Mouse APOBEC3 affects the production of virus-neutralizing antibodies by restricting early retroviral replication, not by altering the B-cell repertoire

ABSTRACT Several host genes control retroviral replication and pathogenesis through the regulation of immune responses to viral antigens. The Rfv3 gene influences the persistence of viremia and production of virus-neutralizing antibodies in mice infected with Friend mouse retrovirus complex (FV). This locus has been mapped within a narrow segment of mouse chromosome 15 harboring the APOBEC3 and BAFF-R loci, both of which show functional polymorphisms among different strains of mice. The exon 5-lacking product of the APOBEC3 allele expressed in FV-resistant C57BL/6 (B6) mice directly restricts viral replication, and mice lacking the B6-derived APOBEC3 exhibit exaggerated pathology and reduced production of neutralizing antibodies. However, the mechanisms by which the polymorphisms at the APOBEC3 locus affect the production of neutralizing antibodies remain unclear. Here we show that the APOBEC3 genotypes do not directly affect the B-cell repertoire, and mice lacking B6-derived APOBEC3 still produce FV-neutralizing antibodies in the presence of primed T helper cells. Instead, higher viral loads at a very early stage of FV infection caused by either a lack of the B6-derived APOBEC3 or a lack of the wild-type BAFF-R resulted in slower production of neutralizing antibodies. Indeed, B cells were hyperactivated soon after infection in the APOBEC3- or BAFF-R-deficient mice. In contrast to mice deficient in the B6-derived APOBEC3, which cleared viremia by 4 weeks after FV infection, mice lacking the functional BAFF-R allele exhibited sustained viremia, indicating that the polymorphisms at the BAFF-R locus may better explain the Rfv3-defining phenotype of persistent viremia.

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

10.1101/2021.08.23.21262508 ◽

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.

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Functional characterization and lineage analysis of broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

10.1101/790642 ◽

2019 ◽

Author(s):

Natasha D. Durham ◽

Aditi Agrawal ◽

Eric Waltari ◽

Derek Croote ◽

Fabio Zanini ◽

...

Keyword(s):

Dengue Virus ◽

B Cell ◽

Neutralizing Antibodies ◽

Somatic Hypermutation ◽

Functional Characterization ◽

Vaccine Design ◽

Protein Domain ◽

Cell Repertoire ◽

B Cell Repertoire ◽

Domain I

AbstractEliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To delineate bNAb targets, we characterized 28 monoclonal antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies revealed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against flaviviruses with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested a memory origin and divergent somatic hypermutation pathways for these bNAbs, and a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a novel epitope that can be exploited for vaccine design.

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B Cell Repertoire Analysis Identifies New Antigenic Domains on Glycoprotein B of Human Cytomegalovirus which Are Target of Neutralizing Antibodies

PLoS Pathogens ◽

10.1371/journal.ppat.1002172 ◽

2011 ◽

Vol 7 (8) ◽

pp. e1002172 ◽

Cited By ~ 96

Author(s):

Sonja Pötzsch ◽

Nadja Spindler ◽

Anna-Katharina Wiegers ◽

Tanja Fisch ◽

Pia Rücker ◽

...

Keyword(s):

B Cell ◽

Human Cytomegalovirus ◽

Neutralizing Antibodies ◽

Glycoprotein B ◽

Cell Repertoire ◽

Repertoire Analysis ◽

B Cell Repertoire ◽

Antigenic Domains

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Broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

eLife ◽

10.7554/elife.52384 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 5

Author(s):

Natasha D Durham ◽

Aditi Agrawal ◽

Eric Waltari ◽

Derek Croote ◽

Fabio Zanini ◽

...

Keyword(s):

Dengue Virus ◽

B Cell ◽

Neutralizing Antibodies ◽

Somatic Hypermutation ◽

Vaccine Design ◽

Protein Domain ◽

Cell Repertoire ◽

B Cell Repertoire ◽

Dengue Virus Serotypes ◽

Domain I

Eliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To define bNAb targets, we characterized 28 antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified J9 and J8, two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies showed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against DENV with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested that J9 and J8 followed divergent somatic hypermutation pathways, and that a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a new epitope that can be exploited for vaccine design.

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A third dose of inactivated vaccine augments the potency, breadth, and duration of anamnestic responses against SARS-CoV-2

10.1101/2021.09.02.21261735 ◽

2021 ◽

Author(s):

Kang Wang ◽

Yunlong Richard Cao ◽

Yunjiao Zhou ◽

Jiajing Wu ◽

Zijing Jia ◽

...

Keyword(s):

B Cell ◽

Neutralizing Antibodies ◽

Humoral Response ◽

Complex Structures ◽

Cell Repertoire ◽

Heat Maps ◽

Structure Activity ◽

B Cell Repertoire ◽

Inactivated Vaccines ◽

Composition Changes

Emergence of variants of concern (VOC) with altered antigenic structures and waning humoral immunity to SARS-CoV-2 are harbingers of a long pandemic. Administration of a third dose of an inactivated virus vaccine can boost the immune response. Here, we have dissected the immunogenic profiles of antibodies from 3-dose vaccinees, 2-dose vaccinees and convalescents. Better neutralization breadth to VOCs, expeditious recall and long-lasting humoral response bolster 3-dose vaccinees in warding off COVID-19. Analysis of 171 complex structures of SARS-CoV-2 neutralizing antibodies identified structure-activity correlates, revealing ultrapotent, VOCs-refractory and broad-spectrum antigenic patches. Construction of immunogenic and mutational heat maps revealed a direct relationship between "hot" immunogenic sites and areas with high mutation frequencies. Ongoing antibody somatic mutation, memory B cell clonal turnover and antibody composition changes in B cell repertoire driven by prolonged and repeated antigen stimulation confer development of monoclonal antibodies with enhanced neutralizing potency and breadth. Our findings rationalize the use of 3-dose immunization regimens for inactivated vaccines.

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Review for "Templated Insertions at VD and DJ junctions Create Unique B‐Cell Receptors in the Healthy B‐Cell Repertoire"

10.1002/eji.202048828/v1/review2 ◽

2018 ◽

Keyword(s):

B Cell ◽

B Cell Receptors ◽

Cell Repertoire ◽

Cell Receptors ◽

B Cell Repertoire

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Selection of the expressed B cell repertoire by infusion of normal immunoglobulin G in a patient with autoimmune thyroiditis

European Journal of Immunology ◽

10.1002/eji.1830231133 ◽

1993 ◽

Vol 23 (11) ◽

pp. 2945-2950 ◽

Cited By ~ 40

Author(s):

Gilles Dietrich ◽

Francisco J. Varela ◽

Vincent Hurez ◽

Majida Bouanani ◽

Michel D. Kazatchkine

Keyword(s):

B Cell ◽

Immunoglobulin G ◽

Autoimmune Thyroiditis ◽

Cell Repertoire ◽

B Cell Repertoire ◽

Selection Of

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Monoclonal CD5+ and CD5- B-lymphocyte expansions are frequent in the peripheral blood of the elderly

Blood ◽

10.1182/blood-2003-09-3277 ◽

2004 ◽

Vol 103 (6) ◽

pp. 2337-2342 ◽

Cited By ~ 164

Author(s):

Paolo Ghia ◽

Giuseppina Prato ◽

Cristina Scielzo ◽

Stefania Stella ◽

Massimo Geuna ◽

...

Keyword(s):

B Cell ◽

Peripheral Blood ◽

B Lymphocyte ◽

The Elderly ◽

Lymphocytic Leukemia ◽

Pcr Analysis ◽

Cell Repertoire ◽

Healthy Elderly ◽

B Cell Repertoire ◽

Igh Genes

Abstract The responsiveness and diversity of peripheral B-cell repertoire decreases with age, possibly because of B-cell clonal expansions, as suggested by the incidence of serum monoclonal immunoglobulins and of monoclonal chronic lymphocytic leukemia (CLL)–like B lymphocytes in clinically silent adults. We phenotyped peripheral blood cells from 500 healthy subjects older than 65 years with no history or suspicion of malignancies and no evidence of lymphocytosis. In 19 cases (3.8%) a κ/λ ratio of more than 3:1 or less than 1:3 was found: 9 were CD5+, CD19+, CD23+, CD20low, CD79blow, sIglow (classic CLL-like phenotype); 3 were CD5+, CD19+, CD23+, CD20high, CD79blow, sIglow (atypical CLL-like), and 7 were CD5-, CD19+, CD20high, CD23-, CD79bbright, FMC7+, sIgbright (non–CLL-like). In 2 subjects, 2 phenotypically distinct unrelated clones were concomitantly evident. No cases were CD10+. Polymerase chain reaction (PCR) analysis demonstrated a monoclonal rearrangement of IgH genes in 15 of 19 cases. No bcl-1 or bcl-2 rearrangements were detected. Using a gating strategy based on CD20/CD5/CD79 expression, 13 additional CLL-like B-cell clones were identified (cumulative frequency of classic CLL-like: 5.5%). Thus, phenotypically heterogeneous monoclonal B-lymphocyte expansions are common among healthy elderly individuals and are not limited to classic CLL-like clones but may have the phenotypic features of different chronic lymphoproliferative disorders, involving also CD5- B cells.

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