Differences in Allelic Frequency and CDRH3 Region Limit the Engagement of HIV Env Immunogens by Putative VRC01 Neutralizing Antibody Precursors

Yacoob, Christina; Pancera, Marie; Вигдорович, В. И.; Oliver, Brian G.; Glenn, Jolene A.; Feng, Junli; Sather, D. Noah; McGuire, Andrew T.; Stamatatos, Leonidas

doi:10.1016/j.celrep.2016.10.017

Cited by 44 publications

(55 citation statements)

References 48 publications

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“…Among this donor’s VRC01-class naive B cells, 89% expressed a kappa variable (Vκ) LC (25 of 28, Figure 1B). κ + VRC01-class bnAbs use a consensus Gln-Gln-Tyr-Glu-Phe (QQYEF) L-CDR3 sequence (20, 21).…”

Section: Resultsmentioning

confidence: 99%

“…Here we found a modest inverse correlation between H-CDR3 length and affinity of naive VRC01-class B cells to eOD-GT8, suggesting slight preferential binding by BCRs with shorter H-CDR3s (p = 0.03, r = 0.28; Figure 2E). A tryptophan (Trp) at the −5 position from the end of the H-CDR3 is present in most VRC01-class bnAbs (also known as Trp100B in VRC01) (20, 28). Although eOD-GT8 was not specifically designed to favor this VRC01-class feature, 31% of VRC01-class naive B cells did contain a Trp at this position (Figure 2F, 21 of 67 with complete HC sequences).…”

Section: Resultsmentioning

confidence: 99%

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The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

et al. 2018

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One Sentence Summary: Inspection of the naive B cell repertoire specific for an HIV vaccine immunogen provides actionable information for human vaccine design and advancement. Traditional vaccine development to prevent some of the worst current pandemic diseases has been unsuccessful, so far. Germline-targeting immunogens have potential to prime protective antibodies (Abs) via more targeted immune responses. Success of germline-targeting vaccines in humans will depend on the composition of the human naive B cell repertoire, including the frequencies and affinities of epitope-specific B cells. However, the human naive B cell repertoire remains largely undefined. Assessment of antigen-specific human naive B cells among hundreds of millions of B cells from multiple donors may be used as pre-Phase I ex vivo human testing to potentially forecast B cell and Ab responses to new vaccine designs. VRC01 is an HIV broadly neutralizing Ab (bnAb) against the Env CD4 binding site (CD4bs). We characterized naive human B cells recognizing eOD-GT8, a germline-targeting HIV-1 vaccine candidate immunogen designed to prime VRC01-class Abs. Several distinct subclasses of VRC01-class naive B cells were identified, sharing sequence characteristics with inferred precursors of known bnAbs VRC01, VRC23, PCIN63, and N6. Multiple naive B cell clones exactly matched mature VRC01-class bnAb L-CDR3 sequences. Non-VRC01-class B cells were also characterized, revealing recurrent public light chain sequences. Unexpectedly, we also identified naive B cells related to the IOMA-class CD4bs bnAb. These different subclasses within the human repertoire had strong initial affinities (KD) to the immunogen, up to 13 nM, and represent encouraging indications that multiple independent pathways may exist for vaccine-elicited VRC01-class bnAb development in most individuals. The frequencies of these distinct eOD-GT8 B cell specificities give insights into antigen-specific compositional features of the human naive B cell repertoire and provide actionable information for vaccine design and advancement.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

et al. 2018

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“…Although putative bNAb precursors have been discovered in HIV-naive repertoires ( Jardine et al., 2016 , Yacoob et al., 2016 ), it is unclear how the antibody repertoires of HIV-infected individuals change from the time before infection through different stages of infection. Furthermore, while ontogeny and structural studies of HIV-reactive antibodies have revealed convergence at the structural level in multiple donors ( Scheid et al., 2011 , Wu et al., 2011 , Zhou et al., 2015 ), the overall differences and similarities in the antibody repertoires of HIV-infected donors have not been characterized.…”

Section: Introductionmentioning

confidence: 99%

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

Setliff

McDonnell

Raju

et al. 2018

Cell Host & Microbe

102

116

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SummaryCharacterization of single antibody lineages within infected individuals has provided insights into the development of Env-specific antibodies. However, a systems-level understanding of the humoral response against HIV-1 is limited. Here, we interrogated the antibody repertoires of multiple HIV-infected donors from an infection-naive state through acute and chronic infection using next-generation sequencing. This analysis revealed the existence of “public” antibody clonotypes that were shared among multiple HIV-infected individuals. The HIV-1 reactivity for representative antibodies from an identified public clonotype shared by three donors was confirmed. Furthermore, a meta-analysis of publicly available antibody repertoire sequencing datasets revealed antibodies with high sequence identity to known HIV-reactive antibodies, even in repertoires that were reported to be HIV naive. The discovery of public antibody clonotypes in HIV-infected individuals represents an avenue of significant potential for better understanding antibody responses to HIV-1 infection, as well as for clonotype-specific vaccine development.

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“…As mentioned before, antibodies of this class are particularly restricted for usage of the VH1-2*02 allele and a 5 amino acid CDRL3 [101]. BCR repertoire analyses revealed that potential VRC01-class precursor B cells are exceptionally rare [147][148][149]. In addition, allelic variation can result in the lack of naïve B cells derived from the key VH1-2*02 allele [149].…”

Section: Informing About Vaccination Strategies (Ii): B Cell Receptormentioning

confidence: 92%

“…BCR repertoire analyses revealed that potential VRC01-class precursor B cells are exceptionally rare [147][148][149]. In addition, allelic variation can result in the lack of naïve B cells derived from the key VH1-2*02 allele [149]. Nevertheless, eOD-GT8-reactive naïve B cells could be identified in a majority of HIV-1-negative donors (14/18) [147,148], providing repertoire analysis-based support for advancing the eOD-GT8 immunogen to be evaluated in a clinical setting.…”

Section: Informing About Vaccination Strategies (Ii): B Cell Receptormentioning

confidence: 99%

Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies

et al. 2020

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The human antibody repertoire is generated by the recombination of different gene segments as well as by processes of somatic mutation. Together these mechanisms result in a tremendous diversity of antibodies that are able to combat various pathogens including viruses and bacteria, or malignant cells. In this review, we summarize the opportunities and challenges that are associated with the analyses of the B cell receptor repertoire and the antigen-specific B cell response. We will discuss how recent advances have increased our understanding of the antibody response and how repertoire analyses can be exploited to inform on vaccine strategies, particularly against HIV-1.Antibodies are composed of heavy and light chains, both of which are divided into a constant and a variable region ( Figure 1a). The different isotypes for the heavy chain constant regions mediate different effector functions and are grouped into the classes IgM, IgD, and IgE [3]. The variable regions of heavy and light chains form the paratope that contacts the epitope on a particular antigen (e.g., on a bacterial or viral surface protein). Two essential steps act during the lifespan of a B cell to generate B cell receptor diversity: (i) the V(D)J recombination process that builds the naïve (i.e., antigen-inexperienced) B cell repertoire, and (ii) somatic hypermutation (SHM) during the process of affinity maturation that generates high affinity B cell receptors and antibodies (i.e., the antigen-experienced repertoire).lifespan of a B cell to generate B cell receptor diversity: i.) the V(D)J recombination process that 52 builds the naïve (i.e., antigen-inexperienced) B cell repertoire, and ii.) somatic hypermutation (SHM) 53 during the process of affinity maturation that generates high affinity B cell receptors and antibodies 54 (i.e., the antigen-experienced repertoire). 55The initial diversity of the B cell repertoire results from the assembly of the B cell receptor 56 during early B cell development in the bone marrow. The recombination-activating gene (RAG) 1/2 57 enzymes recombine variable (V), diversity (D), and joining (J) gene segments of the immunoglobulin 58 heavy (IgH) chain locus to first assemble the heavy chain variable region, followed by V and J gene 59 segment recombination within the Ig kappa (IgK) and Ig lambda (IgL) loci [4]. Junctional diversity is 60 further increased by RAG1/2 and other enzymes through the generation of palindromic (P) 61 nucleotides, as well as by the terminal deoxynuclotidyl transferase (TdT) through the addition of 62 non-template (N) nucleotides [5] (Figure 1b). Heavy and light chain V genes exclusively encode for 63 two complementarity determining regions (CDR1 and CDR2) that are usually structurally exposed 64 at the tip of the antibody and contribute to antigen recognition. A third CDR (CDR3) is generated by 65 the V(D)J recombination process and is the most variable part within B cell receptors and antibodies. 66The CDRs are interspersed and flanked with framework regions (FWR) that mainly function a...

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Differences in Allelic Frequency and CDRH3 Region Limit the Engagement of HIV Env Immunogens by Putative VRC01 Neutralizing Antibody Precursors

Cited by 44 publications

References 48 publications

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

The human naive B cell repertoire contains distinct subclasses for a germline-targeting HIV-1 vaccine immunogen

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

Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies

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