Alternative endocytosis pathway for productive entry of hepatitis C virus

Mami Matsuda, Ryosuke Suzuki, Chikako Kataoka, Koichi Watashi, Hideki Aizaki, Nobuyuki Kato, Yoshiharu Matsuura, Tetsuro Suzuki, Takaji Wakita

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)


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, pHdependent 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 dynaminindependent in Hep3B/miR122 cells. Collectively, these data indicated that HCV entered different target cells through different entry routes.

Original languageEnglish
Pages (from-to)2658-2667
Number of pages10
JournalJournal of General Virology
Publication statusPublished - Dec 1 2014

ASJC Scopus subject areas

  • Virology


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