Claudin Association with CD81 Defines Hepatitis C Virus Entry

Harris, Helen J.; Davis, Chris; Mullins, Jonathan; Hu, Ke; Goodall, Margaret; Farquhar, Michelle J.; Mee, Christopher; McCaffrey, Kathleen; Young, Stephen G.; Drummer, Heidi E.; Balfe, Peter; McKeating, Jane A.

doi:10.1074/jbc.m110.104836

Cited by 187 publications

(217 citation statements)

References 58 publications

(127 reference statements)

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“…It is thought that the viral envelope glycoproteins E1 and E2 interact with these four (co)receptors sequentially and that these interactions are orchestrated by cell signaling processes (6,14,28). SR-BI may act early and the tight junction components may act later in this process (11,13,21,24,42). The exact mechanisms and sequence of the interactions remain to be determined, but the result is known to be the uptake of the virion or a virion-coreceptor complex into an endosomal compartment.…”

mentioning

confidence: 99%

Impact of Intra- and Interspecies Variation of Occludin on Its Function as Coreceptor for Authentic Hepatitis C Virus Particles

Ciesek

Westhaus

Wicht

et al. 2011

J Virol

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Hepatitis C virus (HCV) is characterized by a narrow host range and high interindividual variability in the clinical course of infection. Both of these traits are thought to be largely due to genetic variation between species and between individual hosts. The tight junction component occludin (OCLN) is essential for HCV entry into host cells, and the differences between human and murine OCLN are thought to account in part for the inability of HCV to infect mice and hence preclude their use as a convenient small-animal model. This study assesses the impact of genetic variation in OCLN on cell culture-grown HCV (HCVcc) using a newly generated and characterized OCLN low subclone of the Huh-7.5 cell line (Huh-7.5 subclone in which endogenous OCLN expression has been downregulated by a short hairpin RNA). We report the frequency of coding nonsynonymous single nucleotide polymorphisms, i.e., polymorphisms resulting in amino acid exchanges, present in the human population and determine their ability to function as HCV (co)receptors. Moreover, we show that murine OCLN can sustain HCVcc entry, albeit with about 5-fold reduced efficiency compared to that of human OCLN. This reduction in efficiency is due solely to two amino acid residues previously identified by others using an HCV pseudoparticle approach. Finally, we use the Huh-7.5/OCLN low cell line to show that HCV spread between neighboring cells is strictly dependent on OCLN.The hepatitis C virus (HCV) is a small enveloped viral pathogen of the Flaviviridae family with a single plus-strand RNA genome (26). About 130 million individuals worldwide are currently chronically HCV infected and thus at risk for the development of cirrhosis, end-stage liver disease, and hepatocellular carcinoma (34).HCV primarily infects and replicates in hepatocytes. All stages of its replication cycle are dependent on various hostencoded factors. Completion of the earliest stage of the replication cycle, HCV cell entry, requires at least four host factors on the hepatocyte surface. These include the tetraspanin CD81 (30), scavenger receptor class B type I (SR-BI) (32), and more recently described, the tight junction components claudin 1 (CLDN1) (13) and occludin (OCLN) (27,31). It is thought that the viral envelope glycoproteins E1 and E2 interact with these four (co)receptors sequentially and that these interactions are orchestrated by cell signaling processes (6,14,28). SR-BI may act early and the tight junction components may act later in this process (11,13,21,24,42). The exact mechanisms and sequence of the interactions remain to be determined, but the result is known to be the uptake of the virion or a virion-coreceptor complex into an endosomal compartment. Acidification then triggers fusion of the viral envelope with the endosomal membrane (20,24,40). This releases the nucleocapsid into the cytosol, completing the cell entry process.Only humans and chimpanzees are natural hosts of HCV. This is thought to be because HCV is unable to utilize other species' homologues of several esse...

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mentioning

confidence: 99%

Impact of Intra- and Interspecies Variation of Occludin on Its Function as Coreceptor for Authentic Hepatitis C Virus Particles

Ciesek

Westhaus

Wicht

et al. 2011

J Virol

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“…Concordant with this hypothesis, mutation of residues 32 and 48 in the first extracellular loop of CLDN1 that prevent HCV entry also abolish CLDN1-CD81 interaction [62]. Furthermore, antibodies directed against CLDN1 or CD81, inhibit HCV entry by perturbing CLDN1-CD81 interaction [62,63]. Recently, it has also been shown that epidermal growth factor receptor and ephrin receptor A2 act as host cofactors for HCV entry by regulating CLDN1-CD81 co-receptor association [64].…”

Section: Entry Mechanismsmentioning

confidence: 55%

“…However, it has been shown that CLDN1 and CD81 interact in fluorescence resonance energy transfer (FRET) and fluorescence intensity ratio (FIR) assays [61,62], suggesting that CLDN1 may be a partner of CD81 in a HCV receptor complex. Concordant with this hypothesis, mutation of residues 32 and 48 in the first extracellular loop of CLDN1 that prevent HCV entry also abolish CLDN1-CD81 interaction [62]. Furthermore, antibodies directed against CLDN1 or CD81, inhibit HCV entry by perturbing CLDN1-CD81 interaction [62,63].…”

Section: Entry Mechanismsmentioning

confidence: 99%

Hepatitis C virus entry into the hepatocyte

Belouzard¹,

Cocquerel²,

Dubuisson³

2011

Open Life Sciences

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Hepatitis C virus (HCV) is a small enveloped virus with a positive stranded RNA genome belonging to the Flaviviridae family. The virion has the unique ability of forming a complex with lipoproteins, which is known as the lipoviroparticle. Lipoprotein components as well as the envelope proteins, E1 and E2, play a key role in virus entry into the hepatocyte. HCV entry is a complex multistep process involving sequential interactions with several cell surface proteins. The virus relies on glycosaminoglycans and possibly the low-density lipoprotein receptors to attach to cells. Furthermore, four specific entry factors are involved in the following steps which lead to virus internalization and fusion in early endosomes. These molecules are the scavenger receptor SRB1, tetraspanin CD81 and two tight junction proteins, Claudin-1 and Occludin. Although they are essential to HCV entry, the precise role of these molecules is not completely understood. Finally, hepatocytes are highly polarized cells and which likely affects the entry process. Our current knowledge on HCV entry is summarized in this review.

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“…The choice of these two cell lines was based on the hypothesis that a possible mechanism for anti-CLDN-1 antiviral activity would be the disruption of the interaction between CLDN-1 and CD81 (Harris et al, 2010;Mailly et al, 2015) or other HCV receptors; therefore, we reasoned that using CLDN-1-transfected CHO cells (which do not express either CD81 or SRB1) or HEK 293 cells (not expressing SRB1) would render the surfaces of interaction of CLDN-1 with other HCV receptors more accessible to scFv binding.…”

Section: Resultsmentioning

confidence: 99%

Novel human anti-claudin 1 mAbs inhibit hepatitis C virus infection and may synergize with anti-SRB1 mAb

Paciello

Urbanowicz

Riccio

et al. 2016

Journal of General Virology

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Hepatitis C virus (HCV) is a major cause of chronic hepatitis and liver carcinoma and new therapies based on novel targets are needed. The tight junction protein claudin 1 (CLDN-1) is essential for HCV cell entry and spread, and anti-CLDN-1 rat and mouse mAbs are safe and effective in preventing and treating HCV infection in a human liver chimeric mouse model. To accelerate translation of these observations into a novel approach to treat HCV infection and disease in humans, we screened a phage display library of human single-chain antibody fragments by using a panel of CLDN-1-positive and -negative cell lines and identified phage specifically binding to CLDN-1. The 12 clones showing the highest levels of binding were converted into human IgG4. Some of these mAbs displayed low-nanomolar affinity, and inhibited infection of human hepatoma Huh7.5 cells by different HCV isolates in a dose-dependent manner. Cross-competition experiments identified six inhibitory mAbs that recognized distinct epitopes. Combination of the human anti-SRB1 mAb C-1671 with these anti-CLDN-1 mAbs could either increase or reduce inhibition of cell culture-derived HCV infection in vitro. These novel human anti-CLDN-1 mAbs are potentially useful to develop a new strategy for anti-HCV therapy and lend support to the combined use of antibodies targeting the HCV receptors CLDN-1 and SRB1, but indicate that care must be taken in selecting the proper combination.

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Claudin Association with CD81 Defines Hepatitis C Virus Entry

Cited by 187 publications

References 58 publications

Impact of Intra- and Interspecies Variation of Occludin on Its Function as Coreceptor for Authentic Hepatitis C Virus Particles

Impact of Intra- and Interspecies Variation of Occludin on Its Function as Coreceptor for Authentic Hepatitis C Virus Particles

Hepatitis C virus entry into the hepatocyte

Novel human anti-claudin 1 mAbs inhibit hepatitis C virus infection and may synergize with anti-SRB1 mAb

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