Conformational Plasticity in Broadly Neutralizing HIV-1 Antibodies Triggers Polyreactivity

• Published in: Cell reports (Cambridge) 2018-05, Vol.23 (9), p.2568-2581
• Main Authors: Prigent, Julie, Jarossay, Annaëlle, Planchais, Cyril, Eden, Caroline, Dufloo, Jérémy, Kök, Ayrin, Lorin, Valérie, Vratskikh, Oxana, Couderc, Thérèse, Bruel, Timothée, Schwartz, Olivier, Seaman, Michael S., Ohlenschläger, Oliver, Dimitrov, Jordan D., Mouquet, Hugo
• Format: Article
• Language: English
• Subjects: Adaptive immunology; Antibodies, Neutralizing - chemistry; Antibodies, Neutralizing - immunology; antibody; Autoantigens - immunology; autoreactivity; B cells; Binding Sites, Antibody; Cross Reactions - immunology; env Gene Products, Human Immunodeficiency Virus - metabolism; HIV Antibodies - chemistry; HIV Antibodies - immunology; HIV Antigens - immunology; HIV-1; HIV-1 - immunology; Humans; Hydrophobic and Hydrophilic Interactions; Immunoglobulin Fab Fragments - immunology; Immunology; Life Sciences; Neutralization Tests; polyreactivity; Protein Conformation; Thermodynamics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.04.101

Human high-affinity antibodies to pathogens often recognize unrelated ligands. The molecular origin and the role of this polyreactivity are largely unknown. Here, we report that HIV-1 broadly neutralizing antibodies (bNAbs) are frequently polyreactive, cross-reacting with non-HIV-1 molecules, including self-antigens. Mutating bNAb genes to increase HIV-1 binding and neutralization also results in de novo polyreactivity. Unliganded paratopes of polyreactive bNAbs with improved HIV-1 neutralization exhibit a conformational flexibility, which contributes to enhanced affinity of bNAbs to various HIV-1 envelope glycoproteins and non-HIV antigens. Binding adaptation of polyreactive bNAbs to the divergent ligands mainly involves hydrophophic interactions. Plasticity of bNAbs’ paratopes may, therefore, facilitate accommodating divergent viral variants, but it simultaneously triggers promiscuous binding to non-HIV-1 antigens. Thus, a certain level of polyreactivity can be a mark of adaptable antibodies displaying optimal pathogens’ recognition. [Display omitted] •Most HIV-1 bNAbs are polyreactive and often cross-react with self-antigens•Polyreactivity of bNAbs involves hydrophobic interactions•Mutations enhancing HIV-1 bNAbs’ capacities also induce de novo polyreactivity•Enhanced neutralization and polyreactivity co-emerge by antibody conformational flexibility HIV-1 bNAbs are frequently polyreactive and bind to self-antigens. Prigent et al. show that specific mutations in bNAbs that enhance their neutralizing capacity create an intrinsic structural flexibility of the antibody paratope. This promotes the conformational adaptation that facilitates binding to HIV-1 variants and polyreactivity to topologically distinct non-HIV-1 molecules.