New broadly reactive neutralizing antibodies against hepatitis B virus surface antigen

Kučinskaitė-Kodzė, Indrė; Plečkaitytė, Milda; Bremer, Corinna M.; Seiz, Pia L.; Zilnyte, Milda; Bulavaitė, Aistė; Mickiene, Gitana; Zvirblis, Gintautas; Sasnauskas, Kęstutis; Glebe, Dieter; Žvirblienė, Aurelija

doi:10.1016/j.virusres.2015.10.024

Cited by 27 publications

(25 citation statements)

References 86 publications

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“…The monoclonal MA18/7 anti-PreS1 domain of LHBs was kindly provided by Dr. Dieter Glebe, Giessen [3,19]. The polyclonal rabbit against denatured HBV core K46 [20] was a gift from Dr. Reinhild Prange, Department of Medical Microbiology and Hygiene, Johannes Gutenberg-Universität Mainz, Mainz, Germany.…”

Section: Antibodies and Chemicalsmentioning

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: Antibodies and Chemicalsmentioning

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 monoclonal MA18/7 anti‐PreS1 domain of LHBs and monoclonal HBO1 anti‐SHBs were kindly provided by Dr Glebe, Giessen . PreS2‐specific antibody (mab16986) was purchased from Chemicon ® .…”

Section: Methodsmentioning

confidence: 99%

“…The monoclonal MA18/7 anti-PreS1 domain of LHBs and monoclonal HBO1 anti-SHBs were kindly provided by Dr Glebe, Giessen. 3,27 PreS2-specific antibody (mab16986) was purchased from Chemicon ® . The polyclonal rabbit against denatured HBV core K46 28 was a gift from Reinhild Prange, Department of Medical Microbiology and Hygiene, Johannes Gutenberg-Universität Mainz, Mainz, Germany.…”

Section: Antibodies and Chemicalsmentioning

confidence: 99%

“…33,56 N-terminal myristylated peptides corresponding to this epitope specifically prevent HBV infection in permissive cells. 33,56 The missing 15 aa (aa [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] in the mutant locate in the HBV receptor binding domain and partially overlap with the essential receptor binding residue aa 20-29. 56 Since the essential HBV receptor binding domain is destroyed, it can be assumed that mutant viral particles (∆aa25-39) do not specifically bind to the receptor/complex on hepatocytes and thus fail to establish an infection.…”

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

confidence: 99%

“…14,[21][22][23] Many studies showed that these genetic defects are usually caused by in-frame deletions in the C-terminal PreS1 domain or the middle portion of the PreS2 domain or point mutation(s) in the start codon of the PreS2 domain. [14][15][16]18,22,24 Recently, an HBV mutant with 15 aa deletion (aa [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] in the N-terminus of PreS1 domain was isolated based on the analysis of a large European cohort of HBeAg-negative patients suffering from chronic HBV infection. 25 In this study, we analysed the effects of the N-terminal deletion in the PreS1 domain on the HBsAg synthesis and release, subcellular distribution, as well as the viral and subviral morphology.…”

Section: Introductionmentioning

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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Multiple epitopes of hepatitis B virus surface antigen targeted by human plasma‐derived immunoglobulins coincide with clinically observed escape mutations

Tarafdar

Virata

Yan

et al. 2021

Journal of Medical Virology

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Hepatitis B immune globulin (HBIG) is a human plasma-derived immunoglobulin G concentrate that contains a high titer of neutralizing antibodies (anti-HBs) to the hepatitis B virus (HBV) surface antigen (HBsAg). HBIG is known to be highly effective in treating HBV infections, however, a more systematic characterization of the antibody binding sites on HBsAg and their correlation with emerging "escape" mutations in HBsAg was lacking. By using anti-HBs antibodies from HBIG lots to screen random peptide phage display libraries, we identified five clusters of peptides that corresponded to five distinct anti-HBs binding sites on the HBsAg. Three sites, Site II (C121-C124), Site III (M133-P135), and Site IV (T140-G145), were mapped within the "a" determinant, while the two other sites, Site I (Q101-M103) and Site V (I152-S154), were outside the "a" determinant. We then tested in binding assays HBsAg peptides containing clinically relevant mutations previously reported within these sites, such as Y134S, P142S, and G145R, and observed a significant reduction in anti-HBs binding activity to the mutated sites, suggesting a mechanism the virus may use to avoid HBIG-mediated neutralization. The current HBIG treatment could be improved by supplementing it with site-specific neutralizing monoclonal antibodies that target these mutations for control of HBV infections.

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New broadly reactive neutralizing antibodies against hepatitis B virus surface antigen

Cited by 27 publications

References 86 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

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

Multiple epitopes of hepatitis B virus surface antigen targeted by human plasma‐derived immunoglobulins coincide with clinically observed escape mutations

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