Metabolism and function of hepatitis B virus cccDNA: Implications for the development of cccDNA-targeting antiviral therapeutics

HBx is a hepatitis B virus protein that is required for viral infectivity and replication. Anti-apoptotic Bcl-2 family members are thought to be among the important host targets of HBx. However, the structure and function of HBx are poorly understood and the molecular mechanism of HBx-induced carcinogenesis remains unknown. In this study, we report biochemical and structural characterization of HBx. The recombinant HBx protein contains metal ions, in particular iron and zinc. A BH3-like motif in HBx (residues 110–135) binds Bcl-2 with a dissociation constant of ∼193 μM, which is drastically lower than that for a canonical BH3 motif from Bim or Bad. Structural analysis reveals that, similar to other BH3 motifs, the BH3-like motif of HBx adopts an amphipathic α-helix and binds the conserved BH3-binding groove on Bcl-2. Unlike the helical Bim or Bad BH3 motif, the C-terminal portion of the bound HBx BH3-like motif has an extended conformation and makes considerably fewer interactions with Bcl-2. These observations suggest that HBx may modulate Bcl-2 function in a way that is different from that of the classical BH3-only proteins.

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Interplay Between Non-Canonical NF-κB Signaling and Hepatitis B Virus Infection

Frontiers in Immunology ◽

10.3389/fimmu.2021.730684 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xinyu Lu ◽

Qianhui Chen ◽

Hongyan Liu ◽

Xiaoyong Zhang

Keyword(s):

Immune System ◽

Hepatitis B Virus ◽

Hepatitis B ◽

Signaling Pathway ◽

Hbv Infection ◽

Host Immune System ◽

Novel Drugs ◽

B Virus ◽

And Function ◽

Light Chain Enhancer

The non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway is an important component of NF-κB transcription complex. Activation of this pathway mediates the development and function of host immune system involved in inflammation and viral infection. During hepatitis B virus (HBV) infection, there is a complex interaction between infected hepatocytes and the immune cells, which can hinder antiviral immune responses and is associated with pathological changes in liver tissue. Consistently, the host immune system is closely related to the severity of liver damage and the level of viral replication. Previous studies indicated that the non-canonical NF-κB signaling pathway was affected by HBV and might play an important regulatory role in the antiviral immunity. Therefore, systematically elucidating the interplay between HBV and non-canonical NF-κB signaling will contribute the discovery of more potential therapeutic targets and novel drugs to treat HBV infection.

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Faculty Opinions recommendation of Impact of HBsAg and HBcrAg levels on phenotype and function of HBV-specific T cells in patients with chronic hepatitis B virus infection.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.741064866.793589615 ◽

2021 ◽

Author(s):

Philip Rosenthal

Keyword(s):

T Cells ◽

Chronic Hepatitis ◽

Hepatitis B Virus ◽

Virus Infection ◽

Hepatitis B ◽

Chronic Hepatitis B ◽

Hepatitis B Virus Infection ◽

Chronic Hepatitis B Virus ◽

B Virus ◽

And Function

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The Effect of Chronic Hepatitis B Virus Infection on BDCA3+ Dendritic Cell Frequency and Function

PLoS ONE ◽

10.1371/journal.pone.0161235 ◽

2016 ◽

Vol 11 (8) ◽

pp. e0161235 ◽

Cited By ~ 9

Author(s):

Evelyn van der Aa ◽

Sonja I. Buschow ◽

Paula J. Biesta ◽

Harry L. A. Janssen ◽

Andrea M. Woltman

Keyword(s):

Chronic Hepatitis ◽

Hepatitis B Virus ◽

Dendritic Cell ◽

Virus Infection ◽

Hepatitis B ◽

Hepatitis B Virus Infection ◽

Cell Frequency ◽

Chronic Hepatitis B Virus ◽

B Virus ◽

And Function

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Hepatitis B Virus (HBV) - Induced Hepatocarcinogenesis, a Founding Framework of Cancer Evolution & Development (Cancer Evo-Dev)

10.5772/intechopen.99838 ◽

2021 ◽

Author(s):

Wenbin Liu ◽

Guangwen Cao

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Inflammatory Factors ◽

Cancer Evolution ◽

Uracil Dna Glycosylase ◽

Cytidine Deaminases ◽

Inflammatory Microenvironment ◽

B Virus ◽

Novel Theory ◽

And Function

In this chapter, we present the founding framework of a novel theory termed as Cancer Evolution-Development (Cancer Evo-Dev), based on the current understanding of hepatitis B virus (HBV) induced hepatocarcinogenesis. The interactions of genetic predispositions and HBV infection is responsible for the maintenance of chronic non-resolving inflammation. Under the inflammatory microenvironment, pro-inflammatory factors trans-activate the expression of cytidine deaminases and suppress the expression of uracil DNA glycosylase. The imbalance between the mutagenic forces and mutation-correcting forces facilitates the generations of somatic mutations, viral mutations, and viral integrations into the host genomes. The majority of cells with genomic mutations and mutated viruses are eliminated in survival competition. Only a small percentage of the mutated cells adapted to the hostile environment can survive, retro-differentiate, and function as cancer-initiating cells, representing a process of “mutation-selection-adaptation”. Cancer Evo-Dev lays the theoretical foundation for understanding the mechanisms by which chronic infection of HBV promotes hepatocarcinogenesis. This theory also plays an important role in specific prophylaxis, prediction, early diagnosis, and targeted treatment of cancers.

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Hepatitis B Virus Blocks the CRE/CREB Complex and Prevents TLR9 Transcription and Function in Human B Cells

The Journal of Immunology ◽

10.4049/jimmunol.1701726 ◽

2018 ◽

Vol 201 (8) ◽

pp. 2331-2344 ◽

Cited By ~ 5

Author(s):

Issam Tout ◽

Melissa Gomes ◽

Michelle Ainouze ◽

Marie Marotel ◽

Timothee Pecoul ◽

...

Keyword(s):

Hepatitis B Virus ◽

B Cells ◽

Hepatitis B ◽

Human B Cells ◽

B Virus ◽

And Function

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C/EBP-like proteins binding to the functional box-alpha and box-beta of the second enhancer of hepatitis B virus.

Molecular and Cellular Biology ◽

10.1128/mcb.11.10.5044 ◽

1991 ◽

Vol 11 (10) ◽

pp. 5044-5052 ◽

Cited By ~ 35

Author(s):

C H Yuh ◽

L P Ting

Keyword(s):

Hepatitis B Virus ◽

Hepatitis B ◽

Binding Proteins ◽

Protein A ◽

Reading Frame ◽

B Virus ◽

Unique Model ◽

Enhancer Function ◽

And Function ◽

Enhancer Ii

The second enhancer (enhancer II) of hepatitis B virus is functionally liver specific. Located within an open reading frame of the virus and immediately upstream of the initiation sites of viral major transcripts, enhancer II furnishes a unique model for use in investigating the structure and function of an enhancer. In this study, two functional constituents, a 23-bp box-alpha and a 12-bp box-beta, are identified as being both necessary and sufficient for enhancer II function. Examination of the box-alpha and box-beta sequences reveals a weak homology to the extended consensus for a C/EBP binding site. Gel shift and footprinting analyses indicate that multiple proteins bind to these sequences and thus are candidate transcription factors that mediate the enhancer function. One heat-resistant protein, protein a, and one heat-sensitive protein, protein b, bind to box-alpha. Protein a, which binds to box-alpha in a way indistinguishable from that seen with a recombinant C/EBP, appears not to be identical to C/EBP in that the binding of protein a requires a minimal sequence larger than the canonical C/EBP sites. Two box-beta-binding proteins, c and d, show greater affinity for the C/EBP consensus than for box-beta. However, both proteins c and d are relatively heat sensitive and display a distinct sequence preference from the recombinant C/EBP protein. Since the function of enhancer II is strictly dependent on a bipartite architecture, this system provides a unique model for studies of how the interactions of its binding proteins lead to the enhancer function.

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