Multi-Donor Longitudinal Antibody Repertoire Sequencing Reveals the Existence of Public Antibody Clonotypes in HIV-1 Infection

Setliff, Ian; McDonnell, Wyatt J.; Raju, Nagarajan; Bombardi, Robin; Murji, Amyn A.; Scheepers, Cathrine; Ziki, Rutendo; Mynhardt, Charissa; Shepherd, Bryan E.; Mamchak, Alusha A.; Garrett, Nigel; Karim, Salim Safurdeen. Abdool; Mallal, S.; Crowe, James E.; Morris, Lynn; Georgiev, Ivelin S.

doi:10.1016/j.chom.2018.05.001

Cited by 101 publications

(122 citation statements)

References 48 publications

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“…Among all of the closely examined subjects, we detected a convergent B cell response that displays (1) the presence of shared antibody characteristics, (2) preferences of V genes found in EBOVreactive mAbs and (3) the frequent generation of a V H 3-15/V λ 1-40 EBOV-neutralizing antibody class that showed traits of a recurrent affinity maturation process. Re-occurring antibodies that share the same V genes have occasionally been reported in response to infections with viruses such as HIV-1, Zika and West Nile virus [45][46][47] . For EVD, a longitudinal analysis of four survivors revealed a preference for IGHV3-13 in EBOV-neutralizing antibodies 48 .…”

Section: Discussionmentioning

confidence: 99%

Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV

Ehrhardt

Zehner

Krähling

et al. 2019

Nat Med

102

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Recombinant vesicular stomatitis virus-Zaire Ebola virus (rVSV-ZEBOV) is the most advanced Ebola virus vaccine candidate and is currently being used to combat the outbreak of Ebola virus disease (EVD) in the Democratic Republic of the Congo (DRC). Here we examine the humoral immune response in a subset of human volunteers enrolled in a phase 1 rVSV-ZEBOV vaccination trial by performing comprehensive single B cell and electron microscopy structure analyses. Four studied vaccinees show polyclonal, yet reproducible and convergent B cell responses with shared sequence characteristics. EBOV-targeting antibodies cross-react with other Ebolavirus species, and detailed epitope mapping revealed overlapping target epitopes with antibodies isolated from EVD survivors. Moreover, in all vaccinees, we detected highly potent EBOV-neutralizing antibodies with activities comparable or superior to the monoclonal antibodies currently used in clinical trials. These include antibodies combining the IGHV3-15/IGLV1-40 immunoglobulin gene segments that were identified in all investigated individuals. Our findings will help to evaluate and direct current and future vaccination strategies and offer opportunities for novel EVD therapies.

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Section: Discussionmentioning

confidence: 99%

Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV

Ehrhardt

Zehner

Krähling

et al. 2019

Nat Med

102

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“…Sample preparation for deep sequencing was performed following a previously established two-step primer 349 extension protocol [23]. Genomic DNA was extracted from 5 x 10 6 a, Dose-dependent absorbance curves of supernatant prepared from hybridoma cells expressing antibodies with convergent variable heavy (VH) chain pools for each antigen. b, Flow cytometry histograms of six monoclonal cell populations each utilizing a different convergent OVA-associated or RSV-F associated VH.…”

Section: Deep Sequencing Of Rsv3 Cdrh3 Libraries 348mentioning

confidence: 99%

Convergent selection in antibody repertoires is revealed by deep learning

Friedensohn¹,

Neumeier²,

Khan³

et al. 2020

Preprint

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Adaptive immunity is driven by the ability of lymphocytes to undergo V(D)J recombination and generate a highly diverse set of immune receptors (B cell receptors/secreted antibodies and T cell receptors) and their subsequent clonal selection and expansion upon molecular recognition of foreign antigens. These principles lead to remarkable, unique and dynamic immune receptor repertoires 1 . Deep sequencing provides increasing evidence for the presence of commonly shared (convergent) receptors across individual organisms within one species 2-4 . Convergent selection of specific receptors towards various antigens offers one explanation for these findings. For example, single cases of convergence have been reported in antibody repertoires of viral infection or allergy 5-8 . Recent studies demonstrate that convergent selection of sequence motifs within T cell receptor (TCR) repertoires can be identified on an even wider scale 9,10 . Here we report that there is extensive convergent selection in antibody repertoires of mice for a range of protein antigens and immunization conditions. We employed a deep learning approach utilizing variational autoencoders (VAEs) to model the underlying process of B cell receptor (BCR) recombination and assume that the data generation follows a Gaussian mixture model (GMM) in latent space. This provides both a latent embedding and cluster labels that group similar sequences, thus enabling the discovery of a multitude of convergent, antigen-associated sequence patterns. Using a linear, one-versus-all support vector machine (SVM), we confirm that the identified sequence patterns are predictive of antigenic exposure and outperform predictions based on the occurrence of public clones. Recombinant expression of both natural and in silico-generated antibodies possessing convergent patterns confirms their binding specificity to target antigens. Our work highlights to which extent convergence in antibody repertoires can occur and shows how deep learning can be applied for immunodiagnostics and antibody discovery and engineering.

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“…Clonal expansions of B cells occur in response to specific immune stimulation and evidence for a corresponding convergence of germline gene arrangements has been shown (e.g. Briney B. et al 2019, Setliff, I. et al 2018, Imkeller, K.,and Wardemann, H. 2018. Clonal families represent in vivo antibody molecular evolution to a consensus directed against common epitopes of vaccines or disease.…”

Section: Discussionmentioning

confidence: 99%

Functional Enrichment and Analysis of Antigen-Specific Memory B Cell Antibody Repertoires in PBMCs

Waltari

McGeever

Kim

et al. 2019

Preprint

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Phenotypic screening of antigen-specific antibodies in human blood is a common diagnostic test for infectious agents and a correlate of protection after vaccination. In addition to long-lived antibody secreting plasma cells residing in the bone marrow, memory B cells are a latent source of antigen-experienced, long-term immunity that can be found at low frequencies in circulating PBMCs. Assessing the genotype, clonal frequency, quality, and function of antibodies resulting from an individual's persistent memory B cell repertoire can help inform the success or failure of immune protection. We have applied ELISPOT cell culture methods to functionally expand the memory repertoire from PBMCs and clonally map monoclonal antibodies from this population. We show that combining deep sequencing of stimulated memory B cell repertoires with retrieving single antigen-specific cells is a promising approach in evaluating the latent, functional B cell memory in PBMCs.

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Multi-Donor Longitudinal Antibody Repertoire Sequencing Reveals the Existence of Public Antibody Clonotypes in HIV-1 Infection

Cited by 101 publications

References 48 publications

Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV

Polyclonal and convergent antibody response to Ebola virus vaccine rVSV-ZEBOV

Convergent selection in antibody repertoires is revealed by deep learning

Functional Enrichment and Analysis of Antigen-Specific Memory B Cell Antibody Repertoires in PBMCs

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