Abstract
Hepatitis C virus (HCV) is a model for the study of virus–host interaction and host cell responses to infection. Virus entry into hepatocytes is the first step in the HCV life cycle, and this process requires multiple receptors working together. The scavenger receptor class B type I (SR-BI) and claudin-1 (CLDN1), together with human cluster of differentiation (CD) 81 and occludin (OCLN), constitute the minimal set of HCV entry receptors. Nevertheless, HCV entry is a complex process involving multiple host signaling pathways that form a systematic regulatory network; this network is centrally controlled by upstream regulators epidermal growth factor receptor (EGFR) and transforming growth factor β receptor (TGFβ-R). Further feedback regulation and cell-to-cell spread of the virus contribute to the chronic maintenance of HCV infection. A comprehensive and accurate disclosure of this critical process should provide insights into the viral entry mechanism, and offer new strategies for treatment regimens and targets for HCV therapeutics.
Highlights
Hepatitis C virus (HCV) is a hepatotropic member of the Flaviridae family
The results showed that virus internalization can be divided into the following steps: (1) the inward budding of the plasma membrane and the formation of a clathrin pit induced by particle attachment [47]; (2) the ubiquitination of a co-receptor molecule by c-Cbl upon the association of virus-receptor complexes with clathrin-coated pits, which is essential for the subsequent internalization and sorting into endosomes; (3) actin nucleation; and (4) the induction of clathrin-coated pit curvature and deformation by specialized adapter molecules epsins 1 and 3, and the linkage of clathrin coat to actin cytoskeleton, leading to membrane fission and endocytosis [84]
Extensive studies have been performed to unravel the molecular mechanisms of HCV entry—these studies were not sufficient to provide a complete understanding of virus entry mechanisms [131,132], nor are they sufficient to address the cure for HCV
Summary
Hepatitis C virus (HCV) is a hepatotropic member of the Flaviridae family. HCV causes chronic hepatitis, which may result in tissue damage, fibrosis, cirrhosis, and the eventual development of hepatocellular carcinoma (HCC) [1]. ApoE appears to play a important role for the formation and function of these LVPs [7,8,9,10,11,12] Because of this association, LVPs display a broad buoyant density profile, and the majority of infectious viral RNA in the plasma of infected patients coelute with very low-density lipoproteins (VLDLs) [3,13,14,15]. Since the discovery of HCV in 1989 [16], several experimental systems have been developed for the study of HCV, and numerous functional genomic and proteomic studies have been performed [17,18,19,20,21] These studies showed that HCV entry into hepatocytes involves a complex multi-step process that engages various cellular proteins. Because virus entry into host cells is the first step in the HCV life cycle, a comprehensive and accurate evaluation of the virus entry process should provide further insights into the mechanism, and offer paths for new treatment regimens and targets for HCV therapeutics
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