Divergent preS Sequences in Virion-Associated Hepatitis B Virus Genomes and Subviral HBV Surface Antigen Particles From HBV e Antigen-Negative Patients

Peiffer, Kai‐Henrik; Kuhnhenn, Lisa; Jiang, Bin; Vermehren, Johannes; Knop, Viola; Susser, S.; Walter, Dirk; Dietz, Julia; Carra, Gert; Finkelmeier, Fabian; Zeuzem, Stefan; Sarrazin, Christoph; Hildt, Eberhard

doi:10.1093/infdis/jiy119

Cited by 38 publications

(41 citation statements)

References 24 publications

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“…Quantification of the semi-en- HBsAg-specific antibodies did not show truncated LHBs, presumably due to the transcomplementation from integrated HBV-DNA. 47 Expression of this mutant shows no intracellular HBsAg retention but higher level of HBsAg secretion, which differs from effects of C-terminal mutations in PreS1 on HBsAg production and secretion. [13][14][15]21,23 In general, selective overexpression of LHBs causes the intracellular retention of HBsAg in the ER 48,49 A more detailed analysis revealed that N-terminal residues from aa 6 to aa 19 in the PreS1 domain were responsible for its ER retention.…”

Section: Deletion Of Aa 25-39 In the Pres1 Domain Is A Causative Famentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

“…Based on the analysis of a large European cohort of HBV chronically infected patients, we identified an HBV genotype A mutant with a deletion of 15 aa (aa 25‐39 in the N‐terminal PreS1 domain . Western blot analysis of the serum of the patient using HBsAg‐specific antibodies did not show truncated LHBs, presumably due to the transcomplementation from integrated HBV‐DNA . Expression of this mutant shows no intracellular HBsAg retention but higher level of HBsAg secretion, which differs from effects of C‐terminal mutations in PreS1 on HBsAg production and secretion .…”

Section: Discussionmentioning

confidence: 99%

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Formation of semi‐enveloped particles as a unique feature of a hepatitis B virus PreS1 deletion mutant

Jiang

Kuhnhenn

et al. 2019

Aliment Pharmacol Ther

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Summary Background Naturally occurring variants with deletions or mutations in the C‐terminal PreS1 domain from hepatitis B virus (HBV) chronically infected patients have been shown to promote HBsAg retention, inhibit HBsAg secretion and change the extracellular appearance of PreS1‐containing HBV particles (filaments and virions). Aims To study the impact of N‐terminal deletion in preS1 domain on viral secretion and morphogenesis. Methods An HBV mutant with 15 amino acids (aa 25‐39) deletion in N‐terminal preS1 was isolated. Intracellular and extracellular HBsAg were quantified by Western blot. Subcellular HBsAg distribution was analysed by confocal laser scanning microscopy. The viral morphology was characterised by sucrose density gradient ultracentrifugation, Western blot, electron microscopy, HBV mixed ELISA and HBV particle gel essay. Results Expression of this mutant genome released higher amounts of HBsAg in the form of shorter filaments. A significant fraction of semi‐enveloped virions was observed in the supernatant that has been unprecedented so far. Stepwise insertion of aa 25‐31, aa 32‐39 and aa 25‐39 increased the length of filaments. The rescue of aa 25‐31 and aa 25‐39 drastically reduced the amounts of extracellular HBsAg and semi‐enveloped virions, while such effects could not be observed after insertion of aa 32‐39, arguing against a simple spacer function of this region. The deletion and rescued mutants do not differ in subcellular HBsAg distribution and colocalisation with ER, Golgi and multivesicular bodies markers arguing against differences in release pathways. Conclusion N‐terminal PreS1‐domain (aa 25‐31) determines HBsAg secretion and triggers proper assembly of PreS1‐containing particles.

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Section: Deletion Of Aa 25-39 In the Pres1 Domain Is A Causative Famentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Formation of semi‐enveloped particles as a unique feature of a hepatitis B virus PreS1 deletion mutant

Jiang

Kuhnhenn

et al. 2019

Aliment Pharmacol Ther

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“…The deletion variant was isolated from a patient suffering from chronic HBV infection. Although deep sequencing analysis confirmed the isolated variant as the major variant (≥99% of the quasispecies), only intact LHBs was found in the patient serum, surprisingly . This indicates that the released LHBs (viral particles and filaments) must be derived from different genetic sources.…”

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confidence: 90%

Editorial: HBV—the naked truth? Authors’ reply

Jiang

Peiffer

Hildt

2019

Aliment Pharmacol Ther

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“…This source of HBsAg is relatively inaccessible without cell loss. A better understanding of differences in the composition and source of subviral particles of HBsAg derived from covalently closed circular DNA vs integrated HBV DNA will assist therapeutic strategies …”

Section: Virology Of Hepatitis B and Prospects For A Curementioning

confidence: 99%

Will we need novel combinations to cure HBV infection?

Dusheiko

2020

Liver International

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Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma. Nucleoside analogue therapy may modify the risk. However, maintenance suppressive therapy is required, as a functional cure (generally defined as loss of HBsAg off treatment) is an uncommon outcome of antiviral treatment. Chronic hepatitis B is a numerically important cause of cirrhosis and hepatocellular carcinoma. Nucleoside analogue therapy may modify the risk. However, maintenance suppressive therapy is required, as a functional cure (generally defined as loss of HBsAg off treatment) is an uncommon outcome of antiviral treatment. Currently numerous investigational agents being developed to either interfere with specific steps in HBV replication or as host cellular targeting agents, that inhibit viral replication, and deplete or inactivate cccDNA, or as immune modulators. Synergistic mechanisms will be needed to incorporate a decrease in HBV transcription, impairment of transcription from HBV genomes, loss of cccDNA or altered epigenetic regulation of cccDNA transcription, and immune modulation or immunologically stimulated hepatocyte cell turnover. Nucleoside analogue suppressed patients are being included in many current trials. Trials are progressing to combination therapy as additive or synergistic effects are sought. These trials will provide important insights into the biology of HBV and perturbations of the immune response, required to effect HBsAg loss at different stages of the disease. The prospect of cures of hepatitis B would ensure that a wide range of patients could be deemed candidates for treatment with new compounds if these were highly effective, finite and safe. Withdrawal of therapy in short‐term trials is challenging because short‐term therapies may risk severe hepatitis flares, and hepatic decompensation. The limited clinical trial data to date suggest that combination therapy is inevitable.

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Divergent preS Sequences in Virion-Associated Hepatitis B Virus Genomes and Subviral HBV Surface Antigen Particles From HBV e Antigen-Negative Patients

Cited by 38 publications

References 24 publications

Formation of semi‐enveloped particles as a unique feature of a hepatitis B virus PreS1 deletion mutant

Formation of semi‐enveloped particles as a unique feature of a hepatitis B virus PreS1 deletion mutant

Editorial: HBV—the naked truth? Authors’ reply

Will we need novel combinations to cure HBV infection?

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