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https://www.readbyqxmd.com/read/29453099/impact-of-integrated-viral-dna-on-the-goal-to-clear-hepatitis-b-surface-antigen-with-different-therapeutic-strategies
#1
REVIEW
Magnus Lindh, Gustaf E Rydell, Simon B Larsson
A hallmark of hepatitis B virus (HBV) infection is the presence of hepatitis B surface antigen (HBsAg) in the serum of patients. Sustained loss of HBV DNA and HBsAg from the blood are main goals for treatment, and considered as functional cure. It is rarely achieved with long-term nucleoside analogue treatment though, both because cccDNA, the template for viral replication, is not completely cleared, and probably also because hepatocytes with HBV DNA integrated into their chromosomes persist and continue to produce large amounts of HBsAg...
February 13, 2018: Current Opinion in Virology
https://www.readbyqxmd.com/read/29453098/control-of-viral-transcripts-as-a-concept-for-future-hbv-therapies
#2
REVIEW
Christoph Seeger
Chronic hepatitis B virus infections affect over 250 million people world-wide, and, at present, are not curable. Of those, over 800000 are expected to die yearly from complications including cirrhosis and primary hepatocellular carcinoma (HCC). A viral episomal DNA intermediate, covalently closed circular DNA (cccDNA) can persist in nuclei of infected hepatocytes and trigger production of infectious virus. Current standard of care treatments against chronic HBV infections primarily rely on nucleoside analogs (NA) that inhibit de novo virus production by inhibiting the viral reverse transcriptase and, as a consequence, reducing virus titers...
February 13, 2018: Current Opinion in Virology
https://www.readbyqxmd.com/read/29445209/3d-microfluidic-liver-cultures-as-a-physiological-preclinical-tool-for-hepatitis-b-virus-infection
#3
A M Ortega-Prieto, J K Skelton, S N Wai, E Large, M Lussignol, G Vizcay-Barrena, D Hughes, R A Fleck, M Thursz, M T Catanese, M Dorner
With more than 240 million people infected, hepatitis B virus (HBV) is a major health concern. The inability to mimic the complexity of the liver using cell lines and regular primary human hepatocyte (PHH) cultures pose significant limitations for studying host/pathogen interactions. Here, we describe a 3D microfluidic PHH system permissive to HBV infection, which can be maintained for at least 40 days. This system enables the recapitulation of all steps of the HBV life cycle, including the replication of patient-derived HBV and the maintenance of HBV cccDNA...
February 14, 2018: Nature Communications
https://www.readbyqxmd.com/read/29438098/sustained-antiviral-effects-and-clearance-of-hepatitis-surface-antigen-after-combination-therapy-with-entecavir-and-pegylated-interferon-in-chronic-hepatitis-b
#4
Satoru Hagiwara, Naoshi Nishida, Tomohiro Watanabe, Hiroshi Ida, Toshiharu Sakurai, Kazuomi Ueshima, Masahiro Takita, Yoriaki Komeda, Norihiro Nishijima, Yukio Osaki, Masatoshi Kudo
BACKGROUND: Although the efficacy of combination therapy with lamivudine or tenofovir and pegylated-interferon (Peg-IFN) has been reported in patients with chronic hepatitis B (CHB), the long-term effect of the combination based on the observation of clinical course remains to be clarified. We previously reported the efficacy of combination therapy with entecavir (ETV) and Peg-IFN. Here, we investigated the long-term effect of this combination in patients with CHB. METHODS: We administered both ETV and Peg-IFN α-2a or -2b simultaneously to 26 patients with hepatitis B virus genotype C infection...
February 13, 2018: Antiviral Therapy
https://www.readbyqxmd.com/read/29432776/establishment-of-cre-mediated-hbv-recombinant-cccdna-rcccdna-cell-line-for-cccdna-biology-and-antiviral-screening-assays
#5
Min Wu, Jin Li, Lei Yue, Lu Bai, Yaming Li, Jieliang Chen, Xiaonan Zhang, Zhenghong Yuan
Hepatitis B virus (HBV) covalently closed circular DNA (cccDNA), existing in hepatocyte nuclei as a stable minichromosome, plays a central role in the life cycle of the virus and permits the persistence of infection. Despite being essential for HBV infection, little is known about the molecular mechanisms of cccDNA formation, regulation and degradation, and there is no therapeutic agents directly targeting cccDNA, fore mostly due to the lack of robust, reliable and quantifiable HBV cccDNA models. In this study, combined the Cre/loxP and sleeping beauty transposons system, we established HepG2-derived cell lines integrated with 2-60 copies of monomeric HBV genome flanked by loxP sites (HepG2-HBV/loxP)...
February 9, 2018: Antiviral Research
https://www.readbyqxmd.com/read/29427479/towards-hbv-curative-therapies
#6
REVIEW
Raymond F Schinazi, Maryam Ehteshami, Leda Bassit, Tarik Asselah
Tremendous progress has been made over the last 2 decades to discover and develop approaches to control hepatitis B virus (HBV) infections and to prevent the development of hepatocellular carcinoma using various interferons and small molecules as antiviral agents. However, none of these agents have significant impact on eliminating HBV from infected cells. Currently the emphasis is on silencing or eliminating cccDNA, which could lead to a cure for HBV. Various approaches are being developed including the development of capsid effectors, CRISPR/Cas9, TALENS, siRNA, entry and secretion inhibitors, as well as immunological approaches...
February 2018: Liver International: Official Journal of the International Association for the Study of the Liver
https://www.readbyqxmd.com/read/29414802/proteomics-based-identification-of-autotaxin-as-an-anti-hepatitis-b-virus-factor-and-a-promoter-of-hepatoma-cell-invasion-and-migration
#7
Sha She, Min Yang, Huaidong Hu, Peng Hu, Yixuan Yang, Hong Ren
BACKGROUND/AIMS: Hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma. Therefore, we aimed to obtain further information on HBV pathogenesis, and to search for novel putative molecules for anti-HBV therapy. METHODS: We utilized Isobaric Tags for Relative and Absolute Quantitation (iTRAQ) to identify the secretory proteins that are differentially expressed in the HBV DNA-transfected HepG2.2.15 cell line and its parental HepG2 cell line...
February 1, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29410097/hbv-bypasses-the-innate-immune-response-and-does-not-protect-hcv-from-antiviral-activity-of-interferon
#8
Pascal Mutz, Philippe Metz, Florian A Lempp, Silke Bender, Bingqian Qu, Katrin Schöneweis, Stefan Seitz, Thomas Tu, Agnese Restuccia, Jamie Frankish, Christopher Dächert, Benjamin Schusser, Ronald Koschny, Georgios Polychronidis, Peter Schemmer, Katrin Hoffmann, Thomas F Baumert, Marco Binder, Stephan Urban, Ralf Bartenschlager
BACKGROUND & AIMS: Hepatitis C virus (HCV) infection is sensitive to interferon (IFN)-based therapy whereas HBV infection is not. It is unclear whether HBV escapes detection by the IFN-mediated immune response or actively suppresses it. Moreover, little is known on how HBV and HCV influence each other in co-infected cells. We investigated interactions between HBV and the IFN-mediated immune response using HepaRG cells and primary human hepatocytes (PHHs). We analyzed the effects of HBV on HCV replication, and vice versa, at the single-cell level...
January 31, 2018: Gastroenterology
https://www.readbyqxmd.com/read/29360739/peretinoin-an-acyclic-retinoid-inhibits-hepatitis-b-virus-replication-by-suppressing-sphingosine-metabolic-pathway-in-vitro
#9
Kazuhisa Murai, Takayoshi Shirasaki, Masao Honda, Ryogo Shimizu, Tetsuro Shimakami, Saki Nakasho, Natsumi Shirasaki, Hikari Okada, Yoshio Sakai, Taro Yamashita, Shuichi Kaneko
Hepatocellular carcinoma (HCC) frequently develops from hepatitis C virus (HCV) and hepatitis B virus (HBV) infection. We previously reported that peretinoin, an acyclic retinoid, inhibits HCV replication. This study aimed to examine the influence of peretinoin on the HBV lifecycle. HBV-DNA and covalently closed circular DNA (cccDNA) were evaluated by a qPCR method in HepG2.2.15 cells. Peretinoin significantly reduced the levels of intracellular HBV-DNA, nuclear cccDNA, and HBV transcript at a concentration that did not induce cytotoxicity...
January 23, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29353073/serum-hbv-dna-plus-rna-shows-superiority-in-reflecting-the-activity-of-intrahepatic-cccdna-in-treatment-na%C3%A3-ve-hbv-infected-individuals
#10
Hongxin Huang, Jie Wang, Weijie Li, Ran Chen, Xiangmei Chen, Fengmin Zhang, Dongping Xu, Fengmin Lu
BACKGROUND: Both serum hepatitis B virus (HBV) DNA and RNA can reflect intrahepatic covalently closed circular DNA (cccDNA) activity. However, correlations among viral markers haven't been fully explored. OBJECTIVES: Here we investigated the correlations between serum HBV RNA and other viral markers in acute hepatitis B patients and treatment-naïve chronic HBV-infected individuals. STUDY DESIGN: The serum viral markers of 19 acute hepatitis B patients and 84 treatment-naïve chronic HBV-infected individuals at different infection stages were quantified...
February 2018: Journal of Clinical Virology: the Official Publication of the Pan American Society for Clinical Virology
https://www.readbyqxmd.com/read/29331944/liver-sampling-a-vital-window-into-hbv-pathogenesis-on-the-path-to-functional-cure
#11
REVIEW
Upkar S Gill, Laura J Pallett, Patrick T F Kennedy, Mala K Maini
In order to optimally refine the multiple emerging drug targets for hepatitis B virus (HBV), it is vital to evaluate virological and immunological changes at the site of infection. Traditionally liver biopsy has been the mainstay of HBV disease assessment, but with the emergence of non-invasive markers of liver fibrosis, there has been a move away from tissue sampling. Here we argue that liver biopsy remains an important tool, not only for the clinical assessment of HBV but also for research progress and evaluation of novel agents...
January 13, 2018: Gut
https://www.readbyqxmd.com/read/29321313/tip60-complex-inhibits-hbv-transcription
#12
Hironori Nishitsuji, Saneyuki Ujino, Keisuke Harada, Kunitada Shimotohno
Hepatitis B virus (HBV) is a global major health problem with over one million deaths annually caused by chronic liver damage. Understanding host factors that modulate HBV replication may aid the development of anti-HBV therapies. Our recent genome-wide small interfering RNA screen using recombinant HBV demonstrated that TIP60 inhibited HBV infection. Here, we show that TIP60 complex contributes to anti-HBV defense. The TIP60 complex bound to the HBV promoter and suppressed HBV transcription driven by the precore/core promoter...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29316067/deep-sequencing-shows-low-level-oncogenic-hepatitis-b-virus-variants-persisting-post-liver-transplant-despite-potent-anti-hbv-prophylaxis
#13
Keith Ck Lau, Carla Osiowy, Elizabeth Giles, Beth Lusina, Guido van Marle, Kelly W Burak, Carla S Coffin
Recent studies suggest that withdrawal of hepatitis B immune globulin (HBIG) and nucleos(t)ide analogues (NA) prophylaxis may be considered in HBV surface antigen (HBsAg) negative liver transplant (LT) recipients with a low risk of disease recurrence. However, the frequency of occult HBV infection (OBI) and HBV variants after LT in the current era of potent NA therapy is unknown. 12 LT recipients on prophylaxis were tested in matched plasma and peripheral blood mononuclear cells (PBMC) for HBV quasispecies by in-house nested PCR and next generation sequencing of amplicons...
January 6, 2018: Journal of Viral Hepatitis
https://www.readbyqxmd.com/read/29302257/elisa-for-quantitative-determination-of-hepatitis-b-virus-surface-antigen
#14
Se-Ho Kim
Several studies have reported a good correlation between levels of serum hepatitis B virus surface antigen (HBsAg) and covalently closed circular DNA (cccDNA) before and after antiviral therapy. As a result, the quantification of HBsAg levels has attracted much attention in recent years as an important approach to evaluate viral activity. In this study, mAbs against HBsAg were generated and 9 mAbs (H17, H30, H31, H67, H73, H97, H101, H118, and H128) were investigated for optimization of HBsAg quantitation ELISA...
December 2017: Immune Network
https://www.readbyqxmd.com/read/29280054/recent-advances-in-the-study-of-hepatitis-b-virus-covalently-closed-circular-dna
#15
REVIEW
Mengying Ji, Kanghong Hu
Chronic hepatitis B infection is caused by hepatitis B virus (HBV) and a total cure is yet to be achieved. The viral covalently closed circular DNA (cccDNA) is the key to establish a persistent infection within hepatocytes. Current antiviral strategies have no effect on the pre-existing cccDNA reservoir. Therefore, the study of the molecular mechanism of cccDNA formation is becoming a major focus of HBV research. This review summarizes the current advances in cccDNA molecular biology and the latest studies on the elimination or inactivation of cccDNA, including three major areas: (1) epigenetic regulation of cccDNA by HBV X protein, (2) immune-mediated degradation, and (3) genome-editing nucleases...
December 2017: Virologica Sinica
https://www.readbyqxmd.com/read/29260742/-overexpression-of-dna-methyltransferases-in-persistency-of-cccdna-pool-in-chronic-hepatitis-b
#16
D S Kostyushev, A P Zueva, S A Brezgin, A D Lipatnikov, V N Simirskii, D Glebe, E V Volchkova, G A Shipulin, V P Chulanov
AIM: To define the role of DNA-methyltransferases of type 1 and type 3A in hepatitis B viral cycle. MATERIAL AND METHODS: Human hepatoma cells HepG2 with stable expression of 1.1-mer HBV genome were transfected with vectors encoding DNA-methyltransferase 1 (DNMT1), DNA-methyltransferase 3A (DNMT3A) or were co-transfected with these vectors. Total HBV DNA copy number, relative expression of pregenomic RNA (pgRNA), S-protein-encoding RNA (S-RNA) and cccDNA were analyzed by quantitative and semi-quantitative real-time PCR-analysis with TaqMan probes for assessment of DNMTs-mediated effects on HBV...
2017: Terapevticheskiĭ Arkhiv
https://www.readbyqxmd.com/read/29260740/-hepatitis-c-can-be-cured-will-hepatitis-b-become-next
#17
V P Chulanov, A P Zueva, D S Kostyushev, S A Brezgin, E V Volchkova, V V Maleyev
Chronic hepatitis B (CHB) and C (CHC) are one of the leading causes of cirrhosis and liver cancer with over a million of people dying annually from their consequences. In Russia CHB and CHC morbidity and related mortality show an upward trend. As a result of recent breakthroughs in antiviral therapeutics CHC became a curable disease. Modern therapeutics effectively suppress viral replication in CHB patients, but withdrawal of antivirals usually results in disease relapse. Loss of HBsAg required for the so called 'functional cure' is a very rare event...
2017: Terapevticheskiĭ Arkhiv
https://www.readbyqxmd.com/read/29251788/nucleic-acid-polymer-rep-2139-and-nucleos-t-ide-analogues-act-synergistically-against-chronic-hepadnaviral-infection-in-vivo
#18
Jonathan Quinet, Catherine Jamard, Madeleine Burtin, Matthieu Lemasson, Sylviane Guerret, Camille Sureau, Andrew Vaillant, Lucyna Cova
Nucleic acid polymer (NAP) REP 2139 treatment was shown to block the release of viral surface antigen in DHBV-infected ducks and in patients with chronic HBV or HBV/HDV infection. In this preclinical study, a novel combination therapy consisting of REP 2139 with tenofovir disoproxil fumarate (TDF) and entecavir (ETV) was evaluated in vivo in the chronic DHBV infection model. DHBV-infected duck groups were treated as follows: normal saline (control); REP 2139-Ca; TDF; REP 2139-Ca + TDF; REP 2139-Ca + TDF + ETV...
December 18, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29247725/toll-like-receptor-7-agonist-gs-9620-induces-prolonged-inhibition-of-hbv-via-a-type-i-interferon-dependent-mechanism
#19
Congrong Niu, Li Li, Stephane Daffis, Julie Lucifora, Marc Bonnin, Sarah Maadadi, Eduardo Salas, Ruth Chu, Hilario Ramos, Christine M Livingston, Rudolf K Beran, Abhishek V Garg, Scott Balsitis, David Durantel, Fabien Zoulim, William E Delaney, Simon P Fletcher
BACKGROUND & AIMS: GS-9620, an oral agonist of toll-like receptor 7 (TLR7), is in clinical development for the treatment of chronic hepatitis B (CHB). GS-9620 was previously shown to induce prolonged suppression of serum viral DNA and antigens in the woodchuck and chimpanzee models of CHB. Herein, we investigated the molecular mechanisms that contribute to the antiviral response to GS-9620 using in vitro models of hepatitis B virus (HBV) infection. METHODS: Cryopreserved primary human hepatocytes (PHH) and differentiated HepaRG (dHepaRG) cells were infected with HBV and treated with GS-9620, conditioned media from human peripheral blood mononuclear cells treated with GS-9620 (GS-9620 conditioned media [GS-9620-CM]), or other innate immune stimuli...
December 13, 2017: Journal of Hepatology
https://www.readbyqxmd.com/read/29247188/hepatocytic-expression-of-human-sodium-taurocholate-cotransporting-polypeptide-enables-hepatitis-b-virus-infection-of-macaques
#20
Benjamin J Burwitz, Jochen M Wettengel, Martin A Mück-Häusl, Marc Ringelhan, Chunkyu Ko, Marvin M Festag, Katherine B Hammond, Mina Northrup, Benjamin N Bimber, Thomas Jacob, Jason S Reed, Reed Norris, Byung Park, Sven Moller-Tank, Knud Esser, Justin M Greene, Helen L Wu, Shaheed Abdulhaqq, Gabriela Webb, William F Sutton, Alex Klug, Tonya Swanson, Alfred W Legasse, Tania Q Vu, Aravind Asokan, Nancy L Haigwood, Ulrike Protzer, Jonah B Sacha
Hepatitis B virus (HBV) is a major global health concern, and the development of curative therapeutics is urgently needed. Such efforts are impeded by the lack of a physiologically relevant, pre-clinical animal model of HBV infection. Here, we report that expression of the HBV entry receptor, human sodium-taurocholate cotransporting polypeptide (hNTCP), on macaque primary hepatocytes facilitates HBV infection in vitro, where all replicative intermediates including covalently closed circular DNA (cccDNA) are present...
December 15, 2017: Nature Communications
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