Exosomes from Hepatitis C Infected Patients Transmit HCV Infection and Contain Replication Competent Viral RNA in Complex with Ago2-miR122-HSP90

PLoS Pathogens

Shashi Bala¹  Fatemeh Momen-Heravi¹  Terence N. Bukong¹  Gyongyi Szabo¹  Karen Kodys¹ 

[1]Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America

关键词: Exosomes;    RNA extraction;    Negative-sense RNA viruses;    Hepatitis C virus;    Positive-sense RNA viruses;    RNA viruses;    RNA isolation;    Hepatocytes;   

DOI  :  10.1371/journal.ppat.1004424

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY