scholarly journals Detection and activation of HIV broadly neutralizing antibody precursor B cells using anti-idiotypes

2019 ◽  
Vol 216 (10) ◽  
pp. 2331-2347 ◽  
Author(s):  
Tara Bancroft ◽  
Blair L. DeBuysscher ◽  
Connor Weidle ◽  
Allison Schwartz ◽  
Abigail Wall ◽  
...  
Keyword(s):  
B Cells ◽  
Neutralizing Antibody ◽  
Subunit Vaccines ◽  
Human B Cells ◽  
Immunodeficiency Virus ◽  
Protective Antibodies ◽  
Broadly Neutralizing Antibody ◽  
Precursor B Cells ◽  
Hiv 1

Many tested vaccines fail to provide protection against disease despite the induction of antibodies that bind the pathogen of interest. In light of this, there is much interest in rationally designed subunit vaccines that direct the antibody response to protective epitopes. Here, we produced a panel of anti-idiotype antibodies able to specifically recognize the inferred germline version of the human immunodeficiency virus 1 (HIV-1) broadly neutralizing antibody b12 (iglb12). We determined the crystal structure of two anti-idiotypes in complex with iglb12 and used these anti-idiotypes to identify rare naive human B cells expressing B cell receptors with similarity to iglb12. Immunization with a multimerized version of this anti-idiotype induced the proliferation of transgenic murine B cells expressing the iglb12 heavy chain in vivo, despite the presence of deletion and anergy within this population. Together, our data indicate that anti-idiotypes are a valuable tool for the study and induction of potentially protective antibodies.

scholarly journals Vaccine genetics of IGHV1-2 VRC01-class broadly neutralizing antibody precursor naïve human B cells

2021 ◽  
Author(s):  
Jeong Hyun Lee ◽  
Laura Toy ◽  
Justin T. Kos ◽  
Yana Safonova ◽  
William R. Schief ◽  
...  
Keyword(s):  
B Cells ◽  
Neutralizing Antibody ◽  
Human Populations ◽  
Human B Cells ◽  
Class B ◽  
Gene Usage ◽  
Germline Variation ◽  
Broadly Neutralizing Antibody ◽  
Multiple Donors ◽  
Precursor B Cells

ABSTRACTA successful HIV vaccine must overcome the hurdle of being able to activate naïve precursor B cells encoding features within their germline B cell receptors (BCR) that allow recognition of broadly neutralizing epitopes. Knowledge of whether broadly neutralizing antibody (bnAb) precursor B cells are circulating at sufficient frequencies within individuals in communities heavily impacted by HIV may be important. Using a germline-targeting eOD-GT8 immunogen and high-throughput droplet-based single cell BCR sequencing, we demonstrate that large numbers of paired BCR sequences from multiple donors can be efficiently screened to elucidate precursor frequencies of rare, naïve VRC01-class B cells. The results indicate that IGHV1-2 alleles incompatible with VRC01-class responses are relatively common in various human populations, and germline variation within IGHV1-2 associates with gene usage frequencies in the naïve BCR repertoire.

scholarly journals HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen

Science ◽  
2016 ◽  
Vol 351 (6280) ◽  
pp. 1458-1463 ◽  
Author(s):  
J. G. Jardine ◽  
D. W. Kulp ◽  
C. Havenar-Daughton ◽  
A. Sarkar ◽  
B. Briney ◽  
...  
Keyword(s):  
B Cells ◽  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibody ◽  
Precursor B Cells ◽  
Hiv 1

scholarly journals A Glycoconjugate Antigen Based on the Recognition Motif of a Broadly Neutralizing Human Immunodeficiency Virus Antibody, 2G12, Is Immunogenic but Elicits Antibodies Unable To Bind to the Self Glycans of gp120

2008 ◽  
Vol 82 (13) ◽  
pp. 6359-6368 ◽  
Author(s):  
Rena D. Astronomo ◽  
Hing-Ken Lee ◽  
Christopher N. Scanlan ◽  
Ralph Pantophlet ◽  
Cheng-Yuan Huang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Neutralizing Antibody ◽  
Humoral Immune ◽  
Aids Vaccine ◽  
Humoral Immune Responses ◽  
Copy Numbers ◽  
Immunodeficiency Virus ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1

ABSTRACT The glycan shield of human immunodeficiency virus type 1 (HIV-1) gp120 contributes to viral evasion from humoral immune responses. However, the shield is recognized by the HIV-1 broadly neutralizing antibody (Ab), 2G12, at a relatively conserved cluster of oligomannose glycans. The discovery of 2G12 raises the possibility that a carbohydrate immunogen may be developed that could elicit 2G12-like neutralizing Abs and contribute to an AIDS vaccine. We have previously dissected the fine specificity of 2G12 and reported that the synthetic tetramannoside (Man4) that corresponds to the D1 arm of Man9GlcNAc2 inhibits 2G12 binding to gp120 as efficiently as Man9GlcNAc2 itself, indicating the potential use of Man4 as a building block for creating immunogens. Here, we describe the development of neoglycoconjugates displaying variable copy numbers of Man4 on bovine serum albumin (BSA) molecules by conjugation to Lys residues. The increased valency enhances the apparent affinity of 2G12 for Man4 up to a limit which is achieved at ∼10 copies per BSA molecule, beyond which no further enhancement is observed. Immunization of rabbits with BSA-(Man4)14 elicits significant serum Ab titers to Man4. However, these Abs are unable to bind gp120. Further analysis reveals that the elicited Abs bind a variety of unbranched and, to a lesser extent, branched Man9 derivatives but not natural N-linked oligomannose containing the chitobiose core. These results suggest that Abs can be readily elicited against the D1 arm; however, potential differences in the presentation of Man4 on neoglycoconjugates, compared to glycoproteins, poses challenges for eliciting anti-mannose Abs capable of cross-reacting with gp120 and HIV-1.

scholarly journals Revisiting an IgG Fc Loss-of-Function Experiment: the Role of Complement in HIV Broadly Neutralizing Antibody b12 Activity

mBio ◽  
2021 ◽  
Author(s):  
Benjamin S. Goldberg ◽  
Chengzi I. Kaku ◽  
Jérémy Dufloo ◽  
Timothée Bruel ◽  
Olivier Schwartz ◽  
...  
Keyword(s):  
Neutralizing Antibody ◽  
Loss Of Function ◽  
Wild Type ◽  
Suboptimal Outcome ◽  
Antiviral Activities ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1 ◽  
Prevention Of Hiv

Given the suboptimal outcome of VRC01 antibody-mediated prevention of HIV-1 infection in its first field trial, means to improve diverse antiviral activities in vivo have renewed importance. This work revisits a loss-of-function experiment that investigated the mechanism of action of b12, a similar antibody, and finds that the reason why complement-mediated antiviral activities were not observed to contribute to protection may be the inherent lack of activity of wild-type b12, raising the prospect that this mechanism may contribute in the context of other HIV-specific antibodies.

scholarly journals New Connections: Cell-to-Cell HIV-1 Transmission, Resistance to Broadly Neutralizing Antibodies, and an Envelope Sorting Motif

2017 ◽  
Vol 91 (9) ◽  
Author(s):  
S. Abigail Smith ◽  
Cynthia A. Derdeyn
Keyword(s):  
Neutralizing Antibodies ◽  
Differential Susceptibility ◽  
Neutralizing Antibody ◽  
Dependent Manner ◽  
Broadly Neutralizing Antibodies ◽  
Cell Infection ◽  
Viral Spread ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1

ABSTRACT HIV-1 infection from cell-to-cell may provide an efficient mode of viral spread in vivo and could therefore present a significant challenge for preventative or therapeutic strategies based on broadly neutralizing antibodies. Indeed, Li et al. (H. Li, C. Zony, P. Chen, and B. K. Chen, J. Virol. 91:e02425-16, 2017, https://doi.org/10.1128/JVI.02425-16 ) showed that the potency and magnitude of multiple HIV-1 broadly neutralizing antibody classes are decreased during cell-to-cell infection in a context-dependent manner. A functional motif in gp41 appears to contribute to this differential susceptibility by modulating exposure of neutralization epitopes.

scholarly journals Anti-idiotypic antibodies elicit anti-HIV-1–specific B cell responses

2019 ◽  
Vol 216 (10) ◽  
pp. 2316-2330 ◽  
Author(s):  
Pia Dosenovic ◽  
Anna-Klara Pettersson ◽  
Abigail Wall ◽  
Eddy S. Thientosapol ◽  
Junli Feng ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Neutralizing Antibodies ◽  
Target Cells ◽  
Human B Cells ◽  
Cd4 Binding Site ◽  
Idiotypic Antibody ◽  
Anti Hiv ◽  
Hiv 1

Human anti-HIV-1 broadly neutralizing antibodies (bNAbs) protect against infection in animal models. However, bNAbs have not been elicited by vaccination in diverse wild-type animals or humans, in part because B cells expressing the precursors of these antibodies do not recognize most HIV-1 envelopes (Envs). Immunogens have been designed that activate these B cell precursors in vivo, but they also activate competing off-target responses. Here we report on a complementary approach to expand specific B cells using an anti-idiotypic antibody, iv8, that selects for naive human B cells expressing immunoglobulin light chains with 5–amino acid complementarity determining region 3s, a key feature of anti-CD4 binding site (CD4bs)–specific VRC01-class antibodies. In mice, iv8 induced target cells to expand and mature in the context of a polyclonal immune system and produced serologic responses targeting the CD4bs on Env. In summary, the results demonstrate that an anti-idiotypic antibody can specifically recognize and expand rare B cells that express VRC01-class antibodies against HIV-1.

scholarly journals Cross-Reactivity to Kynureninase Tolerizes B Cells That Express the HIV-1 Broadly Neutralizing Antibody 2F5

2019 ◽  
Vol 203 (12) ◽  
pp. 3268-3281 ◽  
Author(s):  
Joel Finney ◽  
Guang Yang ◽  
Masayuki Kuraoka ◽  
Shengli Song ◽  
Takuya Nojima ◽  
...  
Keyword(s):  
B Cells ◽  
Neutralizing Antibody ◽  
Cross Reactivity ◽  
Broadly Neutralizing Antibody ◽  
Hiv 1

scholarly journals Efficient reprogramming of the heavy-chain CDR3 regions of a human antibody repertoire

2021 ◽  
Author(s):  
Tiangling Ou ◽  
Wenhui He ◽  
Brian D Quinlan ◽  
Yan Guo ◽  
Pabalu Karunadharma ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Human Antibody ◽  
Cell Repertoire ◽  
Viral Control ◽  
Human B Cells ◽  
B Cell Repertoire ◽  
Hiv 1

B cells have been engineered ex vivo to express an HIV-1 broadly neutralizing antibody (bNAb). B-cell reprograming may be scientifically and therapeutically useful, but current approaches limit B-cell repertoire diversity and disrupt the organization of the heavy-chain locus. A more diverse and physiologic B-cell repertoire targeting a key HIV-1 epitope could facilitate evaluation of vaccines designed to elicit bNAbs, help identity more potent and bioavailable bNAb variants, or directly enhance viral control in vivo. Here we address the challenges of generating such a repertoire by replacing the heavy-chain CDR3 (HCDR3) regions of primary human B cells. To do so, we identified and utilized an uncharacterized Cas12a ortholog that recognizes PAM motifs present in human and murine JH genes. We also optimized the design of 200 nucleotide homology-directed repair templates (HDRT) by minimizing the required 3'-5' resection of the HDRT-complementary strand. Using these techniques, we edited primary human B cells to express a hemagglutinin epitope tag and the HCDR3 regions of the bNAbs PG9 and CH01. Those edited with bNAb HCDR3 efficiently bound trimeric HIV-1 antigens, implying they could affinity mature in vivo in response to the same antigens. This approach generates diverse B-cell repertoires recognizing a key HIV-1 neutralizing epitope.

scholarly journals Frequency and Phenotype of Human Immunodeficiency Virus Envelope-Specific B Cells from Patients with Broadly Cross-Neutralizing Antibodies

2008 ◽  
Vol 83 (1) ◽  
pp. 188-199 ◽  
Author(s):  
Nicole A. Doria-Rose ◽  
Rachel M. Klein ◽  
Maura M. Manion ◽  
Sijy O'Dell ◽  
Adhuna Phogat ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
B Cells ◽  
Elispot Assay ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Protein A ◽  
Neutralizing Antibody ◽  
Virus Envelope ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Induction of broadly cross-reactive neutralizing antibodies (NAb) is an important goal for a prophylactic human immunodeficiency virus type 1 (HIV-1) vaccine. Some HIV-infected patients make a NAb response that reacts with diverse strains of HIV-1, but most candidate vaccines have induced NAb only against a subset of highly sensitive isolates. To better understand the nature of broad NAb responses that arise during natural infection, we screened patients for sera able to neutralize diverse HIV strains and explored the frequency and phenotype of their peripheral Envelope-specific B cells. We screened 113 HIV-infected patients of various clinical statuses for the prevalence of broad NAb. Sera able to neutralize at least four of five viral isolates were found in over one-third of progressors and slow progressors, but much less frequently in aviremic long-term nonprogressors. Most Env-specific antibody-secreting B cells were CD27hi CD38hi plasmablasts, and the total plasmablast frequency was higher in HIV-infected patients than in uninfected donors. We found that 0.0031% of B cells and 0.047% of plasmablasts secreted Env-specific immunoglobulin G (IgG) in an enzyme-linked immunospot (ELISPOT) assay. We developed a novel staining protocol to label HIV-specific B cells with Env gp140 protein. A total of 0.09% of B cells were found to be Env-specific by this method, a frequency far higher than that indicated by ELISPOT assay. gp140-labeled B cells were predominantly CD27+ and surface IgG+. These data describe the breadth and titer of serum NAb and the frequency and phenotype of HIV-specific B cells in a cohort of patients with broad cross-neutralizing antibody responses that are potential goals for vaccines for HIV.

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