Syntenin regulates Hepatitis C virus sensitivity to neutralizing antibody by promoting E2 secretion through exosomes

Abstract Background & Aims Hepatitis C virus (HCV) is a major cause of chronic liver disease, infecting approximately 71 million people worldwide. Assembly of infectious HCV particles involves host lipoproteins, giving rise to unique lipo-viro-particles (LVPs), but proteome studies suggest that additional cellular proteins are associated with HCV virions or other particles containing the viral envelope glycoprotein E2. Many of these host cell proteins are common markers of exosomes, most notably the intracellular adaptor protein syntenin required exosome biogenesis. These observations suggest that E2 might be a component of both LVPs and exosomes produced from HCV infected cells. Methods Using HCVcc in both hepatoma cells and primary human hepatocytes (PHHs), we studied biogenesis and function of E2-coated exosomes. Results Knockout of syntenin had negligible impact on HCV replication and virus production whereas ectopic expression of syntenin at physiological level reduced intracellular E2 abundance concomitant with increased secretion of E2-coated exosomes. Importantly, cells expressing syntenin and HCV structural proteins efficiently released exosomes containing E2 but lacking the core protein. Furthermore, infectivity of HCV released from syntenin expressing hepatoma cell and PHHs was more resistant to neutralization by E2-specific antibodies and chronic-phase patient serum. Last, high E2/syntenin levels in sera correlates to lower serum neutralization capability. Conclusions E2- and syntenin-containing exosomes is a major type of particles released from cells high expressing syntenin. Efficient production of E2-coated exosomes in hepatoma cells and PHHs renders HCV infectivity less susceptible to antibody neutralization. Lay summary This study identifies a key role for syntenin in the regulation of E2 secretion via exosomes and sensitivity of HCV to neutralization. These results may have implications for the development of an HCV vaccine.