scholarly journals Theaflavins, polyphenols of black tea, inhibit entry of hepatitis C virus

2018 ◽  
Author(s):  
Pritom Chowdhury ◽  
Marie-Emmanuelle Sahuc ◽  
Yves Rouillé ◽  
Alexandre Vandeputte ◽  
Priscille Brodin ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Black Tea ◽  
Hcv Infection ◽  
Dependent Manner ◽  
Entry Inhibitors ◽  
Substantial Progress ◽  
Combination Study ◽  
Direct Acting ◽  
Dose Dependent

AbstractThe treatment of hepatitis C virus (HCV) infection by combination of direct acting antivirals (DAA), with different mode of action, has made substantial progress in the past few years. However, appearance of resistance and high cost of the therapy is still an obstacle in the achievement of the therapy, more specifically in developing countries. In this context, search for affordable antivirals with new mechanisms of action is still needed. Tea, after water, is the most popular drink worldwide. Polyphenols extracted from green tea have already shown anti-HCV activity as entry inhibitors. Here, three different theaflavins, theaflavin (TF1), theaflavin-3’-monogallate (TF2), and theaflavin-3-3’-digallate (TF3), which are major polyphenols from black tea, were tested against HCV in cell culture. The results showed that all theaflavins inhibit HCV infection in a dose-dependent manner in an early step of infection. Results obtained with HCV pseudotyped virions confirmed their activity on HCV entry and demonstrated their pan-genotypic action. No effect on HCV replication was observed by using HCV replicon. Investigation on the mechanism of action of black tea theaflavins showed that they act directly on the virus particle and are able to inhibit cell-to-cell spread. Combination study with inhibitors most widely used in anti-HCV treatment regimen demonstrated that TF3 exerts additive effect. In conclusion, theaflavins, that are present in high quantity in black tea, are new inhibitors of HCV entry and hold promise for developing in therapeutic arsenal for HCV infection.

scholarly journals Monoclonal Antibodies against Extracellular Domains of Claudin-1 Block Hepatitis C Virus Infection in a Mouse Model

2015 ◽  
Vol 89 (9) ◽  
pp. 4866-4879 ◽  
Author(s):  
Masayoshi Fukasawa ◽  
Shotaro Nagase ◽  
Yoshitaka Shirasago ◽  
Manami Iida ◽  
Mayo Yamashita ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hcv Infection ◽  
Dependent Manner ◽  
Entry Inhibitors ◽  
High Affinity ◽  
Extracellular Domains ◽  
Very High

ABSTRACTHepatitis C virus (HCV) entry into host cells is a complex process requiring multiple host factors, including claudin-1 (CLDN1). Safe and effective therapeutic entry inhibitors need to be developed. We isolated a human hepatic Huh7.5.1-derived cell mutant that is nonpermissive to HCV, and comparative microarray analysis showed that the mutant was CLDN1 defective. Four hybridomas were obtained, which produced monoclonal antibodies (MAbs) that interacted with the parental Huh7.5.1 cell but not with the CLDN1-defective mutant. All MAbs produced by these hybridomas specifically bound to human CLDN1 with a very high affinity and prevented HCV infection of Huh7.5.1 cells in a dose-dependent manner, without apparent cytotoxicity. Two selected MAbs also inhibited HCV infection of human liver-chimeric mice without significant adverse effects. CLDN1 may be a potential target to prevent HCV infectionin vivo. Anti-CLDN1 MAbs may hence be promising candidates as novel anti-HCV agents.IMPORTANCESafe and effective therapeutic entry inhibitors against hepatitis C virus (HCV) are very useful for combination therapies with other anti-HCV drugs, such as direct-acting antivirals. In this study, we first showed an effective strategy for developing functional monoclonal antibodies (MAbs) against extracellular domains of a multimembrane-spanning target protein, claudin-1 (CLDN1), by using parental cells expressing the intact target membrane protein and target-defective cells. The established MAbs against CLDN1, which had a very high affinity for intact CLDN1, efficiently inhibitedin vitroandin vivoHCV infections. These anti-CLDN1 MAbs are promising leads for novel entry inhibitors against HCV.

scholarly journals Extracellular Interactions between Hepatitis C Virus and Secreted Apolipoprotein E

2017 ◽  
Vol 91 (15) ◽  
Author(s):  
Zhihua Li ◽  
Yadong Li ◽  
Yanwei Bi ◽  
Hui Zhang ◽  
Yufeng Yao ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Apolipoprotein E ◽  
Vaccine Development ◽  
Envelope Proteins ◽  
Host Immunity ◽  
Hcv Infection ◽  
Host Cells ◽  
Dependent Manner ◽  
Dose Dependent

ABSTRACT Interactions between hepatitis C virus (HCV) and lipoproteins in humans play an important role in the efficient establishment of chronic infection. Apolipoprotein E (ApoE) on the HCV envelope mediates virus attachment to host cells as well as immune evasion. This interaction is thought to occur in hepatocytes, as ApoE plays dual functions in HCV assembly and maturation as well as cell attachment. In the present study, we found that secreted ApoE (sApoE) can also bind to viral particles via its C-terminal domain after HCV is released from the cell. Furthermore, the binding affinity of interactions between the sApoE N terminus and cell surface receptors affected HCV infectivity in a dose-dependent manner. The extracellular binding of sApoE to HCV is dependent on HCV envelope proteins, and recombinant HCV envelope proteins are also able to bind to sApoE. These results suggest that extracellular interactions between HCV and sApoE may potentially complicate vaccine development and studies of viral pathogenesis. IMPORTANCE End-stage liver disease caused by chronic HCV infection remains a clinical challenge, and there is an urgent need for a prophylactic method of controlling HCV infection. Because host immunity against HCV is poorly understood, additional investigations of host-virus interactions in the context of HCV are important. HCV is primarily transmitted through blood, which is rich in lipoproteins. Therefore, it is of interest to further determine how HCV interacts with lipoproteins in human blood. In this study, we found that secreted ApoE (sApoE), an exchangeable component found in lipoproteins, participates in extracellular interactions with HCV virions. More significantly, different variants of sApoE differentially affect HCV infection efficiency in a dose-dependent manner. These findings provide greater insight into HCV infection and host immunity and could help propel the development of new strategies for preventing HCV infection.

scholarly journals Hepatitis C Virus Glycan-Dependent Interactions and the Potential for Novel Preventative Strategies

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 685
Author(s):  
Emmanuelle V. LeBlanc ◽  
Youjin Kim ◽  
Chantelle J. Capicciotti ◽  
Che C. Colpitts
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Immune Evasion ◽  
Hcv Infection ◽  
Major Contributor ◽  
Effective Management ◽  
Hcv Treatment ◽  
Entry Inhibitors ◽  
Chronic Hepatitis C Virus

Chronic hepatitis C virus (HCV) infections continue to be a major contributor to liver disease worldwide. HCV treatment has become highly effective, yet there are still no vaccines or prophylactic strategies available to prevent infection and allow effective management of the global HCV burden. Glycan-dependent interactions are crucial to many aspects of the highly complex HCV entry process, and also modulate immune evasion. This review provides an overview of the roles of viral and cellular glycans in HCV infection and highlights glycan-focused advances in the development of entry inhibitors and vaccines to effectively prevent HCV infection.

scholarly journals Reply to Padmanabhan and Dixit: Hepatitis C virus entry inhibitors for optimally boosting direct-acting antiviral-based treatments

2017 ◽  
Vol 114 (23) ◽  
pp. E4527-E4529 ◽  
Author(s):  
Hirofumi Ohashi ◽  
Yoshiki Koizumi ◽  
Kento Fukano ◽  
Takaji Wakita ◽  
Alan S. Perelson ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Virus Entry ◽  
Direct Acting Antiviral ◽  
Entry Inhibitors ◽  
Virus Entry Inhibitors ◽  
Direct Acting

Oncogenic transcriptomic profile is sustained in the liver after the eradication of the hepatitis C virus

2021 ◽  
Author(s):  
Haruhiko Takeda ◽  
Atsushi Takai ◽  
Eriko Iguchi ◽  
Masako Mishima ◽  
Soichi Arasawa ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Molecular Basis ◽  
Elevated Serum ◽  
Gene Clusters ◽  
Viral Clearance ◽  
Hcv Infection ◽  
Transcriptomic Profile ◽  
Direct Acting ◽  
Liver Tissues

Abstract Hepatocellular carcinoma (HCC) developing after hepatitis C virus (HCV) eradication is a serious clinical concern. However, molecular basis for the hepatocarcinogenesis after sustained virologic response (SVR) remains unclear. In this study, we aimed to unveil the transcriptomic profile of post-SVR liver tissues and explore the molecules associated with post-SVR carcinogenesis. We analysed 90 RNA-sequencing datasets, consisting of noncancerous liver tissues including 20 post-SVR, 40 HCV-positive and 7 normal livers, along with Huh7 cell line specimens before and after HCV infection and eradication. Comparative analysis demonstrated that cell cycle- and mitochondrial function-associated pathways were altered only in HCV-positive noncancerous liver tissues, while some cancer-related pathways were upregulated in the noncancerous liver tissues of both post-SVR and HCV-positive cases. The persistent upregulation of carcinogenesis-associated gene clusters after viral clearance was reconfirmed through in vitro experiments, of which, CYR61, associated with liver fibrosis and carcinogenesis in several cancer types, was the top enriched gene and co-expressed with cell proliferation-associated gene modules. To evaluate whether this molecule could be a predictor of hepatocarcinogenesis after cure of HCV infection, we also examined 127 sera from independent HCV-positive cohorts treated with direct-acting antivirals, including 60 post-SVR-HCC patients, and found that the elevated serum Cyr61 was significantly associated with early carcinogenesis after receiving direct-acting antiviral therapy. In conclusion, some oncogenic transcriptomic profiles are sustained in liver tissues after HCV eradication, which might be a molecular basis for the liver cancer development even after viral clearance. Among them, upregulated CYR61 could be a possible biomarker for post-SVR HCC.

scholarly journals Statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor)-based therapy for hepatitis C virus (HCV) infection-related diseases in the era of direct-acting antiviral agents

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 223 ◽  
Author(s):  
Sara Sobhy Kishta ◽  
Reem El-Shenawy ◽  
Sobhy Ahmed Kishta
Keyword(s):  
Clinical Trials ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Viral Clearance ◽  
Hcv Infection ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Direct Acting Antiviral Agents

Recent improvements have been made in the treatment of hepatitis C virus (HCV) infection with the introduction of direct-acting antiviral agents (DAAs). However, despite successful viral clearance, many patients continue to have HCV-related disease progression. Therefore, new treatments must be developed to achieve viral clearance and prevent the risk of HCV-related diseases. In particular, the use of pitavastatin together with DAAs may improve the antiviral efficacy as well as decrease the progression of liver fibrosis and the incidence of HCV-related hepatocellular carcinoma. To investigate the management methods for HCV-related diseases using pitavastatin and DAAs, clinical trials should be undertaken. However, concerns have been raised about potential drug interactions between statins and DAAs. Therefore, pre-clinical trials using a replicon system, human hepatocyte-like cells, human neurons and human cardiomyocytes from human-induced pluripotent stem cells should be conducted. Based on these pre-clinical trials, an optimal direct-acting antiviral agent could be selected for combination with pitavastatin and DAAs. Following the pre-clinical trial, the combination of pitavastatin and the optimal direct-acting antiviral agent should be compared to other combinations of DAAs (e.g., sofosbuvir and velpatasvir) according to the antiviral effect on HCV infection, HCV-related diseases and cost-effectiveness.

scholarly journals MK-571, a Cysteinyl Leukotriene Receptor 1 Antagonist, Inhibits Hepatitis C Virus Replication

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Isaac Ruiz ◽  
Quentin Nevers ◽  
Eva Hernández ◽  
Nazim Ahnou ◽  
Rozenn Brillet ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Hepatoma Cell ◽  
Hcv Rna ◽  
Dependent Manner ◽  
Cysteinyl Leukotriene ◽  
Leukotriene Receptor ◽  
Cysteinyl Leukotriene Receptor ◽  
Dose Dependent ◽  
Rna Levels

ABSTRACT The quinoline MK-571 is the most commonly used inhibitor of multidrug resistance protein-1 (MRP-1) but was originally developed as a cysteinyl leukotriene receptor 1 (CysLTR1) antagonist. While studying the modulatory effect of MRP-1 on anti-hepatitis C virus (HCV) direct-acting antiviral (DAA) efficiency, we observed an unexpected anti-HCV effect of compound MK-571 alone. This anti-HCV activity was characterized in Huh7.5 cells stably harboring a subgenomic genotype 1b replicon. A dose-dependent decrease of HCV RNA levels was observed upon MK-571 administration, with a 50% effective concentration (EC50 ± standard deviation) of 9 ± 0.3 μM and a maximum HCV RNA level reduction of approximatively 1 log10. MK-571 also reduced the replication of the HCV full-length J6/JFH1 model in a dose-dependent manner. However, probenecid and apigenin homodimer (APN), two specific inhibitors of MRP-1, had no effect on HCV replication. In contrast, the CysLTR1 antagonist SR2640 increased HCV-subgenomic replicon (SGR) RNA levels in a dose-dependent manner, with a maximum increase of 10-fold. In addition, a combination of natural CysLTR1 agonist (LTD4) or antagonists (zafirlukast, cinalukast, and SR2640) with MK-571 completely reversed its antiviral effect, suggesting its anti-HCV activity is related to CysLTR1 rather to MRP-1 inhibition. In conclusion, we showed that MK-571 inhibits HCV replication in hepatoma cell cultures by acting as a CysLTR1 receptor antagonist, thus unraveling a new host-virus interaction in the HCV life cycle.

scholarly journals Hepatitis C Virus NS3 Inhibitors: Current and Future Perspectives

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Kazi Abdus Salam ◽  
Nobuyoshi Akimitsu
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Protease Inhibitors ◽  
Standard Of Care ◽  
Pegylated Interferon ◽  
Virologic Response ◽  
Hcv Infection ◽  
Main Concern ◽  
Pegylated Interferon Plus Ribavirin ◽  
Direct Acting

Currently, hepatitis C virus (HCV) infection is considered a serious health-care problem all over the world. A good number of direct-acting antivirals (DAAs) against HCV infection are in clinical progress including NS3-4A protease inhibitors, RNA-dependent RNA polymerase inhibitors, and NS5A inhibitors as well as host targeted inhibitors. Two NS3-4A protease inhibitors (telaprevir and boceprevir) have been recently approved for the treatment of hepatitis C in combination with standard of care (pegylated interferon plus ribavirin). The new therapy has significantly improved sustained virologic response (SVR); however, the adverse effects associated with this therapy are still the main concern. In addition to the emergence of viral resistance, other targets must be continually developed. One such underdeveloped target is the helicase portion of the HCV NS3 protein. This review article summarizes our current understanding of HCV treatment, particularly with those of NS3 inhibitors.

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