Hepatitis C Virus Entry Requires a Critical Postinternalization Step and Delivery to Early Endosomes via Clathrin-Coated Vesicles
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TL;DR: Observations indicate that, subsequent to internalization, HCVpp entry necessitates additional, low-pH-dependent interactions, modifications, or trafficking, and that these events are irreversibly disrupted by bafilomycin A1 treatment.
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Abstract: Hepatitis C virus (HCV) is a major human pathogen associated with life-threatening liver disease. Entry into hepatocytes requires CD81 and a putative second receptor. In this study, we elucidated the postreceptor attachment stages of HCV entry using HCV pseudoparticles (HCVpp) as a model system. By means of dominant-negative mutants and short interfering RNAs of various cellular proteins, we showed that HCVpp enter via clathrin-coated vesicles and require delivery to early but not to late endosomes. However, the kinetics of HCV envelope glycoprotein-mediated fusion are delayed compared to those of other viruses that enter in early endosomes. Entry of HCVpp can be efficiently blocked by bafilomycin A1, which neutralizes the pH in early endosomes and impairs progression of endocytosis beyond this stage. However, low-pH exposure of bafilomycin A1-treated target cells does not induce entry of HCVpp at the plasma membrane or in the early stages of endocytosis. These observations indicate that, subsequent to internalization, HCVpp entry necessitates additional, low-pH-dependent interactions, modifications, or trafficking, and that these events are irreversibly disrupted by bafilomycin A1 treatment.
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Citations
Recombinant Flag-tagged E1E2 glycoproteins from three hepatitis C virus genotypes are biologically functional and elicit cross-reactive neutralizing antibodies in mice.
Vasil B. Krapchev,Małgorzata Rychłowska,Alicja M Chmielewska,Karolina Zimmer,Arvind H. Patel,Krystyna Bieńkowska-Szewczyk +5 more
TL;DR: Analysis of immunogenicity of recombinant HCV envelope glycoproteins from genotypes 1a, 1b and 2a, with a Flag tag inserted in the hypervariable region 1 of E2 indicates that E1E2-Flag envelope gly coproteins could be important immunogen candidates for vaccine aiming to induce broad HCV-neutralizing responses.
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A New Model to Produce Infectious Hepatitis C Virus without the Replication Requirement
TL;DR: The production of authentic infectious HCV particles of virtually any genotype without the adaptive mutations associated with in vitro HCV replication represents a new paradigm to decipher the requirements for HCV assembly, release, and entry, amenable to analyses of wild type and genetically modified viruses of the most clinically significant HCV genotypes.
Identification of Piperazinylbenzenesulfonamides as New Inhibitors of Claudin-1 Trafficking and Hepatitis C Virus Entry.
Laura Riva,Ok-Ryul Song,Jannick Prentoe,François Helle,Laurent L'homme,Charles-Henry Gattolliat,Charles-Henry Gattolliat,Alexandre Vandeputte,Lucie Fénéant,Sandrine Belouzard,Thomas F. Baumert,Tarik Asselah,Tarik Asselah,Jens Bukh,Priscille Brodin,Laurence Cocquerel,Yves Rouillé,Jean Dubuisson +17 more
TL;DR: Findings reinforce the hypothesis of a common pathway, shared by several viruses, which involves G-protein-coupled receptor-dependent signaling in late steps of viral entry and suggests a role for the PKA pathway as a regulator of CLDN1 recycling, with impacts on both cell biology and virology.
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Computational identification of interplay between phosphorylation and O-β-glycosylation of human occludin as potential mechanism to impair hepatitis C virus entry
Azeem Mehmood Butt,Dandan Feng,Izza Nasrullah,Shifa Tahir,Muhammad Idrees,Yigang Tong,Jun Lu +6 more
TL;DR: Several conserved phosphorylation residues and kinases that can alter the ability of occludin to regulate the integrity of TJs were identified and a potential novel interplay betweenosphorylation and O-β-glycosylation at the two Yin Yang sites is proposed.
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Expression of human factors CD81, claudin-1, scavenger receptor, and occludin in mouse hepatocytes does not confer susceptibility to HCV entry
Keisuke Hikosaka,Hidenao Noritake,Wataru Kimura,Nishat Sultana,Mohammad Tofael Kabir Sharkar,Yoh-ichi Tagawa,Tadayoshi Uezato,Yoshimasa Kobayashi,Takaji Wakita,Naoyuki Miura +9 more
TL;DR: The expression of the human factors does not confer susceptibility to HCV entry into the liver, and primary mouse hepatocytes have the inhibitory factor(s) in HCVpp entry.
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