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-naive 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 naive cells. Our findings provide
mechanistic evidence for HCV transmission by blood-derived exosomes and highlight
potential therapeutic strategies.
