title: Exosomes from hepatitis C infected patients transmit HCV infection and contain replication competent viral RNA in complex with Ago2-miR122-HSP90.
abstract: Antibodies targeting receptor-mediated entry of HCV into hepatocytes confer limited therapeutic benefits. Evidence suggests that exosomes can transfer genetic materials between cells; however, their role in HCV infection remains obscure. Here, we show that exosomes isolated from sera of chronic HCV infected patients or supernatants of J6/JFH1-HCV-infected Huh7.5 cells contained HCV RNA. These exosomes could mediate viral receptor-independent transmission of HCV to hepatocytes. Negative sense HCV RNA, indicative of replication competent viral RNA, was present in exosomes of all HCV infected treatment non-responders and some treatment-naïve individuals. Remarkably, HCV RNA was associated with Ago2, HSP90 and miR-122 in exosomes isolated from HCV-infected individuals or HCV-infected Huh7.5 cell supernatants. Exosome-loading with a miR-122 inhibitor, or inhibition of HSP90, vacuolar H+-ATPases, and proton pumps, significantly suppressed exosome-mediated HCV transmission to naïve cells. Our findings provide mechanistic evidence for HCV transmission by blood-derived exosomes and highlight potential therapeutic strategies.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Terence N
authors.initials: TN
authors.lastname: Bukong
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Momen-Heravi
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Kodys
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Shashi
authors.initials: S
authors.lastname: Bala
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Gyongyi
authors.initials: G
authors.lastname: Szabo
mesh_terms: D060565:Argonaute Proteins / Q000378:metabolism; D002478:Cells, Cultured; D055354:Exosomes / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology*; D022781:Hepatocytes / Q000821:virology*; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism; D011485:Protein Binding; D012367:RNA, Viral / Q000235:genetics*; D011991:Receptors, Virus / Q000302:isolation & purification; D014779:Virus Replication / Q000502:physiology
chemical_list: C466422:AGO2 protein, human; D060565:Argonaute Proteins; D018841:HSP90 Heat-Shock Proteins; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D012367:RNA, Viral; D011991:Receptors, Virus