Role of anti-HBs in functional cure of HBeAg+ chronic hepatitis B patients infected with HBV genotype A.

Background & Aims: HBsAg-specific antibody responses are difficult to detect during chronic hepatitis B infection (CHB) and are often overlooked. The aim of this study was to examine whether anti-HBs may be involved in functional cure (FC) by profiling anti-HBs responses in patients with CHB using a panel of specific assays.

Methods: Longitudinal serum samples were obtained from 25 patients with CHB who were infected with HBV genotype A and were undergoing nucleos(t)ide analogue (NA) treatment: 14 achieved FC while 11 remained infected (non-FC).

Quantitative analysis of the splice variants expressed by the major hepatitis B virus genotypes.

Hepatitis B virus (HBV) is a major human pathogen that causes liver diseases. The main HBV RNAs are unspliced transcripts that encode the key viral proteins. Recent studies have shown that some of the HBV spliced transcript isoforms are predictive of liver cancer, yet the roles of these spliced transcripts remain elusive.

The Hepatitis B Virus Pre-Core Protein p22 Activates Wnt Signaling.

An emerging theme for Wnt-addicted cancers is that the pathway is regulated at multiple steps via various mechanisms. Infection with hepatitis B virus (HBV) is a major risk factor for liver cancer, as is deregulated Wnt signaling, however, the interaction between these two causes is poorly understood. To investigate this interaction, we screened the effect of the various HBV proteins for their effect on Wnt/β-catenin signaling and identified the pre-core protein p22 as a novel and potent activator of TCF/β-catenin transcription.

HBx-K130M/V131I Promotes Liver Cancer in Transgenic Mice via AKT/FOXO1 Signaling Pathway and Arachidonic Acid Metabolism.

Chronic hepatitis B viral (HBV) infection remains a high underlying cause for hepatocellular carcinoma (HCC) worldwide, while the genetic mechanisms behind this remain unclear. This study elucidated the mechanisms contributing to tumor development induced by the HBV X (HBx) gene of predominantly Asian genotype B HBV and its common HBx variants. To compare the potential tumorigenic effects of K130M/V131I (Mut) and wild-type (WT) HBx on HCC, the () transposon system was used to deliver HBx Mut and WT into the livers of fumarylacetoacetate hydrolase ()-deficient mice and in the context of () deficiency.

Levels of regulatory B cells do not predict serological responses to hepatitis B vaccine.

This study investigated the immunomodulatory influence of IL10 producing B regulatory cells, Bregs (CD19+CD24hiCD38hi) to standard Twinrix® vaccination. We also investigated HBsAg specific T-cell mediated IFN-γ responses to Twinrix® which in theory could provide effective immunity despite low anti-HBs titer. A total of 309 hepatitis B negative health care students and workers completed a standard Twinrix® vaccination schedule (0, 1 and 6 months).

Novel HBsAg mutations correlate with hepatocellular carcinoma, hamper HBsAg secretion and promote cell proliferation in vitro.

Background: An impaired HBsAg-secretion can increase HBV oncogenic-properties. Here, we investigate genetic-determinants in HBsAg correlated with HBV-induced hepatocellular carcinoma (HCC), and their impact on HBsAg-secretion and cell-proliferation.

Methods: This study included 128 chronically HBV-infected patients: 23 with HCC (73.

Stop codons in the hepatitis B surface proteins are enriched during antiviral therapy and are associated with host cell apoptosis.

Premature stop codons in the hepatitis B virus (HBV) surface protein can be associated with nucleos(t)ide analogue resistance due to overlap of the HBV surface and polymerase genes. The aim of this study was to determine the effect of the replication of three common surface stop codon variants on the hepatocyte. Cell lines were transfected with infectious HBV clones encoding surface stop codons rtM204I/sW196*, rtA181T/sW172*, rtV191I/sW182*, and a panel of substitutions in the surface proteins.

In Vitro Studies Show that Sequence Variability Contributes to Marked Variation in Hepatitis B Virus Replication, Protein Expression, and Function Observed across Genotypes.

Unlabelled: The hepatitis B virus (HBV) exists as 9 major genotypes (A to I), one minor strain (designated J) and multiple subtypes. Marked differences in HBV natural history, disease progression and treatment response are exhibited by many of these genotypes and subtypes. For example, HBV genotype C is associated with later hepatitis B e antigen (HBeAg) seroconversion and high rates of liver cancer compared to other HBV genotypes, whereas genotype A2 is rarely associated with HBeAg-negative disease or liver cancer.

Cellular inhibitor of apoptosis proteins prevent clearance of hepatitis B virus.

Hepatitis B virus (HBV) infection can result in a spectrum of outcomes from immune-mediated control to disease progression, cirrhosis, and liver cancer. The host molecular pathways that influence and contribute to these outcomes need to be defined. Using an immunocompetent mouse model of chronic HBV infection, we identified some of the host cellular and molecular factors that impact on infection outcomes.

Mechanisms of hepatitis B virus resistance development.

Hepatitis B virus (HBV) resistance to nucleos(t)ide analogue (NA) therapy is essentially structure specific, with each NA falling within three main structural groups. Resistance to each of these is characterized by specific mutations in the reverse transcriptase domains of the HBV polymerase, and may be associated with compensatory mutations which can increase replication. HBV polymerase is considered to have a traditional 'right-handed' structural conformation, and each of the resistance mutations is predicted to cause a specific structural change of the polymerase, thereby preventing incorporation of NA into replicating DNA.

Hepatitis B virus genotype C encoding resistance mutations that emerge during adefovir dipivoxil therapy: in vitro replication phenotype.

Introduction: Hepatitis B virus (HBV) can be classified into ten genotypes (A-J), with genotypes B and C being the most common in Asia. Recent data suggest that the HBV genotype can influence disease progression, and genotype C has been associated with more aggressive liver disease than that of other genotypes. Although there is a preventative vaccine, chronic infection remains a public health problem with oral nucleos(t)ide analog therapy being the most common treatment.

In vitro replication phenotype of a novel (-1G) hepatitis B virus variant associated with HIV co-infection.

The -1G mutant HBV is more prevalent in individuals co-infected with HIV/HBV than in individuals infected with HBV alone and in some cases is the dominant virus in circulation. This mutant is created by the deletion of a dGMP (-1G) from the guanine rich homopolymer sequence located at nts 2,085-2,090 (numbering from EcoRI site as position 1) in the HBV core gene. This deletion causes a frameshift generating a premature stop codon at (64) Asn in the HBV core gene (codon 93 in the precore gene), that truncates the precore protein, precursor of the secreted hepatitis B "e" antigen (HBeAg), and the core protein which forms the viral nucleocapsid.

Modulation of the immunogenicity of virus-like particles composed of mutant hepatitis B virus envelope subunits.

Virus-like particles (VLPs) are non-infectious subviral protein complexes, which possess structural features identical or closely related to infectious virions. They are utilized as delivery tools for immunologically relevant antigenic sequences. In order to investigate whether mutant subunits can modulate the VLP immunogenicity, comparative immunization studies with wild-type and non-native VLPs were performed.

Coinfection of hepatic cell lines with human immunodeficiency virus and hepatitis B virus leads to an increase in intracellular hepatitis B surface antigen.

Liver-related mortality is increased in the setting of HIV-hepatitis B virus (HBV) coinfection. However, interactions between HIV and HBV to explain this observation have not been described. We hypothesized that HIV infection of hepatocytes directly affects the life cycle of HBV.

The antiviral drug selected hepatitis B virus rtA181T/sW172* mutant has a dominant negative secretion defect and alters the typical profile of viral rebound.

Unlabelled: The hepatitis B virus (HBV) mutation that encodes rtA181T is selected in the viral polymerase during antiviral drug therapy and can also encode a stop codon in the overlapping surface gene at amino acid 172 (sW172*) resulting in truncation of the last 55 amino acids of the C-terminal hydrophobic region of the surface proteins. This mutation is usually detected as a mixed population with wild-type HBV. In vitro analysis revealed that the rtA181T/sW172* variant is not only defective in secretion of viral particles causing intracellular retention of surface proteins, it also has a dominant negative effect on virion but not subviral particle secretion when coexpressed with the wild type.

Major causes of antiviral drug resistance and implications for treatment of hepatitis B virus monoinfection and coinfection with HIV.

The two key events in the life-cycle of the hepatitis B virus (HBV) involve (1) the generation from viral genomic DNA of the covalently closed circular DNA transcriptional template, and (2) the reverse transcription of the viral pregenomic RNA to form the HBV DNA genome. Diversity in the HBV genome is ensured by the low fidelity of the viral reverse transcriptase (rt). Particular selection pressures such as antiviral therapy readily select out escape mutants from this pre-existing quasispecies pool.

The L80I substitution in the reverse transcriptase domain of the hepatitis B virus polymerase is associated with lamivudine resistance and enhanced viral replication in vitro.

Long-term lamivudine (LMV) treatment of chronic hepatitis B almost inevitably engenders viral resistance. Mutations that result in the replacement of the methionine at position 204 of the deoxynucleoside triphosphate-binding site of the hepatitis B virus (HBV) reverse transcriptase (rt) by isoleucine, valine, or (rarely) serine (rtM204I/V/S) confer high-level resistance to LMV but reduce replication efficiency. The subsequent selection or coselection of secondary mutations that partially restore replication efficiency is common and may influence drug resistance.