scholarly journals Hepatitis B virus X protein is not central to the viral life cycle in vitro.

1992 ◽  
Vol 66 (2) ◽  
pp. 1223-1227 ◽  
Author(s):  
H E Blum ◽  
Z S Zhang ◽  
E Galun ◽  
F von Weizsäcker ◽  
B Garner ◽  
...  
Keyword(s):  
Life Cycle ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Viral Life Cycle ◽  
X Protein ◽  
B Virus

scholarly journals Hepatitis B Virus Capsids Have Diverse Structural Responses to Small-Molecule Ligands Bound to the Heteroaryldihydropyrimidine Pocket

2016 ◽  
Vol 90 (8) ◽  
pp. 3994-4004 ◽  
Author(s):  
Balasubramanian Venkatakrishnan ◽  
Sarah P. Katen ◽  
Samson Francis ◽  
Srinivas Chirapu ◽  
M. G. Finn ◽  
...  
Keyword(s):  
Life Cycle ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Drug Design ◽  
Quaternary Structure ◽  
Core Protein ◽  
Viral Life Cycle ◽  
Structural Basis ◽  
Allosteric Modulators ◽  
B Virus

ABSTRACTThough the hepatitis B virus (HBV) core protein is an important participant in many aspects of the viral life cycle, its best-characterized activity is self-assembly into 240-monomer capsids. Small molecules that target core protein (core protein allosteric modulators [CpAMs]) represent a promising antiviral strategy. To better understand the structural basis of the CpAM mechanism, we determined the crystal structure of the HBV capsid in complex with HAP18. HAP18 accelerates assembly, increases protein-protein association more than 100-fold, and induces assembly of nonicosahedral macrostructures. In a preformed capsid, HAP18 is found at quasiequivalent subunit-subunit interfaces. In a detailed comparison to the two other extant CpAM structures, we find that the HAP18-capsid structure presents a paradox. Whereas the two other structures expanded the capsid diameter by up to 10 Å, HAP18 caused only minor changes in quaternary structure and actually decreased the capsid diameter by ∼3 Å. These results indicate that CpAMs do not have a single allosteric effect on capsid structure. We suggest that HBV capsids present an ensemble of states that can be trapped by CpAMs, indicating a more complex basis for antiviral drug design.IMPORTANCEHepatitis B virus core protein has multiple roles in the viral life cycle—assembly, compartment for reverse transcription, intracellular trafficking, and nuclear functions—making it an attractive antiviral target. Core protein allosteric modulators (CpAMs) are an experimental class of antivirals that bind core protein. The most recognized CpAM activity is that they accelerate core protein assembly and strengthen interactions between subunits. In this study, we observe that the CpAM-binding pocket has multiple conformations. We compare structures of capsids cocrystallized with different CpAMs and find that they also affect quaternary structure in different ways. These results suggest that the capsid “breathes” and is trapped in different states by the drug and crystallization. Understanding that the capsid is a moving target will aid drug design and improve our understanding of HBV interaction with its environment.

scholarly journals Hepatitis B Virus-Specific miRNAs and Argonaute2 Play a Role in the Viral Life Cycle

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e47490 ◽  
Author(s):  
C. Nelson Hayes ◽  
Sakura Akamatsu ◽  
Masataka Tsuge ◽  
Daiki Miki ◽  
Rie Akiyama ◽  
...  
Keyword(s):  
Life Cycle ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Viral Life Cycle ◽  
B Virus

scholarly journals Role and Functional Domain of Hepatitis B Virus X Protein in Regulating HBV Transcription and Replication in Vitro and in Vivo

Viruses ◽  
2013 ◽  
Vol 5 (5) ◽  
pp. 1261-1271 ◽  
Author(s):  
Dao-Yin Gong ◽  
En-Qiang Chen ◽  
Fei-Jun Huang ◽  
Xiao-Hua Leng ◽  
Xing Cheng ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Functional Domain ◽  
X Protein ◽  
B Virus ◽  
Transcription And Replication

scholarly journals Antiviral Properties and Mechanism of Action Studies of the Hepatitis B Virus Capsid Assembly Modulator JNJ-56136379

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Jan Martin Berke ◽  
Pascale Dehertogh ◽  
Karen Vergauwen ◽  
Wendy Mostmans ◽  
Koen Vandyck ◽  
...  
Keyword(s):  
Life Cycle ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Core Protein ◽  
Hbv Dna ◽  
Size Exclusion ◽  
Capsid Assembly ◽  
Phase Ii Trials ◽  
B Virus

ABSTRACT Capsid assembly is a critical step in the hepatitis B virus (HBV) life cycle, mediated by the core protein. Core is a potential target for new antiviral therapies, the capsid assembly modulators (CAMs). JNJ-56136379 (JNJ-6379) is a novel and potent CAM currently in phase II trials. We evaluated the mechanisms of action (MOAs) and antiviral properties of JNJ-6379 in vitro. Size exclusion chromatography and electron microscopy studies demonstrated that JNJ-6379 induced the formation of morphologically intact viral capsids devoid of genomic material (primary MOA). JNJ-6379 accelerated the rate and extent of HBV capsid assembly in vitro. JNJ-6379 specifically and potently inhibited HBV replication; its median 50% effective concentration (EC50) was 54 nM (HepG2.117 cells). In HBV-infected primary human hepatocytes (PHHs), JNJ-6379, when added with the viral inoculum, dose-dependently reduced extracellular HBV DNA levels (median EC50 of 93 nM) and prevented covalently closed circular DNA (cccDNA) formation, leading to a dose-dependent reduction of intracellular HBV RNA levels (median EC50 of 876 nM) and reduced antigen levels (secondary MOA). Adding JNJ-6379 to PHHs 4 or 5 days postinfection reduced extracellular HBV DNA and did not prevent cccDNA formation. Time-of-addition PHH studies revealed that JNJ-6379 most likely interfered with postentry processes. Collectively, these data demonstrate that JNJ-6379 has dual MOAs in the early and late steps of the HBV life cycle, which is different from the MOA of nucleos(t)ide analogues. JNJ-6379 is in development for chronic hepatitis B treatment and may translate into higher HBV functional cure rates.

scholarly journals Hepatitis B Virus X Protein Reduces Podocyte Adhesion via Downregulation of α3β1 Integrin

2017 ◽  
Vol 41 (2) ◽  
pp. 689-700 ◽  
Author(s):  
Ping He ◽  
Dajun Liu ◽  
Beiru Zhang ◽  
Guangyu Zhou ◽  
Xuesong Su ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Control Group ◽  
Caspase 8 ◽  
X Protein ◽  
Α3β1 Integrin ◽  
B Virus ◽  
Induced Apoptosis

Background/Aims: Hepatitis B virus (HBV)-associated glomerulonephritis (HBV-GN) is characterized by a reduced number of podocytes due to apoptosis and shedding from the basement membrane. However, the pathological mechanism of HBV-GN is unclear. We previously showed that hepatitis B virus X protein (HBx) promotes apoptosis in tubular epithelial cells. In this study, we transfected podocytes with HBx and examined the effects on adhesion and apoptosis of these cells. Methods: Podocytes were transfected with pc-DNA3.1 (+)-HBx. One control group was not transfected and another control group was transfected with empty plasmids. Podocyte adhesion was assessed by a fluorescence assay, apoptosis was measured by flow cytometry and fluorescence microscopy, and expression of α3β1 integrin was determined by western blotting and the reverse transcription polymerase chain reaction (RT-PCR). Activity of caspase-8 was measured by a spectrophotometric assay. Results: Relative to controls, podocytes with pc-DNA3.1(+)-HBx had reduced cell adhesion, increased apoptosis, reduced expression of α3β1 integrin, and increased caspase-8 activity. β1 integrin blockage reduced podocyte adhesion, but increased apoptosis and caspase-8 activity. Treatment of transfected podocytes with a caspase-8 inhibitor (Z-IETD-FMK) had no effect on the HBx-mediated integrin downregulation and reduced podocyte adhesion, suggesting that α3β1 integrin downregulaton is sufficient to alter cell adhesion. Conclusions: Our in vitro results indicate that HBx reduced podocyte adhesion and expression of α3β1 integrin, and increased apoptosis. Moreover, HBx-mediated downregulation of α3β1 integrin expression is sufficient to reduce podocyte adhesion. HBx-induced apoptosis of podocytes may contribute to HBV-GN.

scholarly journals Anti-oncogene PTPN13 inactivation by hepatitis B virus X protein counteracts IGF2BP1 to promote hepatocellular carcinoma progression

Oncogene ◽  
2020 ◽  
Vol 40 (1) ◽  
pp. 28-45 ◽  
Author(s):  
Yongcong Yan ◽  
Pinbo Huang ◽  
Kai Mao ◽  
Chuanchao He ◽  
Qiaodong Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Tyrosine Phosphatase ◽  
Cellular Protein ◽  
Metabolic Reprogramming ◽  
X Protein ◽  
B Virus

AbstractHepatitis B x protein (HBx) affects cellular protein expression and participates in the tumorigenesis and progression of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Metabolic reprogramming contributed to the HCC development, but its role in HBV-related HCC remains largely unclear. Tyrosine-protein phosphatase nonreceptor type 13 (PTPN13) is a significant regulator in tumor development, however, its specific role in hepatocarcinogenesis remains to be explored. Here, we found that decreased PTPN13 expression was associated with HBV/HBx. Patients with low PTPN13 expression showed a poor prognosis. Functional assays revealed that PTPN13 inhibited proliferation and tumorigenesis in vitro and in vivo. Further mechanistic studies indicated that HBx inhibited PTPN13 expression by upregulating the expression of DNMT3A and interacting with DNMT3A. Furthermore, we found that DNMT3A bound to the PTPN13 promoter (−343 to −313 bp) in an epigenetically controlled manner associated with elevated DNA methylation and then inhibited PTPN13 transcription. In addition, we identified IGF2BP1 as a novel PTPN13-interacting gene and demonstrated that PTPN13 influences c-Myc expression by directly and competitively binding to IGF2BP1 to decrease the intracellular concentration of functional IGF2BP1. Overexpressing PTPN13 promoted c-Myc mRNA degradation independent of the protein tyrosine phosphatase (PTP) activity of PTPN13. Importantly, we discovered that the PTPN13-IGF2BP1-c-Myc axis was important for cancer cell growth through promoting metabolic reprogramming. We verified the significant negative correlations between PTPN13 expression and c-Myc, PSPH, and SLC7A1 expression in clinical HCC tissue samples. In summary, our findings demonstrate that PTPN13 is a novel regulator of HBV-related hepatocarcinogenesis and may play an important role in HCC. PTPN13 may serve as a prognostic marker and therapeutic target in HBV-related HCC patients.

scholarly journals Polo-like kinase 1 inhibition suppresses hepatitis B virus X protein-induced transformation in an in vitro model of liver cancer progression

Hepatology ◽  
2009 ◽  
Vol 50 (2) ◽  
pp. 414-423 ◽  
Author(s):  
Leo L. Studach ◽  
Lova Rakotomalala ◽  
Wen-Horng Wang ◽  
Ronald L. Hullinger ◽  
Stefano Cairo ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Liver Cancer ◽  
Hepatitis B ◽  
Cancer Progression ◽  
In Vitro Model ◽  
X Protein ◽  
B Virus ◽  
Vitro Model

scholarly journals Stimulation of Cellular Proliferation by Hepatitis B Virus X Protein

2001 ◽  
Vol 17 (3) ◽  
pp. 153-157 ◽  
Author(s):  
Charles R. Madden ◽  
Betty L. Slagle
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Cellular Proliferation ◽  
X Protein ◽  
Hepatitis Viruses ◽  
B Virus ◽  
Infected Cells ◽  
Proliferation In Vitro

Chronic infection with the hepatitis B virus (HBV) is a known risk factor in the development of human hepatocellular carcinoma (HCC). The HBV-encoded X protein, HBx, has been investigated for properties that may explain its cancer cofactor role in transgenic mouse lines. We discuss here recent data showing that HBx is able to induce hepatocellular proliferation in vitro and in vivo. This property of HBx is predicted to sensitize hepatocytes to other HCC cofactors, including exposure to carcinogens and to other hepatitis viruses. Cellular proliferation is intimately linked to the mechanism(s) by which most tumor-associated viruses transform virus-infected cells. The HBx alteration of the cell cycle provides an additional mechanism by which chronic HBV infection may contribute to HCC.

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