scholarly journals Hepatitis C Virus Epitope Immunodominance and B Cell Repertoire Diversity

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 983
Author(s):  
Nicholas A. Brasher ◽  
Anurag Adhikari ◽  
Andrew R. Lloyd ◽  
Nicodemus Tedla ◽  
Rowena A. Bull
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
B Cell ◽  
Rational Design ◽  
Current Knowledge ◽  
Cell Repertoire ◽  
B Cell Repertoire ◽  
Gene Usage ◽  
Repertoire Diversity ◽  
Virus Epitope

Despite the advent of effective, curative treatments for hepatitis C virus (HCV), a preventative vaccine remains essential for the global elimination of HCV. It is now clear that the induction of broadly neutralising antibodies (bNAbs) is essential for the rational design of such a vaccine. This review details the current understanding of epitopes on the HCV envelope, characterising the potency, breadth and immunodominance of antibodies induced against these epitopes, as well as describing the interactions between B-cell receptors and HCV infection, with a particular focus on bNAb heavy and light chain variable gene usage. Additionally, we consider the importance of a public repertoire for antibodies against HCV, compiling current knowledge and suggesting that further research in this area may be critical to the rational design of an effective HCV vaccine.

scholarly journals Convergent antibody responses associated with broad neutralization of hepatitis C virus and clearance of infection

2021 ◽  
Author(s):  
Nicole E. Skinner ◽  
Clinton O. Ogega ◽  
Nicole Frumento ◽  
Kaitlyn E. Clark ◽  
Srinivasan Yegnasubramanian ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
B Cell ◽  
Early Development ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
High Plasma ◽  
Spontaneous Clearance ◽  
Cell Repertoire ◽  
Molecular Features

AbstractEarly development of broadly neutralizing antibodies (bNAbs) targeting the hepatitis C virus (HCV) envelope glycoprotein E2 is associated with spontaneous clearance of infection, so induction of bNAbs is a major goal of HCV vaccine development. However, much remains to be learned at a molecular level about protective E2-reactive antibodies, since HCV infection persists in some individuals despite early development of broadly neutralizing plasma. To examine B cell repertoire features associated with broad neutralization and viral clearance, we performed RNA sequencing of the B cell receptors (BCRs) of HCV E2-reactive B cells of people with cleared or persistent HCV, including subjects with high or low plasma neutralizing breadth in both clearance and persistence groups. We identified many E2-reactive public BCR clonotypes, which are antibody clones with the same V and J-genes and identical CDR3 sequences, shared among subjects grouped by either clearance or neutralization status. The majority (89) of these public clonotypes were shared by two subjects with broad plasma neutralizing activity and cleared infection, but not found in subjects with high plasma neutralizing breadth and persistent infection. We cloned a potent, cross-reactive neutralizing monoclonal antibody (mAb) by pairing the most abundant public heavy and light chains from these two subjects, providing evidence that broadly E2-reactive public clonotypes arise in a subset of individuals with broadly neutralizing plasma and spontaneous clearance of infection. Further characterization of the molecular features and function of these antibodies can inform HCV vaccine development.

scholarly journals Shared HIV envelope-specific B cell clonotypes induced by a pox-protein vaccine regimen

2021 ◽  
Author(s):  
Kristen W. Cohen ◽  
Lamar Ballweber-Fleming ◽  
Michael Duff ◽  
Rachael E. Whaley ◽  
Aaron Seese ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Critical Role ◽  
Memory B Cells ◽  
Protein Vaccine ◽  
Cell Repertoire ◽  
B Cell Repertoire ◽  
Specific Igg

An effective HIV-1 vaccine will likely induce potent, broad neutralizing antibodies. No candidate vaccines have elicited these responses presumably because they fail to activate human B cell precursors that can affinity mature to generate broad neutralizing antibodies. To identify the B cell clonotypes that are elicited, we conducted in-depth analyses of the envelope-specific B cell repertoire in recipients of ALVAC-HIV vector (vCP2438) and bivalent subtype C gp120 protein (HVTN100). We observed high frequencies of envelope-specific IgG+ memory B cells with restricted immunogenetic diversity, relative to non-vaccine induced memory B cells, with preferential expansions of distinct variable genes but limited accumulation of mutations. Many envelope-specific clonotypes were shared across vaccinees, but did not overlap with the envelope-negative memory repertoire, within and across subjects. Single-cell sequencing of envelope-specific IgG+ memory B cells often revealed VH1-2*02 and VK3-20 sequence co-expression and in one case, contained a 5 amino acid CDRL3, the canonical signature of VRC01-class antibodies, confirming that these B cells are extremely rare but detectable. Our study provides evidence that immunogens play a critical role in selecting and restricting the responding B cell repertoire and supports the rational design of HIV vaccines targeting specific B cell lineages for induction of broadly-reactive neutralizing antibodies.

scholarly journals Inferring processes underlying B-cell repertoire diversity

2015 ◽  
Vol 370 (1676) ◽  
pp. 20140243 ◽  
Author(s):  
Yuval Elhanati ◽  
Zachary Sethna ◽  
Quentin Marcou ◽  
Curtis G. Callan ◽  
Thierry Mora ◽  
...  
Keyword(s):  
B Cell ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
Statistical Properties ◽  
Cell Repertoire ◽  
Vdj Recombination ◽  
Site Model ◽  
Human B Cells ◽  
B Cell Repertoire ◽  
Repertoire Diversity

We quantify the VDJ recombination and somatic hypermutation processes in human B cells using probabilistic inference methods on high-throughput DNA sequence repertoires of human B-cell receptor heavy chains. Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then after selection for functionality. We also infer statistical properties of the somatic hypermutation machinery (exclusive of subsequent effects of selection). Our main results are the following: the B-cell repertoire is substantially more diverse than T-cell repertoires, owing to longer junctional insertions; sequences that pass initial selection are distinguished by having a higher probability of being generated in a VDJ recombination event; somatic hypermutations have a non-uniform distribution along the V gene that is well explained by an independent site model for the sequence context around the hypermutation site.

V H 1-69 gene is preferentially used by hepatitis C virus–associated B cell lymphomas and by normal B cells responding to the E2 viral antigen

Blood ◽  
2001 ◽  
Vol 97 (4) ◽  
pp. 1023-1026 ◽  
Author(s):  
Chunghuang Hubert Chan ◽  
Kenneth G. Hadlock ◽  
Steven K. H. Foung ◽  
Shoshana Levy
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
B Cells ◽  
B Cell ◽  
Viral Antigen ◽  
Silent Mutation ◽  
B Cell Lymphomas ◽  
Gene Usage ◽  
Vh Gene ◽  
V Region

Abstract Hepatitis C virus (HCV)–associated B cell lymphomas were previously shown to express a restricted repertoire of immunoglobulin VH and VL genes, VH1-69 and VκA27, respectively. Although this suggests a role for antigen selection in the pathogenesis of these lymphomas, the driving antigen involved in the clonal expansion has not been identified. B cell response to a viral antigen, the HCV envelope glycoprotein 2 (E2), was analyzed in an asymptomatic HCV-infected patient. Single B cells, immortalized as hybridomas and selected for binding E2, were analyzed for their V gene usage. Sequences of these V region genes demonstrated that each hybridoma expressed unique VH and VLgenes. Remarkably, these anti-E2 hybridomas preferentially used the VH1-69 gene. Analysis of replacement to silent mutation ratios indicated that the genes underwent somatic mutation and antigenic selection. In a separate report, human anti-E2 antibodies were also shown to express the same VH gene. These data strengthen the hypothesis that the HCV-associated lymphomas are derived from clonally expanded B cells stimulated by HCV.

scholarly journals Inferring processes underlying B-cell repertoire diversity.

2015 ◽  
Author(s):  
Yuval Elhanati ◽  
Zachary Sethna ◽  
Quentin Marcou ◽  
Curtis G Callan ◽  
Thierry Mora ◽  
...  
Keyword(s):  
B Cell ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
Statistical Properties ◽  
Cell Repertoire ◽  
Vdj Recombination ◽  
Site Model ◽  
Human B Cells ◽  
B Cell Repertoire ◽  
Repertoire Diversity

We quantify the VDJ recombination and somatic hypermutation processes in human B-cells using probabilistic inference methods on high-throughput DNA sequence repertoires of human B-cell receptor heavy chains. Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then after selection for functionality. We also infer statistical properties of the somatic hypermutation machinery (exclusive of subsequent effects of selection). Our main results are the following: the B-cell repertoire is substantially more diverse than T-cell repertoires, due to longer junctional insertions; sequences that pass initial selection are distinguished by having a higher probability of being generated in a VDJ recombination event; somatic hypermutations have a non-uniform distribution along the V gene that is well explained by an independent site model for the sequence context around the hypermutation site.

scholarly journals Proof of concept for rational design of hepatitis C virus E2 core nanoparticle vaccines

2020 ◽  
Vol 6 (16) ◽  
pp. eaaz6225 ◽  
Author(s):  
Linling He ◽  
Netanel Tzarum ◽  
Xiaohe Lin ◽  
Benjamin Shapero ◽  
Cindy Sou ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Vaccine Development ◽  
Variable Region ◽  
Improved Stability ◽  
Cell Patterns ◽  
Neutralizing Epitopes

Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are responsible for cell entry, with E2 being the major target of neutralizing antibodies (NAbs). Here, we present a comprehensive strategy for B cell–based HCV vaccine development through E2 optimization and nanoparticle display. We redesigned variable region 2 in a truncated form (tVR2) on E2 cores derived from genotypes 1a and 6a, resulting in improved stability and antigenicity. Crystal structures of three optimized E2 cores with human cross-genotype NAbs (AR3s) revealed how the modified tVR2 stabilizes E2 without altering key neutralizing epitopes. We then displayed these E2 cores on 24- and 60-meric nanoparticles and achieved substantial yield and purity, as well as enhanced antigenicity. In mice, these nanoparticles elicited more effective NAb responses than soluble E2 cores. Next-generation sequencing (NGS) defined distinct B cell patterns associated with nanoparticle-induced antibody responses, which target the conserved neutralizing epitopes on E2 and cross-neutralize HCV genotypes.

scholarly journals B cell repertoire diversity in athymic mice.

1980 ◽  
Vol 151 (3) ◽  
pp. 761-766 ◽  
Author(s):  
M P Cancro ◽  
N R Klinman
Keyword(s):  
B Cell ◽  
Pattern Analysis ◽  
Athymic Mice ◽  
Cell Repertoire ◽  
Reactivity Pattern ◽  
Influenza Hemagglutinin ◽  
Immunoglobulin Allotype ◽  
B Cell Repertoire ◽  
Repertoire Diversity

The extent of B cell repertoire diversity among nu/nu BALB/c mice has been assessed and compared with that of normal BALB/c mice. This was accomplished through the characterization of monoclonal, influenza hemagglutinin-specific antibodies by reactivity pattern analysis. The results indicate that the repertoire of athymic mice is equivalent in diversity to that of normal mice. Moreover, because these responses were obtained in recipients that were histocompatible but distinct at immunoglobulin allotype loci, these findings indicate that a very diverse array of B cell clonotypes may be stimulated in the absence of allotype-identical T cells.

scholarly journals Rational design of hepatitis C virus E2 core nanoparticle vaccines

2019 ◽  
Author(s):  
Linling He ◽  
Netanel Tzarum ◽  
Xiaohe Lin ◽  
Benjamin Shapero ◽  
Cindy Sou ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Vaccine Development ◽  
Variable Region ◽  
High Yield ◽  
Vaccine Strategy ◽  
Neutralizing Epitopes

ABSTRACTHepatitis C virus (HCV) envelope glycoproteins E1 and E2 are critical for cell entry with E2 being the major target of neutralizing antibodies (NAbs). Here, we present a comprehensive strategy for B cell-based HCV vaccine development through E2 optimization and nanoparticle display. We redesigned variable region 2 in a truncated form (tVR2) on E2 cores derived from genotypes 1a and 6a, resulting in improved stability and antigenicity. Crystal structures of three optimized E2 cores with human cross-genotype NAbs (AR3s) revealed how the modified tVR2 stabilizes E2 without altering key neutralizing epitopes. We then displayed these E2 cores on 24- and 60-meric nanoparticles and achieved high yield, high purity, and enhanced antigenicity. In mice, these nanoparticles elicited more effective NAb responses than soluble E2 cores. Next-generation sequencing (NGS) defined distinct B-cell patterns associated with nanoparticle-induced antibody responses, which cross-neutralized HCV by targeting the conserved neutralizing epitopes on E2.One Sentence SummaryAn HCV vaccine strategy is presented that displays redesigned E2 cores on nanoparticles as vaccine candidates for eliciting a broadly neutralizing B-cell response.

scholarly journals Genetic background and immunological status influence B cell repertoire diversity in mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nancy Chaaya ◽  
Melody A. Shahsavarian ◽  
Irene Maffucci ◽  
Alain Friboulet ◽  
Bernard Offmann ◽  
...  
Keyword(s):  
B Cell ◽  
Genetic Background ◽  
High Throughput Sequencing ◽  
Immunoglobulin Gene ◽  
Cell Repertoire ◽  
Immunological Status ◽  
Complex Interactions ◽  
B Cell Repertoire ◽  
Scfv Library ◽  
Repertoire Diversity

Abstract The relationship between the immune repertoire and the physiopathological status of individuals is essential to apprehend the genesis and the evolution of numerous pathologies. Nevertheless, the methodological approaches to understand these complex interactions are challenging. We performed a study evaluating the diversity harbored by different immune repertoires as a function of their physiopathological status. In this study, we base our analysis on a murine scFv library previously described and representing four different immune repertoires: i) healthy and naïve, ii) healthy and immunized, iii) autoimmune prone and naïve, and iv) autoimmune prone and immunized. This library, 2.6 × 109 in size, is submitted to high throughput sequencing (Next Generation Sequencing, NGS) in order to analyze the gene subgroups encoding for immunoglobulins. A comparative study of the distribution of immunoglobulin gene subgroups present in the four libraries has revealed shifts in the B cell repertoire originating from differences in genetic background and immunological status of mice.

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