cas9 knockouts we show that these two lipid receptors, which interact in the late endosome9, are necessary for membrane fusion and delivery of RNA from exo-HAVs into the cytoplasm. The HAVCR1/NPC1 pathway, which Ebola virus exploits to infect cells9, mediates HAV infection by exo-HAV indicating that viral infection by this exosome mimicry mechanism does not require an envelope glycoprotein. The luminal viral RNA but not endosomal uncoating of HAV particles (vpHAV) contained in the exosome is mainly responsible for exo-HAV infectivity as assessed by methylene blue-inactivation of non-encapsidated RNA. In contrast, infectivity of vpHAV is pH-independent and requires HAVCR1 or other yet unidentified receptor(s) but not NPC1. Our findings show that envelope glycoprotein-independent fusion mechanisms are shared by exosomes and viruses, and call for a reassessment of the role of envelope glycoproteins in infection.