Functional Analysis of Claudin-6 and Claudin-9 as Entry Factors for Hepatitis C Virus Infection of Human Hepatocytes by Using Monoclonal Antibodies

Fofana, Isabel; Zona, Laetitia; Thumann, Christine; Heydmann, Laura; Durand, Sarah; Lupberger, Joachim; Blum, Hubert E.; Pessaux, Patrick; Gondeau, Claire; Reynolds, Gary; McKeating, Jane A.; Fritz, Günter; Thompson, John S.; Zeisel, Mirjam B.; Baumert, Thomas F.

doi:10.1128/jvi.01691-13

Cited by 28 publications

(32 citation statements)

References 22 publications

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“…This may be due to the fact that CLDN1 is an essential factor for cell-cell transmission whereas SR-BI may be bypassed by other entry factors [10]. Although accessory receptors CLDN6 and 9 have been suggested to confer partial escape from CLDN1-targeting agents for certain isolates in Huh7.5 cells [56], escape could not be confirmed in primary human hepatocytes where expression of CLDN6 and 9 is very low [57].…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Cell-Cell Transmission and Resistance to Direct-Acting Antiviral Agents

et al. 2014

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Hepatitis C virus (HCV) is transmitted between hepatocytes via classical cell entry but also uses direct cell-cell transfer to infect neighboring hepatocytes. Viral cell-cell transmission has been shown to play an important role in viral persistence allowing evasion from neutralizing antibodies. In contrast, the role of HCV cell-cell transmission for antiviral resistance is unknown. Aiming to address this question we investigated the phenotype of HCV strains exhibiting resistance to direct-acting antivirals (DAAs) in state-of-the-art model systems for cell-cell transmission and spread. Using HCV genotype 2 as a model virus, we show that cell-cell transmission is the main route of viral spread of DAA-resistant HCV. Cell-cell transmission of DAA-resistant viruses results in viral persistence and thus hampers viral eradication. We also show that blocking cell-cell transmission using host-targeting entry inhibitors (HTEIs) was highly effective in inhibiting viral dissemination of resistant genotype 2 viruses. Combining HTEIs with DAAs prevented antiviral resistance and led to rapid elimination of the virus in cell culture model. In conclusion, our work provides evidence that cell-cell transmission plays an important role in dissemination and maintenance of resistant variants in cell culture models. Blocking virus cell-cell transmission prevents emergence of drug resistance in persistent viral infection including resistance to HCV DAAs.

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Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Cell-Cell Transmission and Resistance to Direct-Acting Antiviral Agents

et al. 2014

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“…However, the functional relevance of these findings is not clear. CLDN6 and CLDN9 expression could not be detected at the protein level in primary human hepatocytes [67], and CLDN6 protein expression could not be detected in liver sections [28]. Furthermore, anti-CLDN6 and anti-CLDN9 antibodies did not inhibit HCV infection of hepatoma cells or primary hepatocytes [28].…”

Section: Claudins and Viral Entrymentioning

confidence: 99%

“…CLDN6 and CLDN9 expression could not be detected at the protein level in primary human hepatocytes [67], and CLDN6 protein expression could not be detected in liver sections [28]. Furthermore, anti-CLDN6 and anti-CLDN9 antibodies did not inhibit HCV infection of hepatoma cells or primary hepatocytes [28]. Most importantly, treatment with an anti-CLDN1 monoclonal antibody cured chronically infected human liver chimeric mice, without escape [60].…”

Section: Claudins and Viral Entrymentioning

confidence: 99%

Claudins in viral infection: from entry to spread

Colpitts

Baumert

2016

Pflugers Arch - Eur J Physiol

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Tight junctions are critically important for many physiological functions, including the maintenance of cell polarity, regulation of paracellular permeability and involvement in signal transduction pathways to regulate integral cellular processes. Furthermore, tight junctions enable epithelial cells to form physical barriers, which act as an innate immune mechanism that can impede viral infection. Viruses, in turn, have evolved mechanisms to exploit tight junction proteins to gain access to cells or spread through tissues in an infected host. Claudin family proteins are integral components of tight junctions, and are thought to play crucial roles in regulating their permeability. Claudins have been implicated in the infection process of several medically important human pathogens, including hepatitis C virus, dengue virus, West Nile virus and human immunodeficiency virus, among others. In this review, we summarize the role of claudins in viral infections, and discuss their potential as novel antiviral targets. A better understanding of claudins during viral infection may provide insight into physiological roles of claudins and uncover novel therapeutic antiviral strategies.

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“…Other members of the claudin family, specifically CLDN6 and CLDN9, can also mediate HCV entry (Zheng et al, 2007). However, usage of different claudins appears to be dependent on the HCV isolate (Haid et al, 2014) but less in human hepatocytes (Fofana et al, 2013). …”

Section: Hcv Entry Factorsmentioning

confidence: 99%

The Impact of Hepatitis C Virus Entry on Viral Tropism

Ding

Schaewen

Ploß

2014

Cell Host & Microbe

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Uptake of hepatitis C virus (HCV) into hepatocytes is an orchestrated process, involving numerous host factors, virion-associated lipoproteins and a growing number of cell-associated factors. Several of these factors likely contribute to the hepatotropism and limited host range of this virus. Discerning the minimal set of human-specific factors required for viral uptake into non-human cells has facilitated the development of small animal models with inheritable HCV susceptibility. This review summarizes current knowledge of host factors required for HCV entry, the molecular mechanisms underlying HCV entry into hepatocytes, and aspects of viral entry contributing to HCV host tropism.

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Functional Analysis of Claudin-6 and Claudin-9 as Entry Factors for Hepatitis C Virus Infection of Human Hepatocytes by Using Monoclonal Antibodies

Cited by 28 publications

References 22 publications

Hepatitis C Virus Cell-Cell Transmission and Resistance to Direct-Acting Antiviral Agents

Hepatitis C Virus Cell-Cell Transmission and Resistance to Direct-Acting Antiviral Agents

Claudins in viral infection: from entry to spread

The Impact of Hepatitis C Virus Entry on Viral Tropism

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