An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein

Flyak, Andrew I.; Ruiz, Stormy; Salas, Jordan; Rho, Semi; Bailey, Justin R.; Björkman, Pamela J.

doi:10.7554/elife.53169

Cited by 24 publications

(27 citation statements)

References 32 publications

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“…Moreover, as well as stabilizing the protruding structure and directly altering the antigen contacts, SHM can generate local flexibility that allows the antigen-binding site to engage with its respective target at a variety of angles, significantly improving neutralization activity in some cases [16]. Although rare in human antibody genes, large nucleotide insertions (>40 nt) introduced by sequence duplication during the error-prone repair of SHM have been shown to contribute to antigen recognition [32]. Whilst the high SHM rate is not conducive to their induction via classical vaccination, it does not prevent the use of previously generated BNAbs therapeutically [33,34].…”

Section: The Long Cdr H3 Is Generated Inefficiently In Humansmentioning

confidence: 99%

Broadly Neutralizing Bovine Antibodies: Highly Effective New Tools against Evasive Pathogens?

Burke

Stockley

Boyes

2020

Viruses

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Potent antibody-mediated neutralization is critical for an organism to combat the vast array of pathogens it will face during its lifetime. Due to the potential genetic diversity of some viruses, such as HIV-1 and influenza, standard neutralizing antibodies are often ineffective or easily evaded as their targets are masked or rapidly mutated. This has thwarted efforts to both prevent and treat HIV-1 infections and means that entirely new formulations are required to vaccinate against influenza each year. However, some rare antibodies isolated from infected individuals confer broad and potent neutralization. A subset of these broadly neutralizing antibodies possesses a long complementarity-determining 3 region of the immunoglobulin heavy chain (CDR H3). This feature generates unique antigen binding site configurations that can engage conserved but otherwise inaccessible epitope targets thus neutralizing many viral variants. Remarkably, ultralong CDR H3s are a common feature of the cow antibody repertoire and are encoded by a single variable, diversity, joining (VDJ) recombination that is extensively diversified prior to antigen exposure. Recently, it was shown that cows rapidly generate a broadly neutralizing response upon exposure to HIV-1 and this is primarily mediated by these novel ultralong antibody types. This review summarises the current knowledge of these unusual CDR H3 structures and discusses their known and potential future uses.

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Section: The Long Cdr H3 Is Generated Inefficiently In Humansmentioning

confidence: 99%

Broadly Neutralizing Bovine Antibodies: Highly Effective New Tools against Evasive Pathogens?

Burke

Stockley

Boyes

2020

Viruses

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“…They predominantly overlap with the binding site for CD81 that is composed of (1) a conserved N-terminal region (residues 412–423, epitope I), (2) a front layer region comprising of a short α-helix (aa428–446) and (3) an adjacent loop named CD81-binding loop (aa519–535). Structural characterization of bNAb fragments in a complex with soluble E2 ectodomains or ectodomain fragments revealed that a number of potent cross-neutralizing bnAbs—often derived from the VH 1-69 gene family—recognize a complex conformation-sensitive epitope, called complex “front layer epitope” (CFL) [ 43 , 44 , 45 , 46 ]. However, not all Abs targeting one of these epitopes neutralize HCV infection, although similar contact residues are employed [ 47 , 48 , 49 ].…”

Section: The E2 Glycoproteinmentioning

confidence: 99%

“…The igVR is not defined by electron density in the complex structures with the 2A12 Fab, in the AR3C Fab-E2 core complex structure it adopts a disulfide-constrained loop (C 569 -C 581 ) [ 43 ]. More recently, Flyak and coworkers described four structures of the full-length E2 ectodomain: three from genotype 1b complexed with Fab fragments of the bnAb HEPC3, HEPC76 and AR3X respectively, and one of a genotype 1a ectodomain engaged in a ternary complex with Fab fragments of the bnAbs HEPC46 and HEPC3 [ 44 , 46 ]. Although the four E2 ectodomain structures are derived from different strains, they are very similar in their core region and feature common disulfide bond connectivity [ 44 , 46 ] ( Table 1 ).…”

Section: The E2 Glycoproteinmentioning

confidence: 99%

“…More recently, Flyak and coworkers described four structures of the full-length E2 ectodomain: three from genotype 1b complexed with Fab fragments of the bnAb HEPC3, HEPC76 and AR3X respectively, and one of a genotype 1a ectodomain engaged in a ternary complex with Fab fragments of the bnAbs HEPC46 and HEPC3 [ 44 , 46 ]. Although the four E2 ectodomain structures are derived from different strains, they are very similar in their core region and feature common disulfide bond connectivity [ 44 , 46 ] ( Table 1 ). Of note, the common disulfide bond patterns of the ectodomain structures differ from the one observed in an E2 core fragment of the genotype 1a strain in complex with the bnAb HEPC3 Fab [ 44 ].…”

Section: The E2 Glycoproteinmentioning

confidence: 99%

“…Epitope I (residues Q 412 to N 423 ) adopts two distinct conformations in the ectodomain structures from isolate 1a53 and 1b09 and a third conformation in the HEPC74 complex of isolate 1b09 with clear electron density only for residues G 418 to N 423 [ 44 ]. In contrast, clear electron density was observed for residues W 420 to N 423 in the AR3X complex structure, pointing in a different direction [ 46 ]. In the E2 isolate 1a53 core structure clear electron density was observed only for residues L 422 to N 423 [ 44 ].…”

Section: The E2 Glycoproteinmentioning

confidence: 99%

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HCV Glycoprotein Structure and Implications for B-Cell Vaccine Development

Stroh

Krey

2020

IJMS

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Despite the approval of highly efficient direct-acting antivirals in the last decade Hepatitis C virus (HCV) remains a global health burden and the development of a vaccine would constitute an important step towards the control of HCV. The high genetic variability of the viral glycoproteins E1 and E2, which carry the main neutralizing determinants, together with their intrinsic structural flexibility, the high level of glycosylation that shields conserved neutralization epitopes and immune evasion using decoy epitopes renders the design of an efficient vaccine challenging. Recent structural and functional analyses have highlighted the role of the CD81 receptor binding site on E2, which overlaps with those neutralization epitopes within E2 that have been structurally characterized to date. This CD81 binding site consists of three distinct segments including “epitope I”, “epitope II” and the “CD81 binding loop”. In this review we summarize the structural features of the HCV glycoproteins that have been derived from X-ray structures of neutralizing and non-neutralizing antibody fragments complexed with either recombinant E2 or epitope-derived linear peptides. We focus on the current understanding how neutralizing antibodies interact with their cognate antigen, the structural features of the respective neutralization epitopes targeted by nAbs and discuss the implications for informed vaccine design.

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Prospects for developing an Hepatitis C virus E1E2‐based nanoparticle vaccine

Toth

Andrianov

Fuerst

2023

Reviews in Medical Virology

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Globally, more than 58 million people are chronically infected with Hepatitis C virus (HCV) with 1.5 million new infections occurring each year. An effective vaccine for HCV is therefore a major unmet medical and public health need. Since HCV rapidly accumulates mutations, vaccines must elicit the production of broadly neutralising antibodies (bnAbs) in a reproducible fashion. Decades of research have generated a number of HCV vaccine candidates. Based on the available data and research through clinical development, a vaccine antigen based on the E1E2 glycoprotein complex appears to be the best choice, but robust induction of humoral and cellular responses leading to virus neutralisation has not yet been achieved. One issue that has arisen in developing an HCV vaccine (and many other vaccines as well) is the platform used for antigen delivery. The majority of viral vaccine trials have employed subunit vaccines. However, subunit vaccines often have limited immunogenicity, as seen for HCV, and thus multiple formats must be examined in order to elicit a robust anti‐HCV immune response. Nanoparticle vaccines are gaining prominence in the field due to their ability to facilitate a controlled multivalent presentation and trafficking to lymph nodes, where they can interact with both arms of the immune system. This review discusses the potential for development of a nanoparticle‐based HCV E1E2 vaccine, with an emphasis on the potential benefits of such an approach along with the major challenges facing the incorporation of E1E2 into nanoparticulate delivery systems and how those challenges can be addressed.

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An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein

Cited by 24 publications

References 32 publications

Broadly Neutralizing Bovine Antibodies: Highly Effective New Tools against Evasive Pathogens?

Broadly Neutralizing Bovine Antibodies: Highly Effective New Tools against Evasive Pathogens?

HCV Glycoprotein Structure and Implications for B-Cell Vaccine Development

Prospects for developing an Hepatitis C virus E1E2‐based nanoparticle vaccine

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