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HCV nonstructural

Ira M Jacobson, Eric Lawitz, Paul Y Kwo, Christophe Hézode, Cheng-Yuan Peng, Anita Y M Howe, Peggy Hwang, Janice Wahl, Michael Robertson, Eliav Barr, Barbara A Haber
BACKGROUND & AIMS: Persons with hepatitis C virus (HCV) infection are at risk of progressive liver disease, cirrhosis, and decompensation. We analyzed the effects of the direct-acting antiviral agents elbasvir and grazoprevir in patients with HCV infection and compensated cirrhosis, combining data from 6 clinical trials. METHODS: We performed an integrated analysis of 402 patients with HCV genotype 1, 4, or 6 infection and Child-Pugh A compensated cirrhosis enrolled in 6 clinical trials...
February 10, 2017: Gastroenterology
Foozieh Javadi, Pooneh Rahimi, Mohammad Hossien Modarressi, Azam Bolhassani, Mehdi Shafiee Ardestani, Seyed Mehdi Sadat, Mohammad Reza Aghasadeghi
BACKGROUND: Hepatitis C virus infection is one of global health concern. No vaccine is available so far and nonstructural protein 3 (NS3) is one of the main target antigens for developing studies on therapeutic vaccine and diagnostic application. In the current study, we expressed a truncated recombinant HCV-NS3 protein under native condition and evaluated its potential applications in immunization and diagnosis. METHODS: The recombinant pET-NS3 containing a truncated form of HCV NS3 region was constructed, confirmed by sequencing reactions, and expressed into E...
July 1, 2016: Clinical Laboratory
Koichi Kitagawa, Chika Omoto, Tsugumi Oda, Ayame Araki, Hiroki Saito, Katsumi Shigemura, Takane Katayama, Hak Hotta, Toshiro Shirakawa
We previously generated an oral hepatitis C virus (HCV) vaccine using Bifidobacterium displaying the HCV nonstructural protein 3 (NS3) polypeptide. NS3-specific cellular immunity is important for viral clearance and recovery from HCV infection. In this study, we enhanced the cellular immune responses induced by our oral HCV vaccine, Bifidobacterium longum 2165 (B. longum 2165), by combining interferon-α (IFN-α) as an adjuvant with the vaccine in a mouse experimental model. IFN-α is a widely used cytokine meeting the standard of care (SOC) for HCV infection and plays various immunoregulatory roles...
January 23, 2017: Viral Immunology
Takeya Tsutsumi, Kazuya Okushin, Kenichiro Enooku, Hidetaka Fujinaga, Kyoji Moriya, Hiroshi Yotsuyanagi, Hideki Aizaki, Tetsuro Suzuki, Yoshiharu Matsuura, Kazuhiko Koike
The hepatitis C virus nonstructural protein NS5A is involved in resistance to the host immune response, as well as the viral lifecycle such as replication and maturation. Here, we established transgenic mice expressing NS5A protein in the liver and examined innate immune responses against lipopolysaccharide (LPS) in vivo. Intrahepatic gene expression levels of cytokines such as interleukin-6, tumor necrosis factor-α, and interferon-γ were significantly suppressed after LPS injection in the transgenic mouse liver...
2017: PloS One
Nan Nwe Win, Shingo Nakamoto, Tatsuo Kanda, Hiroki Takahashi, Azusa Takahashi-Nakaguchi, Shin Yasui, Masato Nakamura, Shuang Wu, Fumio Imazeki, Shigeru Mikami, Osamu Yokosuka, Tohru Gonoi, Hiroshi Shirasawa
Determination of hepatitis C virus (HCV) genotypes plays an important role in the direct-acting agent era. Discrepancies between HCV genotyping and serotyping assays are occasionally observed. Eighteen samples with discrepant results between genotyping and serotyping methods were analyzed. HCV serotyping and genotyping were based on the HCV nonstructural 4 (NS4) region and 5'-untranslated region (5'-UTR), respectively. HCV core and NS4 regions were chosen to be sequenced and were compared with the genotyping and serotyping results...
January 17, 2017: International Journal of Molecular Sciences
Ahmed M Fahmy, Patrick Labonté
Hepatitis C virus (HCV) infection induces intracellular membrane rearrangements, thus forming a membranous web (MW) in which HCV replication and assembly occur. The HCV-induced MW is primarily composed of double membrane vesicles (DMVs) transfused by multi-membrane vesicles. The autophagy machinery has been proposed to participate in the formation of such vesicles. However, no clear evidence has been found linking autophagy to the formation of these DMVs. In this study, we evaluated the role of the autophagy elongation complex (ATG5-12/16L1) in HCV replication and MW formation...
January 9, 2017: Scientific Reports
Wenhui Wang, Qiuwei Pan, Gwenny M Fuhler, Ron Smits, Maikel P Peppelenbosch
Hepatitis C virus (HCV) infection is one of the leading causes of hepatocellular carcinoma (HCC) worldwide but the mechanistic basis as to how chronic HCV infection furthers the HCC process remains only poorly understood. Accumulating evidence indicates that HCV core and nonstructural proteins provoke activation of the Wnt/β-catenin signaling pathway, and the evidence supporting a role of Wnt/β-catenin signaling in the onset and progression of HCC is compelling. Convincing molecular explanations as to how expression of viral effectors translates into increased activity of the Wnt/β-catenin signaling machinery are still largely lacking, hampering the design of rational strategies aimed at preventing HCC...
December 29, 2016: Journal of Gastroenterology
Astrid M Newsum, Cynthia K Y Ho, Faydra I Lieveld, Thijs J W van de Laar, Sylvie M Koekkoek, Sjoerd P Rebers, Jan T M van der Meer, Anne M J Wensing, Greet J Boland, Joop E Arends, Karel J van Erpecum, Maria Prins, Richard Molenkamp, Janke Schinkel
OBJECTIVES: The Q80K polymorphism is a naturally occurring resistance-associated variant in the hepatitis C virus (HCV) nonstructural protein 3 (NS3) region and is likely transmissible between hosts. This study describes the Q80K origin and prevalence among HCV risk groups in the Netherlands and examines whether Q80K is linked to specific transmission networks. DESIGN AND METHODS: Stored blood samples from HCV genotype 1a-infected patients were used for PCR and sequencing to reconstruct the NS3 maximum likelihood phylogeny...
January 2, 2017: AIDS
Ling Tong, Wensheng Yu, Lei Chen, Oleg Selyutin, Michael P Dwyer, Anilkumar Gopinadhan Nair, Robert Mazzola, Jae-Hun Kim, Deyou Sha, Jingjun Yin, Rebecca Tamra Ruck, Ian W Davies, Bin Hu, Bin Zhong, Jinglai Hao, Tao Ji, Shuai Zan, Rong Liu, Sony Agrawal, Ellen Xia, Stephanie Curry, Patricia Mcmonagle, Karin Bystol, Frederick Lahser, Donna Carr, Laura Rokosz, Paul Ingravallo, Shiying Chen, Kung-I Feng, Mark Cartwright, Ernest Asante-Appiah, Joseph A Kozlowski
We describe the research that led to the discovery of compound 40 (ruzasvir, MK-8408), a pan-genotypic HCV nonstructural protein 5A (NS5A) inhibitor with a "flat" GT1 mutant profile. This NS5A inhibitor contains a unique tetracyclic indole core, while maintaining the imidazole-proline-valine Moc motifs of our previous NS5A inhibitors. Compound 40 is currently in early clinical trials and is under evaluation as part of an all-oral DAA regimen for the treatment of chronic HCV infection..
November 3, 2016: Journal of Medicinal Chemistry
Rina Barouch-Bentov, Gregory Neveu, Fei Xiao, Melanie Beer, Elena Bekerman, Stanford Schor, Joseph Campbell, Jim Boonyaratanakornkit, Brett Lindenbach, Albert Lu, Yves Jacob, Shirit Einav
: Enveloped viruses commonly utilize late-domain motifs, sometimes cooperatively with ubiquitin, to hijack the endosomal sorting complex required for transport (ESCRT) machinery for budding at the plasma membrane. However, the mechanisms underlying budding of viruses lacking defined late-domain motifs and budding into intracellular compartments are poorly characterized. Here, we map a network of hepatitis C virus (HCV) protein interactions with the ESCRT machinery using a mammalian-cell-based protein interaction screen and reveal nine novel interactions...
November 1, 2016: MBio
Tushar Garimella, Xiaoli You, Reena Wang, Shu-Pang Huang, Hamza Kandoussi, Marc Bifano, Richard Bertz, Timothy Eley
: The treatment of hepatitis C virus (HCV) infection has been revolutionized in recent years by the development of direct-acting antiviral regimens that do not contain peginterferon (pegIFN) and/or ribavirin (RBV). While direct-acting antiviral-based regimens have been shown to be greatly superior to pegIFN/RBV-based regimens in terms of efficacy and safety, they have a greater susceptibility to drug-drug interactions (DDIs). Daclatasvir (DCV)-the benchmark pangenotypic nonstructural protein 5A inhibitor-has been shown to be efficacious and generally well tolerated in partnership with other HCV direct-acting antivirals, including sofosbuvir, asunaprevir (ASV), and ASV plus beclabuvir...
November 2016: Advances in Therapy
Ling Tong, Wensheng Yu, Craig A Coburn, Peter T Meinke, Anilkumar G Nair, Michael P Dwyer, Lei Chen, Oleg Selyutin, Stuart B Rosenblum, Yueheng Jiang, James Fells, Bin Hu, Bin Zhong, Richard M Soll, Rong Liu, Sony Agrawal, Ellen Xia, Ying Zhai, Rong Kong, Paul Ingravallo, Amin Nomeir, Ernest Asante-Appiah, Joseph A Kozlowski
Herein, we describe our research efforts to develop unique cores in molecules which function as HCV nonstructural protein 5A (NS5A) inhibitors. In particular, various fused tetracyclic cores were identified which showed genotype and mutant activities comparable to the indole-based tetracyclic core.
October 15, 2016: Bioorganic & Medicinal Chemistry Letters
Xiaoqiong Shao, Qiumin Luo, Qingxian Cai, Fulong Zhang, Jiangyun Zhu, Ying Liu, Zhixin Zhao, Zhiliang Gao, Xiaohong Zhang
An outbreak of hepatitis C virus (HCV) infections, for which the risk factor was unknown, was previously identified in North Guangdong, China. In the present study, a total of 736 local residents were surveyed regarding their lifetime risk factors for HCV infection. Serum anti‑HCV antibodies and HCV RNA were examined to confirm infection. In the HCV‑positive samples, the core and nonstructural protein 5B sequences were amplified, and phylogenetic analysis was performed to determine the association between HCV subtypes and transmission routes...
November 2016: Molecular Medicine Reports
Wim Schuermans, Hans Orlent, Isabelle Desombere, Patrick Descheemaeker, Hans Van Vlierberghe, Anja Geerts, Xavier Verhelst, Marijke Reynders, Elizaveta Padalko
As different hepatitis C virus (HCV) genotypes respond differently to initiated therapy, correct HCV genotyping is essential. A potential risk for misclassification of the intergenotypic HCV circulating recombinant form (CRF) 2k/1b strains exists, depending on the genotyping method used. The aim was to investigate the differences in HCV genotyping methods with regard to CRF 2k/1b and to gain insight in the prevalence of the CRF 2k/1b. Genotyping results by Versant HCV Genotype Assay were compared with nonstructural protein 5B (NS5B) sequencing...
August 23, 2016: International Journal of Molecular Sciences
Van T T Huynh, Yun-Sook Lim, Si C Tran, Tu M Pham, Lam N Nguyen, Soon B Hwang
The propagation of hepatitis C virus (HCV) is highly dependent on host cellular factors. To identify the cellular factors involved in HCV propagation, we have previously performed protein microarray assays using the HCV nonstructural 5A (NS5A) protein as a probe. Of ∼9,000 host proteins immobilized in a microarray, ∼90 cellular proteins were identified as HCV NS5A interacting partners. Of these candidates, we selected Abelson interactor 1 (Abi1) for further characterization. Binding of HCV NS5A to Abi1 was verified by both in vitro pulldown and coimmunoprecipitation assays...
October 21, 2016: Journal of Biological Chemistry
Mueed Ur Rahman, Hao Liu, Abdul Wadood, Hai-Feng Chen
HCV RNA dependent RNA polymerase (RdRp) nonstructural protein 5B (NS5B) is a major target against hepatitis C virus (HCV) for antiviral therapy. Recently discovered cyclopropylindolobenzazepine derivatives have been considered as the most potent for their ability to bind the thumb site 1 domain and allosterically inhibit HCV NS5B RdRp activity. However, the allosteric mechanism for these derivatives has not been clarified at the molecular level. In this study, fluctuation correlation networks were constructed based on all-atom molecular dynamics simulations to elucidate the allosteric mechanism...
October 18, 2016: Molecular BioSystems
Abdelfattah M Attallah, Sanaa O Abdallah, Mohamed S Albannan, Mohamed M Omran, Ahmed A Attallah, Khaled Farid
Hepatitis C virus (HCV)/Schistosoma mansoni coinfection is common in Egypt and other developing countries. This study aimed to investigate the influence of HCV/S. mansoni coinfection on the concentration of HCV-nonstructural protein-4 (NS4) in addition to collagen III and matrix metalloproteinase-1 (MMP-1) in different hepatic fibrosis stages. We found that coinfected patients (N = 186) showed significantly (P < 0.05, Mann-Whitney U test) higher concentrations of HCV-NS4, collagen III, and collagen III/MMP-1 ratio (CMR) than those with HCV monoinfection (N = 104) in different fibrosis stages...
November 2, 2016: American Journal of Tropical Medicine and Hygiene
Christopher M Owens, Bradley B Brasher, Alex Polemeropoulos, Michael H J Rhodin, Nicole McAllister, Kelly A Wong, Christopher T Jones, Lijuan Jiang, Kai Lin, Yat Sun Or
EDP-239, a potent and selective hepatitis C virus (HCV) nonstructural protein 5A (NS5A) inhibitor developed for the treatment of HCV infection, has been investigated in vitro and in vivo This study sought to characterize genotypic changes in the HCV NS5A sequence of genotype 1 (GT1) replicons and to compare those changes to GT1 viral RNA mutations isolated from clinical trial patients. Resistance selection experiments in vitro using a subgenomic replicon identified resistance-associated mutations (RAMs) at GT1a NS5A amino acid positions 24, 28, 30, 31, and 93 that confer various degrees of resistance to EDP-239...
October 2016: Antimicrobial Agents and Chemotherapy
Christopher M Owens, Bradley B Brasher, Alex Polemeropoulos, Michael H J Rhodin, Nicole McAllister, Xiaowen Peng, Ce Wang, Lu Ying, Hui Cao, Eric Lawitz, Fred Poordad, Juan Rondon, Terry D Box, Stefan Zeuzem, Peter Buggisch, Kai Lin, Yao-Ling Qiu, Lijuan Jiang, Richard Colvin, Yat Sun Or
EDP-239, a novel hepatitis C virus (HCV) inhibitor targeting nonstructural protein 5A (NS5A), has been investigated in vitro and in vivo EDP-239 is a potent, selective inhibitor with potency at picomolar to nanomolar concentrations against HCV genotypes 1 through 6. In the presence of human serum, the potency of EDP-239 was reduced by less than 4-fold. EDP-239 is additive to synergistic with other direct-acting antivirals (DAAs) or host-targeted antivirals (HTAs) in blocking HCV replication and suppresses the selection of resistance in vitro Furthermore, EDP-239 retains potency against known DAA- or HTA-resistant variants, with half-maximal effective concentrations (EC50s) equivalent to those for the wild type...
October 2016: Antimicrobial Agents and Chemotherapy
Aldo Bonaventura, Fabrizio Montecucco
Hepatitis C virus (HCV) affects 3% of the world population. It represents the main cause of chronic liver disease and is responsible for extra-hepatic complications, such as type 2 diabetes and cardiovascular diseases. HCV includes 7 genotypes differing in the nucleotide sequence variability, the geographic distribution, the rates of viral clearance, the risk of progression to liver fibrosis and to hepatocellular carcinoma, and the response to therapy. Last years have seen remarkable advances in the field of HCV infection with the approval of direct antiviral agents (DAAs) targeting key viral proteins involved in the HCV replication...
July 8, 2016: World Journal of Hepatology
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