scholarly journals Persistence of Viremia and Production of Neutralizing Antibodies Differentially Regulated by Polymorphic APOBEC3 and BAFF-R Loci in Friend Virus-Infected Mice

2010 ◽  
Vol 84 (12) ◽  
pp. 6082-6095 ◽  
Author(s):  
Sachiyo Tsuji-Kawahara ◽  
Tomomi Chikaishi ◽  
Eri Takeda ◽  
Maiko Kato ◽  
Saori Kinoshita ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Early Stage ◽  
Chromosome 15 ◽  
Cell Repertoire ◽  
Viral Loads ◽  
Functional Polymorphisms ◽  
B Cell Repertoire ◽  
Retroviral Replication ◽  
Different Strains ◽  
Host Genes

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.

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

Retrovirology ◽  
2009 ◽  
Vol 6 (S2) ◽  
Author(s):  
Masaaki Miyazawa ◽  
Sachiyo Tsuji-Kawahara ◽  
Tomomi Chikaishi ◽  
Maiko Kato ◽  
Shiki Takamura
Keyword(s):  
B Cell ◽  
Neutralizing Antibodies ◽  
Cell Repertoire ◽  
B Cell Repertoire ◽  
Retroviral Replication

scholarly journals Somatic diversification in the absence of antigen-driven responses is the hallmark of the IgM+IgD+CD27+ B cell repertoire in infants

2008 ◽  
Vol 205 (6) ◽  
pp. 1331-1342 ◽  
Author(s):  
Sandra Weller ◽  
Maria Mamani-Matsuda ◽  
Capucine Picard ◽  
Corinne Cordier ◽  
Damiana Lecoeuche ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
Germinal Center ◽  
Early Stage ◽  
Cell Repertoire ◽  
Very Young Children ◽  
B Cell Repertoire ◽  
Somatic Diversification ◽  
The Many

T cell–dependent immune responses develop soon after birth, whereas it takes 2 yr for humans to develop T cell–independent responses. We used this dissociation to analyze the repertoire diversification of IgM+IgD+CD27+ B cells (also known as “IgM memory” B cells), comparing these cells with switched B cells in children <2 yr of age, with the aim of determining whether these two subsets are developmentally related. We show that the repertoire of IgM+IgD+CD27+ B cells in the spleen and blood displays no sign of antigen-driven activation and expansion on H-CDR3 spectratyping, despite the many antigenic challenges provided by childhood vaccinations. This repertoire differed markedly from those of switched B cells and splenic germinal center B cells, even at the early stage of differentiation associated with μ heavy chain expression. These data provide evidence for the developmental diversification of IgM+IgD+CD27+ B cells, at least in very young children, outside of T cell–dependent and –independent immune responses.

scholarly journals Long antibody HCDR3s from HIV-naïve donors presented on a PG9 neutralizing antibody background mediate HIV neutralization

2016 ◽  
Vol 113 (16) ◽  
pp. 4446-4451 ◽  
Author(s):  
Jordan R. Willis ◽  
Jessica A. Finn ◽  
Bryan Briney ◽  
Gopal Sapparapu ◽  
Vidisha Singh ◽  
...  
Keyword(s):  
Amino Acid ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Computational Design ◽  
Cell Repertoire ◽  
B Cell Repertoire ◽  
Amino Acid Length ◽  
Massive Scale ◽  
Amino Acid Mutations ◽  
Hiv 1

Development of broadly neutralizing antibodies (bnAbs) against HIV-1 usually requires prolonged infection and induction of Abs with unusual features, such as long heavy-chain complementarity-determining region 3 (HCDR3) loops. Here we sought to determine whether the repertoires of HIV-1–naïve individuals contain Abs with long HCDR3 loops that could mediate HIV-1 neutralization. We interrogated at massive scale the structural properties of long Ab HCDR3 loops in HIV-1–naïve donors, searching for structured HCDR3s similar to those of the HIV-1 bnAb PG9. We determined the nucleotide sequences encoding 2.3 × 107unique HCDR3 amino acid regions from 70 different HIV-1–naïve donors. Of the 26,917 HCDR3 loops with 30-amino acid length identified, we tested 30 for further study that were predicted to have PG9-like structure when chimerized onto PG9. Three of these 30 PG9 chimeras bound to the HIV-1 gp120 monomer, and two were neutralizing. In addition, we found 14 naturally occurring HCDR3 sequences that acquired the ability to bind to the HIV-1 gp120 monomer when adding 2- to 7-amino acid mutations via computational design. Of those 14 designed Abs, 8 neutralized HIV-1, with IC50values ranging from 0.7 to 98 µg/mL. These data suggest that the repertoire of HIV-1–naïve individuals contains rare B cells that encode HCDR3 loops that bind or neutralize HIV-1 when presented on a PG9 background with relatively few or no additional mutations. Long HCDR3 sequences are present in the HIV-naïve B-cell repertoire, suggesting that this class of bnAbs is a favorable target for rationally designed preventative vaccine efforts.

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 Nucleic acid delivery of immune-focused SARS-CoV-2 nanoparticles drive rapid and potent immunogenicity capable of single-dose protection

2021 ◽  
Author(s):  
Kylie M. Konrath ◽  
Kevin Liaw ◽  
Yuanhan Wu ◽  
Xizhou Zhu ◽  
Susanne N. Walker ◽  
...  
Keyword(s):  
Single Dose ◽  
Neutralizing Antibodies ◽  
Dna Delivery ◽  
Nucleic Acid Delivery ◽  
Wild Type ◽  
Cell Repertoire ◽  
B Cell Repertoire ◽  
Induced Immunity ◽  
Human B Cell

AbstractAntibodies from SARS-CoV-2 vaccines may target epitopes which reduce durability or increase the potential for escape from vaccine-induced immunity. Using a novel synthetic vaccinology pipeline, we developed rationally immune focused SARS-CoV-2 Spike-based vaccines. N-linked glycans can be employed to alter antibody responses to infection and vaccines. Utilizing computational modeling and comprehensive in vitro screening, we incorporated glycans into the Spike Receptor-Binding Domain (RBD) and assessed antigenic profiles. We developed glycan coated RBD immunogens and engineered seven multivalent configurations. Advanced DNA delivery of engineered nanoparticle vaccines rapidly elicited potent neutralizing antibodies in guinea pigs, hamsters and multiple mouse models, including human ACE2 and human B cell repertoire transgenics. RBD nanoparticles encoding wild-type and the P.1 SARS-CoV-2 variant induced high levels of cross-neutralizing antibodies. Single, low dose immunization protected against a lethal SARS-CoV-2 challenge. Single-dose coronavirus vaccines via DNA-launched nanoparticles provide a platform for rapid clinical translation of novel, potent coronavirus vaccines.

scholarly journals Broad sarbecovirus neutralizing antibodies define a key site of vulnerability on the SARS-CoV-2 spike protein

2020 ◽  
Author(s):  
Anna Z. Wec ◽  
Daniel Wrapp ◽  
Andrew S. Herbert ◽  
Daniel Maurer ◽  
Denise Haslwanter ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Rational Design ◽  
Somatic Hypermutation ◽  
Protein A ◽  
Neutralizing Antibody ◽  
Memory B Cells ◽  
Antibody Responses ◽  
Cell Repertoire ◽  
Human Coronavirus ◽  
B Cell Repertoire

Broadly protective vaccines against known and pre-emergent coronaviruses are urgently needed. Critical to their development is a deeper understanding of cross-neutralizing antibody responses induced by natural human coronavirus (HCoV) infections. Here, we mined the memory B cell repertoire of a convalescent SARS donor and identified 200 SARS-CoV-2 binding antibodies that target multiple conserved sites on the spike (S) protein. A large proportion of the antibodies display high levels of somatic hypermutation and cross-react with circulating HCoVs, suggesting recall of pre-existing memory B cells (MBCs) elicited by prior HCoV infections. Several antibodies potently cross-neutralize SARS-CoV, SARS-CoV-2, and the bat SARS-like virus WIV1 by blocking receptor attachment and inducing S1 shedding. These antibodies represent promising candidates for therapeutic intervention and reveal a new target for the rational design of pan-sarbecovirus vaccines.

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

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.

scholarly journals Broad neutralization of SARS-related viruses by human monoclonal antibodies

Science ◽  
2020 ◽  
Vol 369 (6504) ◽  
pp. 731-736 ◽  
Author(s):  
Anna Z. Wec ◽  
Daniel Wrapp ◽  
Andrew S. Herbert ◽  
Daniel P. Maurer ◽  
Denise Haslwanter ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Rational Design ◽  
Somatic Hypermutation ◽  
Protein A ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Human Monoclonal Antibodies ◽  
Cell Repertoire ◽  
B Cell Repertoire ◽  
Human Coronaviruses

Broadly protective vaccines against known and preemergent human coronaviruses (HCoVs) are urgently needed. To gain a deeper understanding of cross-neutralizing antibody responses, we mined the memory B cell repertoire of a convalescent severe acute respiratory syndrome (SARS) donor and identified 200 SARS coronavirus 2 (SARS-CoV-2) binding antibodies that target multiple conserved sites on the spike (S) protein. A large proportion of the non-neutralizing antibodies display high levels of somatic hypermutation and cross-react with circulating HCoVs, suggesting recall of preexisting memory B cells elicited by prior HCoV infections. Several antibodies potently cross-neutralize SARS-CoV, SARS-CoV-2, and the bat SARS-like virus WIV1 by blocking receptor attachment and inducing S1 shedding. These antibodies represent promising candidates for therapeutic intervention and reveal a target for the rational design of pan-sarbecovirus vaccines.

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

2011 ◽  
Vol 7 (8) ◽  
pp. e1002172 ◽  
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

scholarly journals A combination of RBD and NTD neutralizing antibodies limits the generation of SARS-CoV-2 spike neutralization-escape mutants

2021 ◽  
Author(s):  
Denise Haslwanter ◽  
M. Eugenia Dieterle ◽  
Anna Z. Wec ◽  
Cecilia M. O'Brien ◽  
Mrunal Sakharkar ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Yeast Display ◽  
Cell Repertoire ◽  
Neutralization Potential ◽  
S Protein ◽  
B Cell Repertoire ◽  
Escape Mutants ◽  
Vesicular Stomatitis ◽  
Protein Variants

Most known SARS-CoV-2 neutralizing antibodies (nAbs), including those approved by the FDA for emergency use, inhibit viral infection by targeting the receptor-binding domain (RBD) of the spike (S) protein. Variants of concern (VOC) carrying mutations in the RBD or other regions of S reduce the effectiveness of many nAbs and vaccines by evading neutralization. Therefore, therapies that are less susceptible to resistance are urgently needed. Here, we characterized the memory B-cell repertoire of COVID-19 convalescent donors and analyzed their RBD and non-RBD nAbs. We found that many of the non-RBD-targeting nAbs were specific to the N-terminal domain (NTD). Using neutralization assays with authentic SARS-CoV-2 and a recombinant vesicular stomatitis virus carrying SARS-CoV-2 S protein (rVSV-SARS2), we defined a panel of potent RBD and NTD nAbs. Next, we used a combination of neutralization-escape rVSV-SARS2 mutants and a yeast display library of RBD mutants to map their epitopes. The most potent RBD nAb competed with hACE2 binding and targeted an epitope that includes residue F490. The most potent NTD nAb epitope included Y145, K150 and W152. As seen with some of the natural VOC, the neutralization potencies of COVID-19 convalescent sera were reduced by 4-16-fold against rVSV-SARS2 bearing Y145D, K150E or W152R spike mutations. Moreover, we found that combining RBD and NTD nAbs modestly enhanced their neutralization potential. Notably, the same combination of RBD and NTD nAbs limited the development of neutralization-escape mutants in vitro, suggesting such a strategy may have higher efficacy and utility for mitigating the emergence of VOC.

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