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  • 1
    In: The Journal of Infectious Diseases, 2017, Vol. 215(6), pp.902-906
    Description: The World Health Organization (WHO) published 2 alcohol-based formulations to be used in healthcare settings and for outbreak-associated infections, but inactivation efficacies of these products have not been determined against (re-)emerging viruses. In this study, we evaluated the virucidal activity of these WHO products in a comparative analysis. Zika virus (ZIKV), Ebola virus (EBOV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) as (re-)emerging viral pathogens and other enveloped viruses could be efficiently inactivated by both WHO formulations, implicating their use in healthcare systems and viral outbreak situations.
    Keywords: Zika Virus ; Ebola Virus ; Who ; Sars ; Mers.
    ISSN: 0022-1899
    E-ISSN: 1537-6613
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  • 2
    Language: English
    In: Gastroenterology, 2011, Vol.141(3), pp.1057-1066
    Description: Hepatitis C virus (HCV) has a high propensity to establish persistence; better understanding of this process requires the development of a fully permissive and immunocompetent small animal model. Mouse cells can be engineered to express the human orthologs of the entry molecules CD81 and occludin to allow entry of HCV. However, RNA replication is poor in mouse cells, and it is not clear whether they support assembly and release of infectious HCV particles. We used a trans-complementation-based system to demonstrate HCV assembly competence of mouse liver cell lines. A panel of 3 mouse hepatoma cell lines that contain a stable subgenomic HCV replicon was used for ectopic expression of the HCV structural proteins, p7, nonstructural protein 2, and/or apolipoprotein E (apoE). Assembly and release of infectious HCV particles was determined by measuring viral RNA, proteins, and infectivity of virus released into the culture supernatant. Mouse replicon cells released low amounts of HCV particles, but ectopic expression of apoE increased release of infectious HCV to levels observed in the human hepatoma cell line Huh7.5. Thus, apoE is the limiting factor for assembly of HCV in mouse hepatoma cells but probably not in primary mouse hepatocytes. Products of all 3 human alleles of and mouse support HCV assembly with comparable efficiency. Mouse and human cell-derived HCV particles have similar biophysical properties, dependency on entry factors, and levels of association with apoE. Mouse hepatic cells permit HCV assembly and might be developed to create an immunocompetent and fully permissive mouse model of HCV infection.
    Keywords: Hcv Mouse Model ; Hcv Assembly ; Liver Disease ; Virology ; Medicine
    ISSN: 0016-5085
    E-ISSN: 1528-0012
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  • 3
    In: The Journal of Virology, 2010, Vol. 84(2), p.964
    Description: Recently, claudin-1 (CLDN1) was identified as a host protein essential for hepatitis C virus (HCV) infection. To evaluate CLDN1 function during virus entry, we searched for hepatocyte cell lines permissive for HCV RNA replication but with limiting endogenous CLDN1 expression, thus permitting receptor complementation assays. These criteria were met by the human hepatoblastoma cell line HuH6, which (i) displays low endogenous CLDN1 levels, (ii) efficiently replicates HCV RNA, and (iii) produces HCV particles with properties similar to those of particles generated in Huh-7.5 cells. Importantly, naïve cells are resistant to HCV genotype 2a infection unless CLDN1 is expressed. Interestingly, complementation of HCV entry by human, rat, or hamster CLDN1 was highly efficient, while mouse CLDN1 (mCLDN1) supported HCV genotype 2a infection with only moderate efficiency. These differences were observed irrespective of whether cells were infected with HCV pseudoparticles (HCVpp) or cell culture-derived HCV (HCVcc). Comparatively low entry function of mCLDN1 was observed in HuH6 but not 293T cells, suggesting that species-specific usage of CLDN1 is cell type dependent. Moreover, it was linked to three mouse-specific residues in the second extracellular loop (L152, I155) and the fourth transmembrane helix (V180) of the protein. These determinants could modulate the exposure or affinity of a putative viral binding site on CLDN1 or prevent optimal interaction of CLDN1 with other human cofactors, thus precluding highly efficient infection. HuH6 cells represent a valuable model for analysis of the complete HCV replication cycle in vitro and in particular for analysis of CLDN1 function in HCV cell entry.
    Keywords: Biology;
    ISSN: 0022-538X
    ISSN: 0022538X
    E-ISSN: 10985514
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  • 4
    Language: English
    In: PLoS ONE, 01 January 2016, Vol.11(7), p.e0159211
    Description: RNA interference (RNAi) is a post-transcriptional gene silencing mechanism that mediates the sequence-specific degradation of targeted RNA and thus provides a tremendous opportunity for development of oligonucleotide-based drugs. Here, we report...
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 5
    Language: English
    In: Nucleic acids research, 09 January 2017, Vol.45(1), pp.e3
    Description: Successful RNAi applications depend on strategies allowing robust and persistent expression of minimal gene silencing triggers without perturbing endogenous gene expression. Here, we propose a novel avenue which is integration of a promoterless shmiRNA, i.e. a shRNA embedded in a micro-RNA (miRNA) scaffold, into an engineered genomic miRNA locus. For proof-of-concept, we used TALE or CRISPR/Cas9 nucleases to site-specifically integrate an anti-hepatitis C virus (HCV) shmiRNA into the liver-specific miR-122/hcr locus in hepatoma cells, with the aim to obtain cellular clones that are genetically protected against HCV infection. Using reporter assays, Northern blotting and qRT-PCR, we confirmed anti-HCV shmiRNA expression as well as miR-122 integrity and functionality in selected cellular progeny. Moreover, we employed a comprehensive battery of PCR, cDNA/miRNA profiling and whole genome sequencing analyses to validate targeted integration of a single shmiRNA molecule at the expected position, and to rule out deleterious effects on the genomes or transcriptomes of the engineered cells. Importantly, a subgenomic HCV replicon and a full-length reporter virus, but not a Dengue virus control, were significantly impaired in the modified cells. Our original combination of DNA engineering and RNAi expression technologies benefits numerous applications, from miRNA, genome and transgenesis research, to human gene therapy.
    Keywords: Clustered Regularly Interspaced Short Palindromic Repeats ; Genetic Engineering ; RNA Interference ; Hepacivirus -- Genetics ; Micrornas -- Genetics ; RNA, Small Interfering -- Genetics ; Transcription Activator-Like Effector Nucleases -- Genetics
    ISSN: 03051048
    E-ISSN: 1362-4962
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  • 6
    Language: English
    In: Journal of medicinal chemistry, 24 December 2015, Vol.58(24), pp.9546-61
    Description: Hepatitis C virus (HCV) is a major cause of end-stage liver disease. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment, but these are associated with increased drug resistance and toxicity. Thus, the development of host-targeted antiviral agents, such as cyclophilin A inhibitors, is an alternative approach for more effective, selective, and safer treatment. Starting with the discovery of a bis-amide derivative 5 through virtual screening, the lead compound 25 was developed using molecular modeling-based design and systematic exploration of the structure-activity relationship. The lead 25 lacked cytotoxicity, had potent anti-HCV activity, and showed selective and high binding affinity for CypA. Unlike cyclosporin A, 25 lacked immunosuppressive effects, successfully inhibited the HCV replication, restored host immune responses without acute toxicity in vitro and in vivo, and exhibited a high synergistic effect in combination with other drugs. These findings suggest that the bis-amides have significant potential to extend the arsenal of HCV therapeutics.
    Keywords: Antiviral Agents -- Chemistry ; Cyclophilin A -- Antagonists & Inhibitors ; Glycine -- Analogs & Derivatives ; Hepacivirus -- Drug Effects ; Indoleacetic Acids -- Chemistry
    ISSN: 00222623
    E-ISSN: 1520-4804
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  • 7
    Language: English
    In: BioTechniques, November 2015, Vol.59(5), pp.287-93
    Description: After encapsidation, where pregenomic RNA (pgRNA) is packaged into viral nucleocapsids, hepatitis B virus (HBV) uses the pgRNA as a template to replicate its DNA genome by reverse transcription. To date, there are only two encapsidation detection methods for evaluating the amount of pgRNA packaged into nucleocapsids: (i) the RNase protection assay and (ii) the native agarose gel electrophoresis assay. However, these methods are complex and laborious because they require multiple pgRNA purification steps followed by detection via an isotope-labeled probe. Moreover, both assays are unsuitable for evaluating a large number of antiviral agents in a dose-dependent manner. To overcome these limitations, we devised a novel HBV encapsidation assay in a 96-well plate format using nucleocapsid capture plates coated with an anti-HBV core (HBc) antibody, usually employed in enzyme-linked immunosorbent assays, to immobilize viral nucleocapsids. Viral pgRNA is then detected by quantitative RT-PCR (RT-qPCR). This strategy allows fast, convenient, and quantitative analysis of multiple viral RNA samples to evaluate encapsidation inhibitors. Furthermore, our protocol is potentially suitable for high-throughput screening (HTS) of compounds targeting HBV pgRNA encapsidation.
    Keywords: Antiviral Assay ; Encapsidation ; Hepatitis B Virus ; Pregenomic RNA ; Hepatitis B Virus -- Isolation & Purification ; Nucleocapsid -- Isolation & Purification ; RNA, Viral -- Isolation & Purification ; Reverse Transcriptase Polymerase Chain Reaction -- Methods
    ISSN: 07366205
    E-ISSN: 1940-9818
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  • 8
    Language: English
    In: Journal of virology, December 2014, Vol.88(23), pp.13689-98
    Description: DDX3 is a member of the DEAD-box RNA helicase family, involved in mRNA metabolism, including transcription, splicing, and translation. We previously identified DDX3 as a hepatitis B virus (HBV) polymerase (Pol) binding protein, and by using a transient transfection, we found that DDX3 inhibits HBV replication at the posttranscriptional level, perhaps following encapsidation. To determine the exact mechanism of the inhibition, we here employed a diverse HBV experimental system. Inconsistently, we found that DDX3-mediated inhibition occurs at the level of transcription. By using tetracycline-inducible HBV-producing cells, we observed that lentivirus-mediated DDX3 expression led to a reduced level of HBV RNAs. Importantly, knockdown of DDX3 by short hairpin RNA resulted in augmentation of HBV RNAs in two distinct HBV replication systems: (i) tetracycline-inducible HBV-producing cells and (ii) constitutive HBV-producing HepG2.2.15 cells. Moreover, DDX3 knockdown in HBV-susceptible HepG2-NTCP cells, where covalently closed circular DNA (cccDNA) serves as the template for viral transcription, resulted in increased HBV RNAs, validating that transcription regulation by DDX3 occurs on a physiological template. Overall, our results demonstrate that DDX3 represents an intrinsic host antiviral factor that restricts HBV transcription. Upon entry into host cells, viruses encounter host factors that restrict viral infection. During evolution, viruses have acquired the ability to subvert cellular factors that adversely affect their replication. Such host factors include TRIM5α and APOBEC3G, which were discovered in retroviruses. The discovery of host restriction factors provided deeper insight into the innate immune response and viral pathogenesis, leading to better understanding of host-virus interactions. In contrast to the case with retroviruses, little is known about host factors that restrict hepatitis B virus (HBV), a virus distantly related to retroviruses. DDX3 DEAD box RNA helicase is best characterized as an RNA helicase involved in RNA metabolism, such as RNA processing and translation. Here, we show that DDX3 inhibits HBV infection at the level of viral transcription.
    Keywords: Host-Pathogen Interactions ; Transcription, Genetic ; Virus Replication ; Dead-Box RNA Helicases -- Metabolism ; Hepatitis B Virus -- Immunology
    ISSN: 0022538X
    E-ISSN: 1098-5514
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  • 9
    Language: English
    In: Antiviral therapy, 2015, Vol.20(8), pp.835-42
    Description: Little is known about the early steps of the HBV life cycle due to the lack of susceptible cells permissive for viral infection. Hence, viral entry has not been exploited for antiviral targets, but the recent seminal discovery of sodium taurocholate co-transporting polypeptide (NTCP) as the cellular receptor for HBV entry opened up many avenues of investigation, making HBV entry amenable to therapeutic intervention. In order to exploit HBV entry, we established a HepG2-NTCP cell line that supports HBV infection. Over 70% of cells were infected at a dose of 10(4) genome equivalents (GEq) per cell. Several FDA-approved drugs with NTCP-inhibiting activity were tested for their ability to inhibit HBV infection of the cell line. Consistent with their NTCP inhibitory activities, our results showed that several of them inhibit HBV infection. In particular, irbesartan, a drug used for the treatment of hypertension, inhibits HBV infection at the 50% effective concentration value of 35 μM. The observation that the pharmacological inhibitors of the NTCP transporter could block HBV entry suggests that NTCP represents an attractive molecular target for therapeutic intervention in HBV infection.
    Keywords: Gene Expression ; Antiviral Agents -- Pharmacology ; Biphenyl Compounds -- Pharmacology ; Hepatitis B Virus -- Drug Effects ; Organic Anion Transporters, Sodium-Dependent -- Genetics ; Symporters -- Genetics ; Tetrazoles -- Pharmacology
    ISSN: 13596535
    E-ISSN: 2040-2058
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  • 10
    Language: English
    In: Current Medicinal Chemistry, 2018, Vol.25(23), p.2709-2721
    Description: Hepatitis B Virus (HBV) is a major global health burden. Interferon alpha and nucleos(t)ide analogues are currently the standard-of-care for chronic HBV infection. However, these antiviral agents have limited efficacy and do not result in a sustained virological response in the majority of infected patients. Virtual Screening (VS) strategies have now a strong impact on drug discovery, the strength of this research field has been corroborated by recent contributions in the development of novel drug candidates which are in clinical trials or which are already available in the clinics. In this context, different VS strategies have been applied to HBV in order to discover novel inhibitors. In this review, we summarize the VS efforts to identify and design novel HBV interventions. We believe that the combination of in silico and in vitro tools can lead to faster validation of novel drug targets which could accelerate the HBV drug discovery and development efforts.
    Keywords: Ligand-Based Virtual Screening Structure-Based Virtual Screening Quantitative Structure-Activity Relationships Docking Hepatitis B Virus Inhibitors Workflow.
    ISSN: 0929-8673
    E-ISSN: 1875-533X
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