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The Viruses
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
The virion genome is DNA (3.2 kb) in a relaxed circular, partially duplex strand. The + strand is shorter and more variable in length than the - strand. The genome is highly compact and every nucleotide is used for coding. HBV has some unusual features in its mode of replication: (1) it uses an RNA intermediate called the pre-genomic RNA or pgRNA, (2) it uses a reverse transcriptase to convert pgRNA into viral DNA, (3) it uses a duplex DNA form in its infectious particle, (4) more than one type of virus particle is produced, and (5) it converts the relaxed DNA into a covalent closed circular DNA (cccDNA) in the nucleus prior to transcription. Following attachment and entry the virus DNA is delivered to the nucleus and is con» verted to cccDNA. This process requires repair of the single strand, removal of the 5′ terminal structure consisting of RNA and P protein, and covalent ligation of the strands. HBV has two major classes of transcripts, these are genomic and subgenomic. Each contains multiple members. All are capped, unspliced, and polyadenylated. HBV uses both overlapping reading frames and multiple initiation codons thereby making efficient use of its DNA. The hepadnaviral reverse transcriptase pathway is similar to the process of replication in retroviruses. The process of reverse transcription takes place in the subvirai core particles.
Order Blubervirales: Core Protein
Published in Paul Pumpens, Peter Pushko, Philippe Le Mercier, Virus-Like Particles, 2022
Paul Pumpens, Peter Pushko, Philippe Le Mercier
The HBc protein undergoes self-assembly and acts in the HBV life cycle as an icosahedral scaffold of the HBV nucleocapsid, which carries genomic HBV DNA, polymerase and possibly cellular protein kinase. In addition to the HBV nucleocapsid building function, the core-related proteins, mostly in the HBc form, participate in every step of the HBV life cycle and regulation by (i) synthesizing dsDNA through the specific recognition of pgRNA and self-assembly on the pgRNA complex together with HBV polymerase, (ii) complexing HBV DNA and affecting its epigenetics through preferential binding to CpG islands, (iii) signaling the completion of reverse transcription and maturation of nucleocapsids carrying partially double-stranded relaxed circular DNA (rcDNA), (iv) recognizing specific sites on the HBV envelope proteins, thereby enveloping and further supporting the egress of HBV virions, (v) regulating envelopment via the 3D structure and content of the nucleocapsids, since DNA- but not RNA-containing nucleocapsids undergo envelopment, (vi) performing highly specific phosphorylation, when hyper- and hypo-phosphorylation refer to the DNA- and RNA-containing particles, respectively, and (vii) providing nuclear localization signals that target nucleocapsids to the cell nucleus after infection and form an HBV minichromosome carrying HBV covalently closed circular DNA (cccDNA) that acts as a template for the synthesis of HBV mRNAs.
Viral hepatitis.
Published in Michael JG Farthing, Anne B Ballinger, Drug Therapy for Gastrointestinal and Liver Diseases, 2019
Eleanor Barnes, George Webster, Geoffrey M Dusheiko
The replicative cycle of HBV is complex but an understanding of this is central to understanding the therapeutic approaches that have been adopted (Fig. 11.1). Although a DNA virus, replication occurs via reverse transcription of an intermediate RNA pregenome. After initial infection of the hepatocyte, viral genome DNA is converted to closed circular covalent molecule (cccDNA), which functions as a transcriptional template. Eradication of cccDNA has proved particularly problematical.
The premise of capsid assembly modulators towards eliminating HBV persistence
Published in Expert Opinion on Drug Discovery, 2023
Leda Bassit, Franck Amblard, Dharmeshkumar Patel, Nicolas Biteau, Zhe Chen, Mahesh Kasthuri, Shaoman Zhou, Raymond F. Schinazi
The covalently closed circular DNA (cccDNA) has a central role in the replication of HBV as, in the nuclei of hepatocyte, is the transcription template for all four viral RNAs that encode seven proteins: large (L), middle (M), surface (S), X, pre-core, core, and polymerase proteins, and the template for the reverse transcription of the pre-genomic RNA (pg-RNA) [8]. The core (capsid) protein (Cp) plays a crucial function in forming the nucleocapsids where viral replication emerges [9]. Once the pg-RNA is released to the cytoplasm, it is soon encapsidated inside the nucleocapsid with the HBV polymerase and reverse-transcribed into minus-strand DNA. Finally, the plus-stranded DNA is synthesized to form the partially double-stranded relaxed circular DNA (rcDNA); at this step of viral replication, the matured nucleocapsid can be either recycled to the nucleus of the hepatocyte for amplification/recycling of cccDNA or enveloped by the envelope proteins and excreted from cells to infect naïve cells [10–12]. The current antiviral therapies (NUC and interferon-alpha (IFN-a) pegylated or non-pegylated) reduce the viral loads of chronically infected individuals. The three mostly recommended antiviral NUC, entecavir (ETV), tenofovir disoproxil fumarate (TDF), or tenofovir alafenamide (TAF), are used worldwide for the treatment of chronic HBV to inhibit reverse transcriptase and HBV DNA replication.
Developments in pharmacotherapeutic agents for hepatitis B – how close are we to a functional cure?
Published in Expert Opinion on Pharmacotherapy, 2023
Naoshin Khan, Mohamed Ramzi Almajed, Mary Grace Fitzmaurice, Syed-Mohammed Jafri
Understanding the HBV replication cycle allows the development of agents to target various key steps to prevent and mitigate the infection [Figure 1]. HBV attaches to surface cell-associated heparan sulfate proteoglycans and binds to hepatocyte surface receptors. Endocytosis and fusion of the viral envelope occurs at the cellular surface, releasing the viral nucleocapsid into the cytoplasm; entry inhibitors target this step. The nucleocapsid is transported along cellular microtubules to the nucleus where viral DNA is released into the nucleoplasm. Viral DNA undergoes repair by viral polymerases and cellular enzymes to create covalently closed circular DNA (cccDNA) which acts as a template for transcription within the cell. cccDNA utilizes the host cell’s transcription processes to create the viral RNA needed for viral protein production and replication. Viral RNA is then transported to the cytoplasm where it undergoes translation to produce viral proteins; small interfering RNAs target this step. Viral proteins and nuclear material then forms new HBV RNA-containing nucleocapsids; capsid inhibitors and capsid assembly modulators target this step. Polymerases convert these into DNA-containing nucleocapsids; polymerase inhibitors such as nucleos(t)ide analogs and non-nucleos(t)ide analogs target this step. Novel nucleocapsids are thereafter either imported back into the nucleolus where they replicate further or enveloped and secreted out of the cell; HbsAg inhibitors target this step [9,10].
Hepatitis B virus: promising drug targets and therapeutic implications
Published in Expert Opinion on Therapeutic Targets, 2021
Mohube Betty Maepa, Kristie Bloom, Abdullah Ely, Patrick Arbuthnot
Cures from HBV infection have been classified according to the degree to which markers of the virus are eliminated [2]. A functional cure is defined as elimination of HBsAg from the serum of HBV-infected individuals with or without eradication of cccDNA. Given the capabilities of existing technologies, accomplishing functional cure is considered the most feasible current treatment objective. Purging all HBV-derived molecules, including host genome integrated sequences, is desirable but considerably more difficult and does not yet seem safely achievable. Establishing that such cures have occurred in clinical settings may itself be challenging. A difficulty is that reliable and easily implemented assays for cccDNA are currently not available. Measurement of cccDNA in liver biopsies requires an invasive procedure. This is not without complications, and assay of the viral DNA in small liver samples is not necessarily representative of cccDNA presence in the whole liver. Assay of viral RNAs [12] in serum and HBV core related antigens (HBcrAgs) [13] are useful but their value is yet to be fully established.