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Hepatitis C Virus NS4B

Chao Zhang, Rui Hua, Yuanyuan Cui, Shasha Wang, Hongqing Yan, Dongmei Li, Yonghong Zhang, Zhengkun Tu, Pei Hao, Xinyue Chen, Jin Zhong, Junqi Niu, Xia Jin
Elucidating protective immunity against HCV is important for the development of a preventative vaccine. We hypothesize that spontaneous resolution of acute HCV infection offers clue to protective immune responses, and that DAA therapy affects the quality and quantity of HCV-specific T cell responses. To test these hypotheses, we performed T cell epitope mapping in 111 HCV-infected individuals including 61 chronically HCV-1b (CHC-1b) infected, 24 chronically HCV-2a (CHC-2a) infected and 26 spontaneously recovered (SPR) patients with 376 overlapping peptides covering the entire HCV polyprotein...
2017: PloS One
Bertrand Boson, Solène Denolly, Fanny Turlure, Christophe Chamot, Marlène Dreux, François-Loïc Cosset
BACKGROUND & AIMS: Daclatasvir is a direct-acting antiviral agent and potent inhibitor of NS5A, which is involved in replication of the hepatitis C virus (HCV) genome, presumably via membranous web shaping, and assembly of new virions, likely via transfer of the HCV RNA genome to viral particle assembly sites. Daclatasvir inhibits the formation of new membranous web structures and, ultimately, of replication complex vesicles, but also inhibits an early assembly step. We investigated the relationship between daclatasvir-induced clustering of HCV proteins, intracellular localization of viral RNAs, and inhibition of viral particle assembly...
December 5, 2016: Gastroenterology
Debanjali Gupta, Kallol Saha, Aritra Biswas, Rushna Firdaus, Monika Ghosh, Provash Chandra Sadhukhan
Recombination in RNA virus is a rare event in the survival and evolution to evade host immune system. This is increasing within high risk group population (HRG) due to super infection that occurs by continuous sharing of common drug equipment by HCV infected or HIV-HCV co-infected recurrent drug users. Recombination causes impediment to vaccine development and therapeutic intervention as standard HCV treatment is still genotype specific. Blood samples of 194 people who inject drugs (PWID) were collected from an Opioid Substitution Therapy Centre in Kolkata, India...
December 5, 2016: Infection, Genetics and Evolution
Ken-Ichi Mori, Akihiro Matsumoto, Noboru Maki, Yuki Ichikawa, Eiji Tanaka, Shintaro Yagi
BACKGROUND: Despite the high prevalence of genotype 1b hepatitis C virus (HCV) among patients, a cell culture system that permits entire viral life cycle of genotype 1b isolates is limited. To develop a cell-cultured hepatitis C virus (HCVcc) of genotype 1b, the proper combination of HCV genomic variants and host cells is essential. HCV genomes isolated from patients with distinctive symptoms may provide the variants required to establish an HCVcc of genotype 1b. RESULTS: We first established subgenomic replicons in Huh7 cells using HCV cDNAs isolated from two patients: one with fulminant hepatitis after liver transplantation (TPF1) and another with acute hepatitis and moderate symptoms (sAH)...
September 27, 2016: BMC Microbiology
Jason D Graci, Stephen P Jung, John Pichardo, Frederick Lahser, Xiao Tong, Zhengxian Gu, Joseph M Colacino
PTC725 is a small molecule NS4B-targeting inhibitor of hepatitis C virus (HCV) genotype (gt) 1 RNA replication that lacks activity against HCV gt2. We analyzed the Los Alamos HCV sequence database to predict susceptible/resistant HCV gt's according to the prevalence of known resistance-conferring amino acids in the NS4B protein. Our analysis predicted that HCV gt3 would be highly susceptible to the activity of PTC725. Indeed, PTC725 was shown to be active against a gt3 subgenomic replicon with a 50% effective concentration of ∼5 nM...
December 2016: Antimicrobial Agents and Chemotherapy
Wataru Ito, Masaaki Toyama, Mika Okamoto, Masanori Ikeda, Koichi Watashi, Takaji Wakita, Yuichi Hashimoto, Masanori Baba
BACKGROUND: The novel phenanthridinone derivative HA-719 has recently been identified as a highly potent and selective inhibitor of hepatitis C virus replication. To elucidate its mechanism of inhibition, we have isolated and analyzed a clone of hepatitis C virus replicon cells resistant to HA-719. METHODS: To isolate HA-719-resistant replicon cells, Huh-7 cells containing subgenomic hepatitis C virus replicons (genotype 1b) with a luciferase reporter (LucNeo#2) were cultured in the presence of G418 and escalating concentrations of HA-719...
August 8, 2016: Antiviral Chemistry & Chemotherapy
Mun-Teng Wong, Steve S Chen
UNLABELLED: Hepatitis C virus (HCV) infection reorganizes cellular membranes to create an active viral replication site named the membranous web (MW). The role that human choline kinase-α (hCKα) plays in HCV replication remains elusive. Here, we first showed that hCKα activity, not the CDP-choline pathway, promoted viral RNA replication. Confocal microscopy and subcellular fractionation of HCV-infected cells revealed that a small fraction of hCKα colocalized with the viral replication complex (RC) on the endoplasmic reticulum (ER) and that HCV infection increased hCKα localization to the ER...
October 15, 2016: Journal of Virology
Sajid Mansoor, Aneela Javed, Amjad Ali, Atika Mansoor
Hepatitis C virus (HCV) displays excessive genetic heterogeneity and exists in several genotypes and subtypes. Characterizing these genotypes and subtypes becomes extremely important for diagnostic and epidemiological reasons. Present study analyzed HCV genome using a simple genome analysis approach. We combined manual sectioning of a reference genome alignment (RA) followed by a comprehensive comparative phylogenetic analysis. The main aim was to identify heterogeneous locations on HCV genome suitable for genotyping/subtyping...
October 2016: Infection, Genetics and Evolution
Bo Hu, Shanshan Li, Zhanfeng Zhang, Shenggao Xie, Yuqian Hu, Xianzhang Huang, Yi Zheng
Hepatitis C virus (HCV) nonstructural protein 4B (NS4B) is a multi-transmembrane protein, but little is known about how NS4B contributes to HCV replication and tumorigenesis. Its C-terminal domain (CTD) has been shown to associate with intracellular membrane, and we have previously shown that NS4B CTD contains a class I PDZ-binding motif (PBM). Here, we demonstrated that NS4B PBM interacts with the PDZ-containing tumor suppressor protein, Scribble, using immunofluorescence and co-immunoprecipitation assays, and this interaction requires at least three contiguous PDZ domains of Scribble...
September 2016: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Yan Li, Ruirui Wang, Xiaogang Du, Mingwang Zhang, Meng Xie
Hepatitis C virus (HCV) is a major cause of liver disease and has been estimated to infect approximately 2%-3% of the world's population. HCV genotype 1 is the subject of intense research and clinical investigations because of its worldwide prevalence and poor access to treatment for patients in developing countries and marginalized populations. The predominant subtypes 1a and 1b of HCV genotype 1 present considerable differences in epidemiological features. However, the genetic signature underlying such phenotypic functional divergence is still an open question...
July 2016: Canadian Journal of Microbiology
Ke-Qin Hu, Wei Cui
UNLABELLED: The current standard in diagnosing hepatitis C virus (HCV) infection requires two sequential steps: anti-HCV test to screen, followed by HCV RNA reverse-transcription polymerase chain reaction to confirm viremic HCV (V-HCV) infection. HCV core antigen tests provided potential for possible one-step diagnosis. However, low sensitivity and specificity limit their clinical utility. The present study developed a novel HCV antigens enzyme immunoassay (HCV-Ags EIA) and assessed its sensitivity, specificity, and utility for one-step diagnosis of V-HCV infection using 365 serum specimens, including 176 without and 189 with V-HCV infection...
August 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Avik Biswas, Jason Treadaway, Timothy L Tellinghuisen
UNLABELLED: The hepatitis C virus NS5A protein is tethered to cellular membranes via an amphipathic amino-terminal helix that is inserted in-plane into the outer endoplasmic reticulum (ER)-derived membrane leaflet. The charged face of the helix faces the cytoplasm and may contribute to interactions involved in replicase assembly and function. Using an aggressive charge flip mutagenesis strategy, we identified a number of essential residues for replication on the charged face of the NS5A anchor and identified a double charge face mutant that is lethal for RNA replication but generates suppressor mutations in the carboxy-terminal helix of the NS4B protein...
August 15, 2016: Journal of Virology
Kittirat Glab-Ampai, Aijaz Ahmad Malik, Monrat Chulanetra, Jeeraphong Thanongsaksrikul, Kanyarat Thueng-In, Potjanee Srimanote, Pongsri Tongtawe, Wanpen Chaicumpa
NS4B of hepatitis C virus (HCV) initiates membrane web formation, binds RNA and other HCV proteins for viral replication complex (RC) formation, hydrolyses NTP, and inhibits innate anti-viral immunity. Thus, NS4B is an attractive target of a novel anti-HCV agent. In this study, humanized-nanobodies (VHs/VHHs) that bound to recombinant NS4B were produced by means of phage display technology. The nanobodies were linked molecularly to a cell penetrating peptide, penetratin (PEN), for making them cell penetrable (become transbodies)...
August 5, 2016: Biochemical and Biophysical Research Communications
Marie-Laure Fogeron, Vlastimil Jirasko, Susanne Penzel, David Paul, Roland Montserret, Clément Danis, Denis Lacabanne, Aurélie Badillo, Jérôme Gouttenoire, Darius Moradpour, Ralf Bartenschlager, François Penin, Beat H Meier, Anja Böckmann
We describe the expression of the hepatitis C virus nonstructural protein 4B (NS4B), which is an integral membrane protein, in a wheat germ cell-free system, the subsequent purification and characterization of NS4B and its insertion into proteoliposomes in amounts sufficient for multidimensional solid-state NMR spectroscopy. First spectra of the isotopically [(2)H,(13)C,(15)N]-labeled protein are shown to yield narrow (13)C resonance lines and a proper, predominantly α-helical fold. Clean residue-selective leucine, isoleucine and threonine-labeling is demonstrated...
June 2016: Journal of Biomolecular NMR
Lingbao Kong, Shanshan Li, Xilan Yu, Xiaonan Fang, Ahui Xu, Mingjie Huang, Xiaoyu Wu, Yunli Guo, Fenglin Guo, Jin Xu
Oxidative stress induces the activation of signal transducer and activator of transcription 3 (STAT3), which plays an important role in hepatocellular carcinoma (HCC). We have previously reported that hepatitis C virus (HCV) and its protein NS4B induce the production of reactive oxygen species (ROS) via the endoplasmic reticulum overload response (EOR) in human hepatocytes. Here, we found that NS4B and HCV induce STAT3 activation and stimulate the expression of cancer-related STAT3 target genes, including VEGF, c-myc, MMP-9 and Mcl-1, by EOR in human hepatocytes...
August 2016: Archives of Virology
Jeffrey B Joy, Rosemary M McCloskey, Thuy Nguyen, Richard H Liang, Yury Khudyakov, Andrea Olmstead, Mel Krajden, John W Ward, P Richard Harrigan, Julio S G Montaner, Art F Y Poon
BACKGROUND: The timing of the initial spread of hepatitis C virus genotype 1a in North America is controversial. In particular, how and when hepatitis C virus reached extraordinary prevalence in specific demographic groups remains unclear. We quantified, using all available hepatitis C virus sequence data and phylodynamic methods, the timing of the spread of hepatitis C virus genotype 1a in North America. METHODS: We screened 45 316 publicly available sequences of hepatitis C virus genotype 1a for location and genotype, and then did phylogenetic analyses of available North American sequences from five hepatitis C virus genes (E1, E2, NS2, NS4B, NS5B), with an emphasis on including as many sequences with early collection dates as possible...
June 2016: Lancet Infectious Diseases
Alexsandro S Galdino, José C Santos, Marilen Q Souza, Yanna K M Nóbrega, Mary-Ann E Xavier, Maria S S Felipe, Sonia M Freitas, Fernando A G Torres
Hepatitis C virus (HCV) has emerged as the major pathogen of liver diseases in recent years leading to worldwide blood-transmitted chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Accurate diagnosis for differentiation of hepatitis C from other viruses is thus of pivotal importance for proper treatment. In this work we developed a recombinant multiepitope protein (rMEHCV) for hepatitis C diagnostic purposes based on conserved and immunodominant epitopes from core, NS3, NS4A, NS4B, and NS5 regions of the virus polyprotein of genotypes 1a, 1b, and 3a, the most prevalent genotypes in South America (especially in Brazil)...
2016: Hepatitis Research and Treatment
Shufeng Liu, Ting Zhao, BenBen Song, Jianhua Zhou, Tony T Wang
Hepatitis C virus (HCV) poses a global threat to public health. HCV envelop protein E2 is the major component on the virus envelope, which plays an important role in virus entry and morphogenesis. Here, for the first time, we affinity purified E2 complex formed in HCV-infected human hepatoma cells and conducted comparative mass spectrometric analyses. 85 cellular proteins and three viral proteins were successfully identified in three independent trials, among which alphafetoprotein (AFP), UDP-glucose: glycoprotein glucosyltransferase 1 (UGT1) and HCV NS4B were further validated as novel E2 binding partners...
2016: PloS One
Nanjing Zhang, Anthony Turpoff, Xiaoyan Zhang, Song Huang, Yalei Liu, Neil Almstead, F George Njoroge, Zhengxian Gu, Jason Graci, Stephen P Jung, John Pichardo, Joseph Colacino, Fred Lahser, Paul Ingravallo, Marla Weetall, Amin Nomeir, Gary M Karp
A novel series of 2-(4-sulfonamidophenyl)-indole 3-carboxamides was identified and optimized for activity against the HCV genotype 1b replicon resulting in compounds with potent and selective activity. Further evaluation of this series demonstrated potent activity across HCV genotypes 1a, 2a and 3a. Compound 4z had reduced activity against HCV genotype 1b replicons containing single mutations in the NS4B coding sequence (F98C and V105M) indicating that NS4B is the target. This novel series of 2-(4-sulfonamidophenyl)-indole 3-carboxamides serves as a promising starting point for a pan-genotype HCV discovery program...
January 15, 2016: Bioorganic & Medicinal Chemistry Letters
Zhenya Wang, Xinli Chen, Chunli Wu, Haiwei Xu, Hongmin Liu
Hepatitis C virus (HCV) infection is a major worldwide epidemic disease. It is estimated that more than 170 million individuals are infected with HCV and with three to four million new cases each year. Many new direct-acting antiviral (DAA) agents that specifically target HCV NS3 protease or NS5B polymerase inhibitors are therefore in development, with a significant effect for the patient and for the market recently. The non-structural 4B (NS4B) protein, is among the least characterized of the HCV proteins...
2016: Current Topics in Medicinal Chemistry
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