Molecular Basis for the Interaction of the Hepatitis B Virus Core Antigen with the Surface Immunoglobulin Receptor on Naive B Cells

Lazdina, Una; Cao, Tinghua; Steinbergs, Juris; Alheim, Mats; Pumpens, Paul; Peterson, D L; Milich, David R.; Leroux‐Roels, Geert; Sällberg, Matti

doi:10.1128/jvi.75.14.6367-6374.2001

Cited by 57 publications

(42 citation statements)

References 28 publications

(33 reference statements)

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“…23,52 In brief, spleen cells were resuspended in PBS/1% FCS (FACS buffer) and incubated with Fcblocking antibodies. Cells were then washed and incubated with H-2D b :Ig preloaded with NS3/4A-derived peptide.…”

Section: Quantification Of Ns3/4a-specific Ctls By Flow Cytometrymentioning

confidence: 99%

Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene

et al. 2004

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We have recently shown that the NS3-based genetic immunogens should contain also hepatitis C virus (HCV) nonstructural (NS) 4A to utilize fully the immunogenicity of NS3. The next step was to try to enhance immunogenicity by modifying translation or mRNA synthesis. To enhance translation efficiency, a synthetic NS3/4A-based DNA (coNS3/4A-DNA) vaccine was generated in which the codon usage was optimized (co) for human cells. In a second approach, expression of the wild-type (wt) NS3/4A gene was enhanced by mRNA amplification using the Semliki forest virus (SFV) replicon (wtNS3/4A-SFV). Transient tranfections of human HepG2 cells showed that the coNS3/4A gene gave 11-fold higher levels of NS3 as compared to the wtNS3/4A gene when using the CMV promoter. We have previously shown that the presence of NS4A enhances the expression by SFV. Both codon optimization and mRNA amplification resulted in an improved immunogenicity as evidenced by higher levels of NS3-specific antibodies. This improved immunogenicity also resulted in a more rapid priming of cytotoxic T lymphocytes (CTLs). Since HCV is a noncytolytic virus, the functionality of the primed CTL responses was evaluated by an in vivo challenge with NS3/4A-expressing syngeneic tumor cells. The priming of a tumor protective immunity required an endogenous production of the immunogen and CD8 þ CTLs, but was independent of B and CD4 þ T cells. This model confirmed the more rapid in vivo activation of an NS3/4A-specific tumor-inhibiting immunity by codon optimization and mRNA amplification. Finally, therapeutic vaccination with the coNS3/4A gene using gene gun 6-12 days after injection of tumors significantly reduced the tumor growth in vivo. Codon optimization and mRNA amplification effectively enhances the overall immunogenicity of NS3/4A. Thus, either, or both, of these approaches should be utilized in an NS3/4A-based HCV genetic vaccine.

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Section: Quantification Of Ns3/4a-specific Ctls By Flow Cytometrymentioning

confidence: 99%

Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene

et al. 2004

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“…We have demonstrated previously that HBcAg binds to BCRs through a common motif expressed by germ line Ig receptors on naive B cells (Lazdina et al, 2001a). We were therefore interested to map the region on the HBcAg particle responsible for binding sIg.…”

Section: Mapping Of the Binding Site On The Hbcag Particle For Naive mentioning

confidence: 99%

“…We were therefore interested to map the region on the HBcAg particle responsible for binding sIg. The panel of recombinant HBcAg particles was assayed for direct binding to B cells by flow cytometry, as described previously (Lazdina et al, 2001a). T cell-depleted naive splenocytes were incubated with the recombinant particles on ice to prevent endocytosis.…”

Section: Mapping Of the Binding Site On The Hbcag Particle For Naive mentioning

confidence: 99%

“…Repetitive, highly ordered protein spikes on the core shell surface might be optimal for cross-linking of the B cell antigen receptors (BCRs) (Bottcher et al, 1997;Milich et al, 1997). The binding of HBcAg to naive B cells occurs through linear motifs present on the surface immunoglobulin (sIg) molecule, encoded by some murine and human germ line gene families (Lazdina et al, 2001a). The region on HBcAg involved in binding to sIg on naive B cells has not been mapped.…”

Section: Introductionmentioning

confidence: 99%

“…HBcAg binds directly to a large proportion of naive human and mice B cells through this non-traditional antigen-antibody interaction (Cao et al, 2001;Lazdina et al, 2001a;Milich et al, 1997). The B cells become activated upon BCR cross-linking by HBcAg, as evidenced by an increase in the surface expression of B7-2 (Lazdina et al, 2001a;Milich et al, 1997). After binding and processing of HBcAg, naive B cells act as efficient antigen-presenting cells (APCs) that present HBcAg to T helper cells (Milich et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Priming of cytotoxic T cell responses to exogenous hepatitis B virus core antigen is B cell dependent

Lazdina

Alheim

Nyström

et al. 2003

Journal of General Virology

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The hepatitis B virus (HBV) core antigen (HBcAg) has a unique ability to bind a high frequency of naive human and murine B cells. The role of HBcAg-binding naive B cells in the immunogenicity of HBcAg is not clear. The HBcAg-binding properties of naive B cells were characterized using HBcAg particles with mutated spike region (residues 76-85) sequences. Deletion of residues 76-85 (HBcD76-85) destroyed naive B cell binding, whereas deletion of residues 79-85 did not. HBcAg particles with an Ile instead of the natural Ala at position 80 did not bind naive B cells, whereas reversion of Ile 80 RAla restored B cell binding. Destroying the B cell-binding ability of HBcAg had a marginal effect on the overall B cell immunogenicity of the different particles, suggesting that they were equally efficient in priming T helper cells. Therefore, the importance of HBcAg-binding B cells is studied with relation to the priming of HBcAg-specific cytotoxic T cells (CTLs). The role of HBcAg-binding B cells in the priming of HBcAg-specific CTLs was evaluated by immunization with endogenous HBcAg (DNA immunization) and exogenous recombinant HBcAg particles. Endogenous HBcAg primed HBcAg-specific CTLs in wild-type and B cell-deficient mice, whereas exogenous HBcAg primed HBcAg-specific CTLs only in wild-type mice. Importantly, HBcD76-85 did not prime CTLs despite the presence of B cells. Thus, the ability of exogenous HBcAg particles to prime specific CTLs is B cell dependent, suggesting a possible role for HBcAgbinding B cells in HBV infections.

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A fusion product of the complete Borrelia burgdorferi outer surface protein A (OspA) and the hepatitis B virus capsid protein is highly immunogenic and induces protective immunity similar to that seen with an effective lipidated OspA vaccine formula

et al. 2005

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The immunogenicity of peptides and protein fragments can be considerably enhanced by their presentation on particulate carriers such as capsid‐like particles (CLP) from hepatitis B virus (HBV). Here we tested the suitability of the HBV capsid protein as a carrier for a relevant full‐length pathogen‐derived protein antigen. The entire 255‐amino acid ectodomain of the outer surface protein A (OspA) from Borrelia burgdorferi, the causative agent of Lyme disease, was inserted into the major B cell epitope of the HBV capsid, yielding a multimerization‐competent fusion protein, termed coreOspA. CoreOspA, consisting only in part of regular CLP, induced antibodies to OspA, including the Ig isotype profile and specificity for the protective epitope LA‐2, with an efficiency similar to that of recombinant lipidated OspA, the first generation vaccine against Lyme disease. Moreover, coreOspA actively and passively protected mice against subsequent challenge with B. burgdorferi. The data demonstrate the capacity of the HBV capsid protein to act as a potent immunomodulator even for full‐length and structurally complex polypeptide chains and thus opens new avenues for novel vaccine designs.

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Molecular Basis for the Interaction of the Hepatitis B Virus Core Antigen with the Surface Immunoglobulin Receptor on Naive B Cells

Cited by 57 publications

References 28 publications

Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene

Codon optimization and mRNA amplification effectively enhances the immunogenicity of the hepatitis C virus nonstructural 3/4A gene

Priming of cytotoxic T cell responses to exogenous hepatitis B virus core antigen is B cell dependent

A fusion product of the complete Borrelia burgdorferi outer surface protein A (OspA) and the hepatitis B virus capsid protein is highly immunogenic and induces protective immunity similar to that seen with an effective lipidated OspA vaccine formula

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