Abstract
HCV entry involves a complex interplay between viral and host molecules. During post-binding interactions, the viral E2 complexes with CD81 receptor for delivery to the tight junction proteins CLDN1 and OCLN, which aid in viral internalization. Targeting HCV entry receptors represents an appealing approach to inhibit viral infectivity. This study aimed at investigating the impact of targeting CLDN1 by microRNAs on HCV infectivity. miR-155 was previously shown to target the 3′UTR of CLDN1 mRNA. Therefore, miR-155 was used as a control in this study. In-silico analysis and luciferase reporter assay were utilized to identify potential targeting miRNAs. The impact of the identified miRNAs on CLDN1 mRNA and protein expression was examined by qRT-PCR, indirect immunofluorescence and western blotting, respectively. The role of the selected miRNAs on HCV infectivity was assessed by measuring the viral load following the ectopic expression of the selected miRNAs. miR-182 was identified in-silico and by experimental validation to target CLDN1. Both miR-155 and miR-182 inhibited CLDN1 mRNA and protein expression in infected Huh7 cells. Ectopic expression of miR-155 increased, while miR-182 reduced the viral load. In conclusion, despite repressing CLDN1, the impact of miR-155 and miR-182 on HCV infectivity is contradictory. Ectopic miR-182 expression is suggested as an upstream regulator of the entry factor CLDN1, harnessing HCV infection.
Highlights
Hepatitis C Virus (HCV, order unassigned, family Flaviviridae, genus Hepacivirus, species Hepatitis C virus) entry is a multistep process requiring a coordinated interaction between viral and host factors
Potential microRNAs that target the 3′UTR of CLDN1 were identified using the in silico analysis tools, miRanda, TargetScan, mirDIP, and miRwalk, which agreed upon the prediction of miR-182 to target the 3′UTR of CLDN1 with a high binding score (Figure 1A)
HCV entry into hepatocytes represents a pivotal step in the viral lifecycle essential for the initiation, spread, and maintenance of infection
Summary
Hepatitis C Virus (HCV, order unassigned, family Flaviviridae, genus Hepacivirus, species Hepatitis C virus) entry is a multistep process requiring a coordinated interaction between viral and host factors. LVPs initially interact with non-specific entry factors such as glycosaminoglycan (GAG) and LDL receptor (LDL-R) (Monazahian et al, 1999; Barth et al, 2003). This is followed by interaction miR-182 Represses CLDN1 with specific entry factors including the scavenger receptor B1 (SRB1), which in turn facilitates interaction of viral envelope proteins with CD81 receptor (Brazzoli et al, 2008; Dao Thi et al, 2012). In addition to its role in HCV entry, CLDN1 was shown to be essential for HCV spread between hepatocytes via cell-cell transmission (Timpe et al, 2008)
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