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J Hepatol. 2019 Mar 15. pii: S0168-8278(19)30147-3. doi: 10.1016/j.jhep.2019.03.006. [Epub ahead of print]

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

Author information

1
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; College of Life Sciences, Shanghai University, Shanghai, China.
2
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
3
Department of Infectious Diseases, Molecular Virology, Heidelberg University, 69120 Heidelberg, Germany.
4
Department of Hepatology, First Hospital, Jilin University, Changchun, China.
5
State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences.
6
Department of Infectious Diseases, Molecular Virology, Heidelberg University, 69120 Heidelberg, Germany; German Center for Infectious Diseases, Heidelberg Partner Site, 69120 Heidelberg, Germany.
7
Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. Electronic address: glong@ips.ac.cn.

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.

KEYWORDS:

Exosome; HCV; Neutralizing antibodies; Syntenin

PMID:
30880226
DOI:
10.1016/j.jhep.2019.03.006

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