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Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies.

ABSTRACT: A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb. Two autologous neutralizing antibody lineages selected for virus escape mutations and consequently allowed initiation and affinity maturation of a V3-glycan bnAb lineage. The nucleotide substitution required to initiate the bnAb lineage occurred at a low-probability site for activation-induced cytidine deaminase activity. Cooperation of B cell lineages and an improbable mutation critical for bnAb activity defined the necessary events leading to breadth in this V3-glycan bnAb lineage. These findings may, in part, explain why initiation of V3-glycan bnAbs is rare, and suggest an immunization strategy for inducing similar V3-glycan bnAbs.

SUBMITTER: Bonsignori M

PROVIDER: S-EPMC5562350 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies.

Bonsignori Mattia M Kreider Edward F EF Fera Daniela D Meyerhoff R Ryan RR Bradley Todd T Wiehe Kevin K Alam S Munir SM Aussedat Baptiste B Walkowicz William E WE Hwang Kwan-Ki KK Saunders Kevin O KO Zhang Ruijun R Gladden Morgan A MA Monroe Anthony A Kumar Amit A Xia Shi-Mao SM Cooper Melissa M Louder Mark K MK McKee Krisha K Bailer Robert T RT Pier Brendan W BW Jette Claudia A CA Kelsoe Garnett G Williams Wilton B WB Morris Lynn L Kappes John J Wagh Kshitij K Kamanga Gift G Cohen Myron S MS Hraber Peter T PT Montefiori David C DC Trama Ashley A Liao Hua-Xin HX Kepler Thomas B TB Moody M Anthony MA Gao Feng F Danishefsky Samuel J SJ Mascola John R JR Shaw George M GM Hahn Beatrice H BH Harrison Stephen C SC Korber Bette T BT Haynes Barton F BF

Science translational medicine 20170301 381

A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among ...[more]

PMID: 28298420

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Project description:IntroductionA primary focus of HIV-1 vaccine development is the activation of B cell receptors for naïve or precursor broadly neutralizing antibodies (bnAbs), followed by expansion and maturation of bnAb B cell lineage intermediates leading to highly affinity-matured bnAbs. HIV-1 envelope (Env) encodes epitopes for bnAbs of different specificities. Design of immunogens to induce bnAb precursors of different specificities and mature them into bnAb status is a goal for HIV-1 vaccine development. We review vaccine strategies for bnAb lineages development and highlight the immunological barriers that these strategies must overcome to generate bnAbs.MethodsWe provide perspectives based on published research articles and reviews.DiscussionThe recent Antibody Mediated Protection (AMP) trial that tested the protective efficacy of one HIV-1 Env bnAb specificity demonstrated that relatively high levels of long-lasting serum titers of multiple specificities of bnAbs will be required for protection from HIV-1 transmission. Current vaccine efforts for induction of bnAb lineages are focused on immunogens designed to expand naïve HIV-1 bnAb precursor B cells following the recent success of vaccine-induction of bnAb precursor B cells in macaques and humans. BnAb precursor B cells serve as templates for priming-immunogen design. However, design of boosting immunogens for bnAb maturation requires knowledge of the optimal immunogen design and immunological environment for bnAb B cell lineage affinity maturation. BnAb lineages acquire rare genetic changes as mutations during B cell maturation. Moreover, the immunological environment that supports bnAb development during HIV-1 infection is perturbed with an altered B cell repertoire and dysfunctional immunoregulatory controls, suggesting that in normal settings, bnAb development will be disfavoured. Thus, strategies for vaccine induction of bnAbs must circumvent immunological barriers for bnAb development that normally constrain bnAb B cell affinity maturation.ConclusionsA fully protective HIV-1 vaccine needs to induce durable high titers of bnAbs that can be generated by a sequential set of Env immunogens for expansion and maturation of bnAb B cell lineages in a permitted immunological environment. Moreover, multiple specificities of bnAbs will be required to be sufficiently broad to prevent the escape of HIV-1 strains during transmission.

Dataset Information

Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies.

Publications

Staged induction of HIV-1 glycan-dependent broadly neutralizing antibodies.

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