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.
Highlights
Hepatitis C virus (HCV) infection is one of the leading causes of liver disease with over 170 million individuals chronically infected worldwide [1,2]
Evidence suggests that small host extracellular vesicles can mediate receptor-independent transfer of genetic material between cells, though their role in HCV transmission remains uncertain
Our study provides novel insights to an alternative mechanism of HCV transmission that can compromise anti-HCV immune therapies and proposes potential therapeutic approaches to block exosomemediated transmission of HCV infection
Summary
Hepatitis C virus (HCV) infection is one of the leading causes of liver disease with over 170 million individuals chronically infected worldwide [1,2]. Recent therapies with anti-HCV E1-E2 or other neutralizing antibodies that attempted to block HCV transmission achieved only limited success [4,5,6,7]. Given the importance of these viral envelope proteins in regulating HCV infection, numerous immune therapies have been developed to target and/or neutralize HCV envelope proteins [7,13,14,15]. Targeted antibody therapies have offered limited success in preventing liver allograft infection by HCV. A potent human-derived monoclonal antibody was demonstrated to effectively prevent and treat HCV1 infection in chimpanzees [7]. The same antibody was not completely effective in humans [7], raising the possibility of other mechanisms of virus entry into hepatocytes. Previous reports have suggested receptor independent transmission of HCV [6,16], though the precise mechanisms or possible therapeutic strategies remain to be explored
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