A new approach for therapeutic vaccination against chronic HBV infections

Zahn, Tobias; Akhras, Sami; Spengler, Catrina; Murra, Robin Oliver; Holzhauser, Thomas; Hildt, Eberhard

doi:10.1016/j.vaccine.2020.02.063

Cited by 10 publications

(14 citation statements)

References 57 publications

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“…The N-terminus of LHBs harbours a myristoylation motif. Myristoylation of LHBs is crucial for HBV infectivity [ 1 ]. The envelope proteins are not only constitutive components of the surface envelope of viral particles, but also assemble into subviral particles with the shape of spheres and filaments lacking any capsid and viral DNA [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

The N-Terminus Makes the Difference: Impact of Genotype-Specific Disparities in the N-Terminal Part of The Hepatitis B Virus Large Surface Protein on Morphogenesis of Viral and Subviral Particles

Jiang

Wen

et al. 2020

Cells

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The N-terminus of the hepatitis B virus (HBV) large surface protein (LHB) differs with respect to genotypes. Compared to the amino terminus of genotype (Gt)D, in GtA, GtB and GtC, an additional identical 11 amino acids (aa) are found, while GtE and GtG share another similar 10 aa. Variants of GtB and GtC affecting this N-terminal part are associated with hepatoma formation. Deletion of these amino-terminal 11 aa in GtA reduces the amount of LHBs and changes subcellular accumulation (GtA-like pattern) to a dispersed distribution (GtD-like pattern). Vice versa, the fusion of the GtA-derived N-terminal 11 aa to GtD causes a GtA-like phenotype. However, insertion of the corresponding GtE-derived 10 aa to GtD has no effect. Deletion of these 11aa decreases filament size while neither the number of released viral genomes nor virion size and infectivity are affected. A negative regulatory element (aa 2–8) and a dominant positive regulatory element (aa 9–11) affecting the amount of LHBs were identified. The fusion of this motif to eGFP revealed that the effect on protein amount and subcellular distribution is not restricted to LHBs. These data identify a novel region in the N-terminus of LHBs affecting the amount and subcellular distribution of LHBs and identify release-promoting and -inhibiting aa residues within this motive.

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Section: Introductionmentioning

confidence: 99%

The N-Terminus Makes the Difference: Impact of Genotype-Specific Disparities in the N-Terminal Part of The Hepatitis B Virus Large Surface Protein on Morphogenesis of Viral and Subviral Particles

Jiang

Wen

et al. 2020

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“…13,72,83,84 In addition, several other proteinbased forms of antigen delivery are currently assessed in pre-clinical studies: modified cellpermeable HBV capsids are tested to deliver HBV antigens to the DCs cytoplasm to favor HLA I presentation. 85,86 Furthermore, a chimeric fusion protein consisting of the Fc fragment of a murine antibody and HBV antigens is tested targeting HBV antigens to DCs via Fcɣ and mannose receptors. 87 Possibly, one platform alone may not do the job.…”

Section: Vaccination Platformmentioning

confidence: 99%

Designing the next‐generation therapeutic vaccines to cure chronic hepatitis B: focus on antigen presentation, vaccine properties and effect measures

et al. 2021

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In the mid-90s, hepatitis B virus (HBV)-directed immune responses were for the first time investigated in detail and revealed suboptimal T-cell responses in chronic HBV patients. Based on these studies, therapeutic vaccination exploiting the antigen presentation capacity of dendritic cells to prime and/or boost HBVspecific T-cell responses was considered highly promising. Now, 25 years later, it has not yet delivered this promise. In this review, we summarise what has been clinically tested in terms of antigen targets and vaccine forms, how the immunological and therapeutic effects of these vaccines were assessed and what major clinical and immunological findings were reported. We combine the lessons learned from these trials with the most recent insights on HBV antigen presentation, T-cell responses, vaccine composition, antiviral and immune-modulatory drugs and disease biomarkers to derive novel opportunities for the next generation of therapeutic vaccines designed to cure chronic HBV either alone or in combination therapy.

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“…It has been described as a novel tool for the delivery of proteins and nucleic acids into tissues and cells [59][60][61][62][63][64][65]. The functionality of TLM depends on a defined pattern of hydrophilic and hydrophobic amino acids that form a labile amphipathic alpha helix [60,62,64,66]. Fusion of the TLM to HBc enables the formation of fully-assembled capsids (VLPs) that are decorated with the TLM-peptide.…”

Section: Intracellular Cytoplasmic Transport After Viral Uptakementioning

confidence: 99%

Intracellular Trafficking of HBV Particles

Jiang

Hildt

2020

Cells

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The human hepatitis B virus (HBV), that is causative for more than 240 million cases of chronic liver inflammation (hepatitis), is an enveloped virus with a partially double-stranded DNA genome. After virion uptake by receptor-mediated endocytosis, the viral nucleocapsid is transported towards the nuclear pore complex. In the nuclear basket, the nucleocapsid disassembles. The viral genome that is covalently linked to the viral polymerase, which harbors a bipartite NLS, is imported into the nucleus. Here, the partially double-stranded DNA genome is converted in a minichromosome-like structure, the covalently closed circular DNA (cccDNA). The DNA virus HBV replicates via a pregenomic RNA (pgRNA)-intermediate that is reverse transcribed into DNA. HBV-infected cells release apart from the infectious viral parrticle two forms of non-infectious subviral particles (spheres and filaments), which are assembled by the surface proteins but lack any capsid and nucleic acid. In addition, naked capsids are released by HBV replicating cells. Infectious viral particles and filaments are released via multivesicular bodies; spheres are secreted by the classic constitutive secretory pathway. The release of naked capsids is still not fully understood, autophagosomal processes are discussed. This review describes intracellular trafficking pathways involved in virus entry, morphogenesis and release of (sub)viral particles.

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A new approach for therapeutic vaccination against chronic HBV infections

Cited by 10 publications

References 57 publications

The N-Terminus Makes the Difference: Impact of Genotype-Specific Disparities in the N-Terminal Part of The Hepatitis B Virus Large Surface Protein on Morphogenesis of Viral and Subviral Particles

The N-Terminus Makes the Difference: Impact of Genotype-Specific Disparities in the N-Terminal Part of The Hepatitis B Virus Large Surface Protein on Morphogenesis of Viral and Subviral Particles

Designing the next‐generation therapeutic vaccines to cure chronic hepatitis B: focus on antigen presentation, vaccine properties and effect measures

Intracellular Trafficking of HBV Particles

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