HCV transmission by hepatic exosomes establishes a productive infection

Abstract

Recent evidence indicates there is a role for small mem- brane vesicles, including exosomes, as vehicles for intercellular com- munication. Exosomes secreted by most cell types can mediate transfer of proteins, mRNAs, and microRNAs, but their role in the transmission of infectious agents is less established. Recent studies have shown that hepatocyte-derived exosomes containing hepatitis C virus (HCV) RNA can activate innate immune cells, but the role of exosomes in the transmission of HCV between hepatocytes remains unknown. In this study, we investigated whether exosomes transfer HCV in the presence of neutralizing antibodies. Purified exo- somes isolated from HCV-infected human hepatoma HuH7.5.1 cells were shown to contain full-length viral RNA, viral protein, and par- ticles, as determined by RT-PCR, mass spectrometry, and transmis- sion electron microscopy. Exosomes from HCV-infected cells were capable of transmitting infection to naive human hepatoma HuH7.5.1 cells and establishing a productive infection. Even with subgenomic replicons, lacking structural viral proteins, exosome- mediated transmission of HCV RNA was observed. Treatment with patient-derived IgGs showed a variable degree of neutralization of exosome-mediated infection compared with free virus. In conclusion, this study showed that hepatic exosomes can transmit productive HCV infection in vitro and are partially resistant to antibody neutral- ization. This discovery sheds light on neutralizing antibodies resistant to HCV transmission by exosomes as a potential immune evasion mechanism.