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https://www.readbyqxmd.com/read/29331944/liver-sampling-a-vital-window-into-hbv-pathogenesis-on-the-path-to-functional-cure
#1
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
#2
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
#3
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
#4
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/29287110/the-role-of-host-dna-ligases-in-hepadnavirus-covalently-closed-circular-dna-formation
#5
Quanxin Long, Ran Yan, Jieli Hu, Dawei Cai, Bidisha Mitra, Elena S Kim, Alexander Marchetti, Hu Zhang, Soujuan Wang, Yuanjie Liu, Ailong Huang, Haitao Guo
Hepadnavirus covalently closed circular (ccc) DNA is the bona fide viral transcription template, which plays a pivotal role in viral infection and persistence. Upon infection, the non-replicative cccDNA is converted from the incoming and de novo synthesized viral genomic relaxed circular (rc) DNA, presumably through employment of the host cell's DNA repair mechanisms in the nucleus. The conversion of rcDNA into cccDNA requires preparation of the extremities at the nick/gap regions of rcDNA for strand ligation...
December 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/29280054/recent-advances-in-the-study-of-hepatitis-b-virus-covalently-closed-circular-dna
#6
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
#7
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
#8
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
#9
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
#10
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. Here 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 (PBMCs) 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
#11
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
https://www.readbyqxmd.com/read/29216213/a-multi-scale-spatial-model-of-hepatitis-b-viral-dynamics
#12
Quentin Cangelosi, Shawn A Means, Harvey Ho
Chronic hepatitis B viral infection (HBV) afflicts around 250 million individuals globally and few options for treatment exist. Once infected, the virus entrenches itself in the liver with a notoriously resilient colonisation of viral DNA (covalently-closed circular DNA, cccDNA). The majority of infections are cleared, yet we do not understand why 5% of adult immune responses fail leading to the chronic state with its collateral morbid effects such as cirrhosis and eventual hepatic carcinoma. The liver environment exhibits particularly complex spatial structures for metabolic processing and corresponding distributions of nutrients and transporters that may influence successful HBV entrenchment...
2017: PloS One
https://www.readbyqxmd.com/read/29170915/potential-use-of-serum-hbv-rna-in-antiviral-therapy-for-chronic-hepatitis-b-in-the-era-of-nucleos-t-ide-analogs
#13
REVIEW
Fengmin Lu, Jie Wang, Xiangmei Chen, Dongping Xu, Ningshao Xia
Although the efficacy of nucleos(t)ide analogue (NA) has been confirmed for treatment of chronic hepatitis B, long-term therapy has been recommended due to the high frequency of off-therapy viral DNA rebound and disease relapse. In this review, the RNA virion-like particles of hepatitis B virus (HBV) are integrated into the life cycle of HBV replication, and the potential significance of serum HBV RNA is systematically described. The production of HBV RNA virion-like particles should not be blocked by NA; in this regard, serum HBV RNA is found to be a suitable surrogate marker for the activity of intrahepatic covalently closed circular DNA (cccDNA), particularly among patients receiving NA therapy...
November 23, 2017: Frontiers of Medicine
https://www.readbyqxmd.com/read/29170913/impact-of-hbv-replication-in-peripheral-blood-mononuclear-cell-on-hbv-intrauterine-transmission
#14
Xiaohong Shi, Xuefei Wang, Xixi Xu, Yongliang Feng, Shuzhen Li, Shuying Feng, Bo Wang, Suping Wang
This study determined the effect of hepatitis B virus (HBV) replication in peripheral blood mononuclear cell (PBMC) from HBsAg-positive mothers on HBV intrauterine transmission. A total of 150 HBsAg-positive mothers and their neonates were recruited in this study. Within 24 h after birth, HBV serological markers, serum HBV DNA, PBMC HBV relaxed circular DNA (rcDNA), and covalently closed circular DNA (cccDNA) were measured in the HBsAg-positive mothers and their neonates before passive-active immune prophylaxis...
November 23, 2017: Frontiers of Medicine
https://www.readbyqxmd.com/read/29169914/low-incidence-of-precore-w28-mutant-variants-in-treated-hepatitis-b-virus-and-human-immunodeficiency-virus-co-infected-patients
#15
Anders Boyd, Karine Lacombe, Fabien Lavocat, Patrick Miailhes, Caroline Lascoux-Combe, Pierre-Maire Girard, Fabien Zoulim
The precore (pc) W28* mutation arises from immune-selective pressures during the hepatitis B "e" antigen (HBeAg)-positive phase of chronic hepatitis B virus (HBV) infection and has been linked to severe liver-related morbidity. Here, we examined the determinants of harboring this mutation and its rate of emergence in treated patients co-infected with human immunodeficiency virus (HIV) and HBV. In a three-year prospective cohort of 165 HIV-HBV co-infected patients, pcW28* mutation was determined via DNA-chip during yearly sampling...
November 20, 2017: Antiviral Research
https://www.readbyqxmd.com/read/29159681/advanced-strategies-for-eliminating-the-cccdna-of-hbv
#16
REVIEW
Jingwu Dong, Jie Ying, Xiaoyan Qiu, Yu Lu, Miaomiao Zhang
Persistent hepatitis B virus (HBV) infection of hepatocytes is associated with a covalently closed circular DNA (cccDNA) episome. Although serologic hepatitis B surface antigen tests are negative, the presence of cccDNA is obviously increased in HBeAg-positive patients compared with that in HBeAg-negative patients, inactive carriers and patients. Moreover, trace cccDNA levels can also be found in the liver cells of patients with resolved hepatitis B infections. Therefore, clearance of cccDNA in hepatocytes could be an effective cure for HBV...
November 20, 2017: Digestive Diseases and Sciences
https://www.readbyqxmd.com/read/29156567/the-role-of-infected-cell-proliferation-in-the-clearance-of-acute-hbv-infection-in-humans
#17
Ashish Goyal, Ruy M Ribeiro, Alan S Perelson
Around 90-95% of hepatitis B virus (HBV) infected adults do not progress to the chronic phase and, instead, recover naturally. The strengths of the cytolytic and non-cytolytic immune responses are key players that decide the fate of acute HBV infection. In addition, it has been hypothesized that proliferation of infected cells resulting in uninfected progeny and/or cytokine-mediated degradation of covalently closed circular DNA (cccDNA) leading to the cure of infected cells are two major mechanisms assisting the adaptive immune response in the clearance of acute HBV infection in humans...
November 18, 2017: Viruses
https://www.readbyqxmd.com/read/29129707/apobec3b-edits-hbv-dna-and-inhibits-hbv-replication-during-reverse-transcription
#18
Yanmeng Chen, Jie Hu, Xuefei Cai, Yao Huang, Xing Zhou, Zeng Tu, Jieli Hu, John E Tavis, Ni Tang, Ailong Huang, Yuan Hu
Hepatitis B virus is a partially double-stranded DNA virus that replicates by reverse transcription, which occurs within viral core particles in the cytoplasm. The cytidine deaminase APOBEC3B is a cellular restriction factor for HBV. Recently, it was reported that APOBEC3B can edit HBV cccDNA in the nucleus, causing its degradation. However, whether and how it can edit HBV core-associated DNAs during reverse transcription is unclear. Our studies to address this question revealed the following: First, silencing endogenous APOBEC3B in an HBV infection system lead to upregulation of HBV replication...
November 10, 2017: Antiviral Research
https://www.readbyqxmd.com/read/29079518/efficacy-of-nvr-3-778-alone-and-in-combination-with-pegylated-interferon-vs-entecavir-in-upa-scid-mice-with-humanized-livers-and-hbv-infection
#19
Klaus Klumpp, Takashi Shimada, Lena Allweiss, Tassilo Volz, Marc Lütgehetmann, G Hartman, Osvaldo A Flores, Angela M Lam, Maura Dandri
BACKGROUND & AIMS: NVR3-778 is a capsid assembly modulator in clinical development. We determined the in vivo anti-viral efficacy and effects on innate and endoplasmic reticulum (ER) stress responses of NVR3-778 alone or in combination with pegylated interferon alpha (peg-IFN) and compared with entecavir. METHODS: We performed 2 studies, with a total of 61 uPA/SCID mice with humanized livers. Mice were infected with a HBV genotype C preparation; we waited 8 weeks for persistent infection of the human hepatocytes in livers of mice...
October 24, 2017: Gastroenterology
https://www.readbyqxmd.com/read/29065733/hepatitis-b-core-protein-as-a-therapeutic-target
#20
Lung-Yi Mak, Danny Ka-Ho Wong, Wai-Kay Seto, Ching-Lung Lai, Man Fung Yuen
Chronic hepatitis B virus (HBV) infection is difficult to cure, due to the presence of covalently-closed-circular DNA and virus-mediated blunting of host immune response. Existing therapies with nucleos(t)ide analogue or pegylated-interferon are not sufficient to achieve a high rate of HBV surface antigen seroclearance, a more desirable treatment outcome. Novel therapeutic agents targeting alternative viral replication steps are being developed. In this review, we will discuss the hepatitis B core antigen (HBcAg) as a therapeutic target...
December 2017: Expert Opinion on Therapeutic Targets
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