Project

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Study of the HIV-specific naïve B cell repertoire and Fc contribution of broadly neutralizing antibodies as tools for HIV-vaccine improvement

Applicant Bianchi Matteo
Number 160970
Funding scheme Return CH Advanced Postdoc.Mobility
Research institution Institut für Medizinische Virologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Infectious Diseases
Start/End 01.07.2018 - 31.03.2019
Approved amount 76'673.00
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Keywords (5)

HIV; Broadly neutralizing antibody; Naïve B cells; B-cell receptor; Next Generation Sequencing

Lay Summary (Italian)

Lead
La ricerca sui cosiddetti anticorpi ampiamente neutralizzanti (broadly neutralizing antibodies, bnAbs) dimostra che la comunità di ricerca sull’HIV non é tutt’ora capace di generare una produttiva risposta immunitaria neutralizzante tramite vaccinazione. Una mancanza di conoscenza risiede al livello dei linfociti B nativi; più precisamente su come ingaggiarne il recettore (BCR) per stimolarne la proliferazione e la differenziazione in cellule capaci di produrre bnAbs.
Lay summary

Obiettivi
L’obiettivo principale di questo progetto é di studiare, in individui che non sono stati esposti all’HIV, la popolazione di linfociti B nativi che può essere stimolata da proteine membranali (Env) tramite caratterizzazione di specificità e diversità dei recettori BCR che rispondono allo stimolo. Linfociti B nativi che riconoscono epitopi virali esistono, altrimenti non ci sarebbe la produzione di anticorpi neutralizzanti e non-neutralizzanti. Ma quali sono le caratteristiche di queste cellule capaci di rispondere a proteine membranali Env? È possibile distinguere linfociti B precursori di bnAbs conosciuti?

Importanza del progetto
Con questo progetto un sistema d’identificazione di linfociti B nativi rispondenti ad antigeni Env del virus HIV sarà creato, e il loro profilo genetico caratterizzato. La risultante banca dati potrà poi essere utilizzata per l’interpretazione di dati di Next Generation Sequencing (NGS) ottenuti da pazienti infettati o vaccinati. Tale analisi aiuterà a capire i primi processi della generazione di anticorpi specifici contro le proteine membranali Env, e darà indicazioni per nuove generazioni di vaccini.

Direct link to Lay Summary Last update: 17.09.2016

Lay Summary (English)

Lead
Research on broadly neutralizing antibodies (bnAbs) shows that the human immunodeficiency virus (HIV)-research community is still not in a position to elicit a productive neutralizing antibody response by immunization. A large knowledge gap resides at the naïve B-cell level; more precisely on how to engage the precursor B-cell receptor (BCR) in order to efficiently induce proliferation, and how to differentiate B cells to generate such anti-HIV bnAbs.
Lay summary

Goals
The main goal of this project is to investigate the naïve B-cell population that can be activated by HIV envelope (Env) proteins by characterizing the responding BCR specificities and diversity in individuals who have not been exposed to the virus. Naïve B-cells that can recognize HIV epitopes exist; otherwise no neutralizing and non-neutralizing antibodies would be developed. But what are the characteristics of this HIV Env-responding cell population? Is it possible to already distinguish naïve B cell of known bnAbs?

Significance of the project
With this project, a system allowing identification of antigen-responding naïve B cells will be created, and the genetic profile of these cells characterized. The created reference database could than be used to interpret Next Generation Sequencing (NGS) data obtained from naturally infected or immunized individuals, will help the understanding of early processes during the generation of the HIV Env-specific antibody response, and will give indications for new vaccines-design.

Direct link to Lay Summary Last update: 17.09.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Vaccine-Induced Protection from Homologous Tier 2 SHIV Challenge in Nonhuman Primates Depends on Serum-Neutralizing Antibody Titers
Pauthner Matthias G., Nkolola Joseph P., Havenar-Daughton Colin, Murrell Ben, Reiss Samantha M., Bastidas Raiza, Prévost Jérémie, Nedellec Rebecca, von Bredow Benjamin, Abbink Peter, Cottrell Christopher A., Kulp Daniel W., Tokatlian Talar, Nogal Bartek, Bianchi Matteo, Li Hui, Lee Jeong Hyun, Butera Salvatore T., Evans David T., Hangartner Lars, Finzi Andrés, Wilson Ian A., Wyatt Richard T., Irvine Darrell J., et al. (2019), Vaccine-Induced Protection from Homologous Tier 2 SHIV Challenge in Nonhuman Primates Depends on Serum-Neutralizing Antibody Titers, in Immunity, 50(1), 241-252.e6.
Electron-Microscopy-Based Epitope Mapping Defines Specificities of Polyclonal Antibodies Elicited during HIV-1 BG505 Envelope Trimer Immunization
Bianchi Matteo, Turner Hannah L., Nogal Bartek, Cottrell Christopher A., Oyen David, Pauthner Matthias, Bastidas Raiza, Nedellec Rebecca, McCoy Laura E., Wilson Ian A., Burton Dennis R., Ward Andrew B., Hangartner Lars (2018), Electron-Microscopy-Based Epitope Mapping Defines Specificities of Polyclonal Antibodies Elicited during HIV-1 BG505 Envelope Trimer Immunization, in Immunity, 49(2), 288-300.e8.

Collaboration

Group / person Country
Types of collaboration
Prof. Lars Hangartner, The Scripps Research Institute United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Andrew Ward, The Scripps Research Institute United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
6 Katalog der datierten Handschriften in der Schweiz 01.10.1975 Project funding

Abstract

The main goal of this proposal is to investigate the naïve B cell population that can be activated by HIV envelope proteins by characterizing the responding B cell receptor (BCR) specificities and diversity in individuals who have not been exposed to the virus. Naïve B cells that can recognize HIV epitopes exist, otherwise no neutralizing and non-neutralizing antibodies would be developed. But what are the characteristics of this HIV Env-responding cell population? Is it possible to already distinguish naïve B cell of known bnAbs? In order to answer these questions, naïve B cells will be purified from HIV-negative donors, and then activated with different HIV antigens and co-stimuli. Engagement of these B cells will be analyzed by early to late activation markers, and activated cells will be isolated. From there, two parallel lines of research will be conducted. On the first line, all BCR of the responding B cells will be analyzed by Next Generation Sequencing (NGS) to obtain the responding repertoire. In parallel, a subset of the responding B cells will be clonally expanded by the help of a robot to obtain the phenotype of a large number of these antibodies. The use of a robot will result in high throughput heavy/light chain-linked BCR cloning and will allow enzyme-linked immunosorbent assay (ELISA) and neutralization assays to evaluate the properties of the produced antibodies. Of particular interest will be the assessment of the HIV Env epitopes recognized and possible polyreactivities. With this approach, a database allowing identification of HIV Env-responding naïve B cells will be created, that could be used to monitor natural infections or immunizations in order to improve antigen design for future vaccine development.Additionally, the role of bnAbs effector functions is also planned to be elucidated. It is largely debated whether bnAbs need effector functions additionally to their neutralizing capacity. Fc function will therefore be studied in vivo by comparing wild type to corresponding Fc-deficient bnAbs. It is intended to compare first generation HIV bnAbs, like b12, to more recent and potent bnAbs, like the PGT121. Titration of such antibodies should give more insight about the role and weight of Fc and neutralization by bnAbs.
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