Exosomes from hepatitis C infected patients transmit HCV infection and contain replication competent viral RNA in complex with Ago2-miR122-HSP90

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...

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Bibliographic Details
Published in:PLoS pathogens 2014-10, Vol.10 (10), p.e1004424-e1004424
Main Authors: Bukong, Terence N, Momen-Heravi, Fatemeh, Kodys, Karen, Bala, Shashi, Szabo, Gyongyi
Format: Article
Language:English
Subjects:
Argonaute Proteins - metabolism
Biology and Life Sciences
Cells, Cultured
Colleges & universities
Exosomes - metabolism
Experiments
Hepacivirus - physiology
Hepatitis
Hepatocytes - virology
HIV
HSP90 Heat-Shock Proteins - metabolism
Human immunodeficiency virus
Humans
Infections
Interferon
Liver
Liver diseases
Medicine and Health Sciences
MicroRNAs - metabolism
Microscopy
Protein Binding
Proteins
Receptors, Virus - isolation & purification
RNA, Viral - genetics
Signal transduction
Virus Replication - physiology
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Summary: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.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1004424