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https://www.readbyqxmd.com/read/29415072/ns2-proteases-from-hepatitis-c-virus-and-related-hepaciviruses-share-composite-active-sites-and-previously-unrecognized-intrinsic-proteolytic-activities
#1
Célia Boukadida, Matthieu Fritz, Brigitte Blumen, Marie-Laure Fogeron, François Penin, Annette Martin
Over the recent years, several homologues with varying degrees of genetic relatedness to hepatitis C virus (HCV) have been identified in a wide range of mammalian species. HCV infectious life cycle relies on a first critical proteolytic event of its single polyprotein, which is carried out by nonstructural protein 2 (NS2) and allows replicase assembly and genome replication. In this study, we characterized and evaluated the conservation of the proteolytic mode of action and regulatory mechanisms of NS2 across HCV and animal hepaciviruses...
February 7, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29404492/concomitant-proton-pump-inhibitor-use-does-not-reduce-the-efficacy-of-elbasvir-grazoprevir-a-pooled-analysis-of-1-322-patients-with-hepatitis-c-infection
#2
Nancy Reau, Michael N Robertson, Hwa-Ping Feng, Luzelena Caro, Wendy W Yeh, Bach-Yen T Nguyen, Janice Wahl, Eliav Barr, Peggy Hwang, Stephanie O Klopfer
Concomitant proton pump inhibitor (PPI) use reduces plasma concentrations of certain nonstructural protein 5A inhibitors, which are key components of modern hepatitis C infection (HCV) treatments. These reduced concentrations may decrease efficacy, leading to challenging treatment failures due to the development of resistance-associated substitutions. This post-hoc analysis assessed 12-week sustained viral response (SVR12) and pharmacokinetics of fixed-dose combination elbasvir/grazoprevir (EBR/GZR) in patients with HCV infection and self-reported PPI use...
October 2017: Hepatology Communications
https://www.readbyqxmd.com/read/29404457/sofosbuvir-based-regimens-for-the-treatment-of-chronic-hepatitis-c-in-severe-renal-dysfunction
#3
Paula Cox-North, Kelsey L Hawkins, Sean T Rossiter, Marie N Hawley, Renuka Bhattacharya, Charles S Landis
Sofosbuvir (SOF) is a nonstructural 5B polymerase inhibitor with activity in all hepatitis C virus (HCV) genotypes and is the backbone of many anti-HCV drug regimens. SOF is converted into inactive metabolites that undergo renal excretion. Patients with an estimated glomerular filtration rate (eGFR) < 30 mL/minute/1.73 m2 may experience increased drug exposure and thus potential toxicities along with decreased efficacy due to dose reduction or drug discontinuation. This is a single-center study evaluating safety and effectiveness of SOF-based regimens in patients with severe renal dysfunction, defined as eGFR <30 mL/minute/1...
May 2017: Hepatology Communications
https://www.readbyqxmd.com/read/29391202/phylogenetic-analysis-structure-modeling-and-docking-study-of-hcv-ns3-protease-for-the-identification-of-potent-inhibitors
#4
Asad Zia, Sumra Wajid Abbasi, Shabeer Ahmad, Muhammad Zia, Abida Raza
The nonstructural protein 3 (NS3) helicase of HCV is believed to be a plausible target for the identification and designing of potent antiviral drugs. NS3 protein is involved in a positive sense single-stranded viral replication as well as it also cleaves viral poly protein into diverse mature proteins at different time spans. Structural exploration of NS3 revealed that HCV helicase could also act as translocase. In order to identify potential inhibitors for HCV-3a, the current study has been designed. Serum samples from the Pakistani HCV positive patients were collected, sequenced and after purification included in the present study...
January 29, 2018: Infection, Genetics and Evolution
https://www.readbyqxmd.com/read/29385522/the-hepatitis-c-viral-nonstructural-protein-5a-stabilizes-growth-regulatory-human-transcripts
#5
Liang Guo, Suresh D Sharma, Jose Debes, Daniel Beisang, Bernd Rattenbacher, Irina Vlasova-St Louis, Darin L Wiesner, Craig E Cameron, Paul R Bohjanen
Numerous mammalian proto-oncogene and other growth-regulatory transcripts are upregulated in malignancy due to abnormal mRNA stabilization. In hepatoma cells expressing a hepatitis C virus (HCV) subgenomic replicon, we found that the viral nonstructural protein 5A (NS5A), a protein known to bind to viral RNA, also bound specifically to human cellular transcripts that encode regulators of cell growth and apoptosis, and this binding correlated with transcript stabilization. An important subset of human NS5A-target transcripts contained GU-rich elements, sequences known to destabilize mRNA...
January 29, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29325290/-effect-of-hepatitis-c-virus-nonstructural-protein-5a-and-its-domains-ii-on-hepatocyte-gluconeogenesis-in-mice
#6
J J Zhang, Q Liu, L Qiao
Objective: To investigate the role of hepatitis C virus nonstructural protein 5A (NS5A) and its domains I, II, and III in regulating gluconeogenesis in mice and the underlying mechanism. Methods: A total of 60 male C57BL/6J mice were randomly divided into six groups. Recombinant lentiviral particles with specific expression of full-length NS5A, NS5A domain I, NS5A domain II, or NS5A domain III were injected via the caudal vein to establish a mouse model, and the group without injection and the group with the injection of the lentiviral particles containing enhanced green fluorescent protein (EGFP) were established as negative control...
December 20, 2017: Zhonghua Gan Zang Bing za Zhi, Zhonghua Ganzangbing Zazhi, Chinese Journal of Hepatology
https://www.readbyqxmd.com/read/29285674/hcv-nonstructural-protein-4-is-associated-with-aggressiveness-features-of-breast-cancer
#7
Abdelfattah M Attallah, Mohamed El-Far, Mohamed A Abdelrazek, Mohamed M Omran, Ashraf Z Mahmoud, Hager S Khalifa, Mohamed M Ahmed, Ibrahim El-Dosoky
BACKGROUND: Hepatitis C virus (HCV) has the lymphotropic feature that is supposed to be the reason of related extrahepatic manifestation. HCV viral oncoproteins may participate in the regulation of some gene expression that has been implicated in tumorigenesis. Our aim is to evaluate the HCV-NS4 circulating levels in breast cancer (BC) and to investigate its relation with BC tumor aggressiveness. METHODS: This study was performed among 158 Egyptian women (120 with BC and 38 with benign breast diseases)...
December 28, 2017: Breast Cancer: the Journal of the Japanese Breast Cancer Society
https://www.readbyqxmd.com/read/29250328/sequence-analysis-of-hepatitis-c-virus-nonstructural-protein-3-4a-serine-protease-and-prediction-of-conserved-b-and-t-cell-epitopes
#8
Ayesha Naeem, Yasir Waheed
The hepatitis C virus (HCV) is a global health issue. The nonstructural protein 3 (NS3)-4Agene of HCV is responsible for serine protease activity. The aim of the present study was to develop a global consensus sequence of HCV serine protease, analyze conserved residues, and predict highly conserved B- and T-cell binding epitopes in the NS3-4A protein. A total of 160 NS3-4A sequences from the six genotypes of HCV were refracted in the current study. The amino acid sequences were aligned to obtain a global consensus sequence...
December 2017: Biomedical Reports
https://www.readbyqxmd.com/read/29167346/glycine-zipper-motifs-in-hepatitis-c-virus-nonstructural-protein-4b-are-required-for-the-establishment-of-viral-replication-organelles
#9
David Paul, Vanesa Madan, Omar Ramirez, Maja Bencun, Ina Karen Stoeck, Vlastimil Jirasko, Ralf Bartenschlager
Hepatitis C virus (HCV) RNA replication occurs in tight association with remodeled host cell membranes, presenting as cytoplasmic accumulations of single, double and multi membrane vesicles in infected cells. Formation of these so-called replication organelles is mediated by a complex interplay of host cell factors and viral replicase proteins. Of these, nonstructural protein 4B (NS4B), an integral transmembrane protein, appears to play a key role, but little is known about the molecular mechanisms how this protein contributes to organelle biogenesis...
November 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29142571/in-vitro-transcription-analysis-of-ns5a-from-hcv-3a-circulating-in-pakistani-patients-with-chronic-hepatitis-c-and-their-differential-response-to-antiviral-therapy
#10
Shameem Bhatti, Sobia Manzoor, Fahed Parvaiz, Javed Ashraf, Farakh Javed
Objective: Mutations in HCV nonstructural protein 5A (NS5A) play a vital role in virus resistance. The aim of this study was to develop a correlation between NS5A mutations (genotype 3a) and virological response towards interferon alpha (IFN-α) plus ribavirin therapy. Methods: In this study, which was conducted from 09-02-2013 to 25-11-2015 in the rural area of Province Sindh - Pakistan, total patients' responses to peg-IFN therapy were investigated. Patients were given peg-IFN therapy for 24 to 48 weeks and categorized as sustained virologic responders (SVR) or non-responders (NR) to HCV infection...
September 2017: Pakistan Journal of Medical Sciences Quarterly
https://www.readbyqxmd.com/read/29080280/usefulness-of-semiquantitative-pcr-invader-assay-for-selecting-candidates-for-daclatasvir-plus-asunaprevir-combination-therapy-among-patients-with-hepatitis-c-virus-genotype-1b
#11
Koichi Honda, Masataka Seike, Junya Oribe, Mizuki Endo, Mie Arakawa, Masanori Tokoro, Masao Iwao, Tetsu Mori, Junko Nishimura, Yukou Takahashi, Kaoru Omori, Tsutomu Yamashita, Toyokichi Muro, Kazunari Murakami
BACKGROUND & AIMS: PCR-Invader is a highly sensitive assay for detecting nonstructural protein 5A (NS5A) resistance-associated variants (RAVs) of hepatitis C virus (HCV). Here, we validated the accuracy of the semiquantitative PCR-Invader (SQ-PI) assay compared to direct sequencing (DS) for identifying NS5A RAVs, and we evaluated the treatment efficacy of daclatasvir plus asunaprevir (DCV+ASV) for patients judged to be nonpositive for NS5A RAVs by SQ-PI. METHODS: Detection rates of NS5A RAVs by SQ-PI and DS were compared for 204 patients with HCV genotype 1b...
October 28, 2017: Hepatology Research: the Official Journal of the Japan Society of Hepatology
https://www.readbyqxmd.com/read/29070684/ns3-from-hcv-strain-jfh-1-is-an-unusually-robust-helicase-that-is-primed-to-bind-and-unwind-viral-rna
#12
Ting Zhou, Xiaoming Ren, Rebecca L Adams, Anna Marie Pyle
Hepatitis C viruses (HCV) encode a helicase enzyme that is essential for viral replication and assembly (NS3). This helicase has become the focus of extensive basic research on general helicase mechanism and it is also of interest as a novel drug target. Despite the importance of this protein, mechanistic work on NS3 has been conducted almost exclusively on variants from HCV genotype 1. Our understanding of NS3 from the highly active HCV strains that are used to study HCV genetics and mechanism in cell culture (such as JFH-1) is lacking...
October 25, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28973992/3d-spatially-resolved-models-of-the-intracellular-dynamics-of-the-hepatitis-c-genome-replication-cycle
#13
Markus M Knodel, Sebastian Reiter, Paul Targett-Adams, Alfio Grillo, Eva Herrmann, Gabriel Wittum
Mathematical models of virus dynamics have not previously acknowledged spatial resolution at the intracellular level despite substantial arguments that favor the consideration of intracellular spatial dependence. The replication of the hepatitis C virus (HCV) viral RNA (vRNA) occurs within special replication complexes formed from membranes derived from endoplasmatic reticulum (ER). These regions, termed membranous webs, are generated primarily through specific interactions between nonstructural virus-encoded proteins (NSPs) and host cellular factors...
September 30, 2017: Viruses
https://www.readbyqxmd.com/read/28969940/immune-response-of-th17-associated-cytokines-by-peripheral-blood-mononuclear-cells-from-patients-with-chronic-hepatitis-c-virus-infection
#14
Milena S Cabral, Taciana P S Santos, Priscila L Santos, Maria Isabel Schinoni, Isabela S Oliveira, Ariana B Pereira, Ajax M Atta, Maria Luiza B Sousa-Atta
Hepatitis C virus (HCV) chronic infection causes severe cellular immune dysfunction. Here, we investigated the production of Th17-associated cytokines by peripheral blood mononuclear cells (PBMCs) of untreated patients with HCV, patients presenting an early virologic response (EVR) after 12weeks of treatment with interferon-α plus ribavirin with or without HCV protease inhibitors, and patients who were nonresponders to HCV therapy. PBMCs were stimulated with HCV core and nonstructural antigens, and the production of Th17-associated cytokines was measured with a Milliplex MAP immunoassay...
September 29, 2017: Cytokine
https://www.readbyqxmd.com/read/28882564/searching-for-synergy-identifying-optimal-antiviral-combination-therapy-using-hepatitis-c-virus-hcv-agents-in-a-replicon-system
#15
Justin J Pomeroy, George L Drusano, Jaime L Rodriquez, Ashley N Brown
Direct acting antiviral agents (DAAs) are potent inhibitors of Hepatitis C virus (HCV) that have revolutionized the treatment landscape for this important viral disease. There are currently four classes of DAAs that inhibit HCV replication via distinct mechanisms of action: nonstructural protein (NS) 3/4a protease inhibitors, NS5A inhibitors, NS5B nucleoside polymerase inhibitors, and NS5B non-nucleoside polymerase inhibitors. Combination therapy with two or more DAAs has great potential to further enhance antiviral potency...
October 2017: Antiviral Research
https://www.readbyqxmd.com/read/28852124/oxidative-stress-and-immune-responses-during-hepatitis-c-virus-infection-in-tupaia-belangeri
#16
Mohammad Enamul Hoque Kayesh, Sayeh Ezzikouri, Takahiro Sanada, Haiying Chi, Yukiko Hayashi, Khadija Rebbani, Bouchra Kitab, Aya Matsuu, Noriaki Miyoshi, Tsunekazu Hishima, Michinori Kohara, Kyoko Tsukiyama-Kohara
Hepatitis C virus (HCV) is a leading cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma. To address the molecular basis of HCV pathogenesis using tupaias (Tupaia belangeri), we characterized host responses upon HCV infection. Adult tupaias were infected with HCV genotypes 1a, 1b, 2a, or 4a. Viral RNA, alanine aminotransferase, anti-HCV core and anti-nonstructural protein NS3 antibody titres, reactive oxygen species (ROS), and anti-3β-hydroxysterol-Δ24reductase (DHCR24) antibody levels were measured at 2-week intervals from 0 to 41 weeks postinfection...
August 29, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28833932/nonstructural-protein-5a-ns5a-resistance-profile-in-patients-with-chronic-hepatitis-c-treated-with-ledipasvir-containing-regimens-without-sofosbuvir
#17
Kathryn M Kitrinos, Amoreena C Corsa, Angela Worth, Charlotte Hedskog, Diana Brainard, Michael D Miller, Hongmei Mo
The study aimed to evaluate the effects of baseline hepatitis C virus (HCV) NS5A resistance-associated substitutions (RASs) on sustained virologic response to ledipasvir (LDV)-containing regimens in the absence of sofosbuvir (SOF) in patients with HCV genotype (GT) 1 infection across 6 phase 2 clinical studies. We analyzed data from 1103 patients who received either LDV+vedroprevir (NS3 PI)+tegobuvir (NS5B inhibitor)±ribavirin or LDV+ribavirin+pegylated interferon. Population sequencing of HCV NS5A was performed at baseline and at virologic failure from patient plasma samples...
August 20, 2017: Journal of Viral Hepatitis
https://www.readbyqxmd.com/read/28820725/understanding-hepatitis-c-virus-drug-resistance-clinical-implications-for-current-and-future-regimens
#18
David L Wyles, Anne F Luetkemeyer
Viral resistance to direct-acting antiviral drugs may impact their effectiveness during treatment of hepatitis C virus (HCV) infection. Most data on HCV drug resistance concern genotypes 1 and 3. The clinical impact of resistance to HCV nonstructural protein 5A (NS5A) inhibitors and a practical approach to indications and methods for resistance testing are discussed.
July 2017: Topics in Antiviral Medicine
https://www.readbyqxmd.com/read/28815532/hepatitis-c-virus-replication
#19
Tetsuro Suzuki
Viruses use synthetic mechanism and organelles of the host cells to facilitate their replication and make new viruses. Host's ATP provides necessary energy. Hepatitis C virus (HCV) is a major cause of liver disease. Like other positive-strand RNA viruses, the HCV genome is thought to be synthesized by the replication complex, which consists of viral- and host cell-derived factors, in tight association with structurally rearranged vesicle-like cytoplasmic membranes. The virus-induced remodeling of subcellular membranes, which protect the viral RNA from nucleases in the cytoplasm, promotes efficient replication of HCV genome...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28809743/outcomes-for-cirrhotic-patients-with-hepatitis-c-virus-1b-treated-with-asunaprevir-and-daclatasvir-combination
#20
Akihiro Tamori, Hoang Hai, Sawako Uchida-Kobayashi, Masaru Enomoto, Ritsuzo Kozuka, Hiroyuki Motoyama, Etsushi Kawamura, Atsushi Hagihara, Yuga Teranishi, Kanako Yoshida, Hiroyasu Morikawa, Yoshiki Murakami, Norifumi Kawada
BACKGROUND: The efficacy and safety of asunaprevir + daclatasvir combination therapy for treatment of hepatitis C virus (HCV) in compensated cirrhotic patients was not fully evaluated in real-world. Outcomes were assessed in cirrhotic patients with sustained viral response (SVR). MATERIAL AND METHODS: A total of 145 patients without resistance-associated substitutions (RASs) at L31 and Y93 in the nonstructural protein 5A of HCV genotype 1b, consisting of 49 hepatic cirrhotic and 96 non-cirrhotic patients, were enrolled to the therapy...
September 2017: Annals of Hepatology
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