Abstract
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.
Highlights
Jawed vertebrates generate millions of B cells every day, each of which expresses a unique antigen receptor, either on the cell surface as a B-cell receptor (BCR) or secreted in the form of an antibody (Ab)
The framework regions (FRs) are associated with structural stability and act as a scaffold for the Ab structure, whereas the complementarity-determining regions (CDRs) are hyper-mutable and form the antigen binding site that interacts with a specific region of the antigen
This review focuses on such BNAbs, and in particular on their extended CDR H3, a striking feature that has been shown to facilitate the broad neutralization of HIV-1 and other viruses
Summary
Jawed vertebrates generate millions of B cells every day, each of which expresses a unique antigen receptor, either on the cell surface as a B-cell receptor (BCR) or secreted in the form of an antibody (Ab). The ability of B cells to discriminate the affinity of their unique receptor for an antigen efficiently ensures that advantageous mutations are favoured, with a concomitant improvement in antigen binding [10,11] Owing to their limited number of Ig gene segments, cows (Bos taurus) depend upon this AID-induced SHM to expand their limited pre-immune Ab repertoire prior to antigen exposure [12]. Some viruses, including HIV-1, influenza and Ebola, utilise a multitude of evasive tools to circumvent the host immune system Some of these pathogens have an enormous variety of globally circulating strains, can rapidly diversify their surface antigens, or occlude epitopes that are evolutionary conserved, to limit their immunogenicity. We will summarise the current knowledge of these unusual CDR H3 structures in humans and cows, whilst exploring differences in the diversification mechanisms between these species, and discuss future strategies for the utilisation of the novel properties of BNAbs
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
