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J Gen Virol. 2014 Dec;95(Pt 12):2658-67. doi: 10.1099/vir.0.068528-0. Epub 2014 Aug 5.

Alternative endocytosis pathway for productive entry of hepatitis C virus.

Author information

1
Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan.
2
Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan ryosuke@niid.go.jp.
3
Department of Tumor Virology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
4
Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
5
Department of Infectious Diseases, Hamamatsu University School of Medicine, Shizuoka, Japan.

Abstract

Previous studies have shown that hepatitis C virus (HCV) enters human hepatic cells through interaction with a series of cellular receptors, followed by clathrin-mediated, pH-dependent endocytosis. Here, we investigated the mechanisms of HCV entry into multiple HCV-permissive human hepatocyte-derived cells using trans-complemented HCV particles (HCVtcp). Knockdown of CD81 and claudin-1, or treatment with bafilomycin A1, reduced infection in Huh-7 and Huh7.5.1 cells, suggesting that HCV entered both cell types via receptor-mediated, pH-dependent endocytosis. Interestingly, knockdown of the clathrin heavy chain or dynamin-2 (Dyn2), as well as expression of the dominant-negative form of Dyn2, reduced infection of Huh-7 cells with HCVtcp, whereas infectious entry of HCVtcp into Huh7.5.1 cells was not impaired. Infection of Huh7.5.1 cells with culture-derived HCV (HCVcc) via a clathrin-independent pathway was also observed. Knockdown of caveolin-1, ADP-ribosylation factor 6 (Arf6), flotillin, p21-activated kinase 1 (PAK1) and the PAK1 effector C-terminal binding protein 1 of E1A had no inhibitory effects on HCVtcp infection into Huh7.5.1 cells, thus suggesting that the infectious entry pathway of HCV into Huh7.5.1 cells was not caveolae-mediated, or Arf6- and flotillin-mediated endocytosis and macropinocytosis, but rather may have occurred via an undefined endocytic pathway. Further analysis revealed that HCV entry was clathrin- and dynamin-dependent in ORL8c and HepCD81/miR122 cells, but productive entry of HCV was clathrin- and dynamin-independent in Hep3B/miR122 cells. Collectively, these data indicated that HCV entered different target cells through different entry routes.

PMID:
25096815
DOI:
10.1099/vir.0.068528-0
[Indexed for MEDLINE]

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