[R01] Antigen recognition and activation of HIV-specific B cell antigen receptors
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2029-07-31
Importo max: 1.028.461 EUR
Paese: US
Descrizione
Abstract
B cell antigen receptor (BCR)-antigen interactions that govern the activation of B cells with a pre-vaccinated B-
cell repertoire are not clearly defined for HIV-1 broadly neutralizing antibody (bnAb) lineages. Our recent studies
show that B cell activation is dependent on antigen-binding association rate and not on the overall affinity (KD
value), indicating that antigen sensing has a kinetic component. In this renewal application we will expand our
studies to define the biophysical properties of antigen binding and cell surface interactions that lead to activation
of B cells expressing germline precursor or early lineage intermediate BCRs of different HIV-1 bnAb specificities
(CD4-binding site, V3-glycan). We will build upon our hypothesis that the exposure of the BCR to antigens that
bind with enhanced association kinetics leads to re-organization and localization of receptors with co-stimulatory
molecules on the B cell membrane, and together these parameters contribute to B cell activation and selection
of functional mutations that lead to the development of neutralization breadth. In Aim 1, we will use Ramos B
cell lines and purified BCR-complexes to perform biophysical interactions and structural analyses to define the
properties of BCR-antigen interactions that govern signaling and activation of bnAb precursors and selection of
functional mutations following immunizations in relevant knock-in mouse models. In Aim 2, we will define the
role of the CH1 domain in class-specific antigen sensing, and the role of the immunoreceptor coupling and
organization motifs (ICOM) interactome in the regulation and activation of HIV-specific BCRs on naïve and
memory-type B cells. In Aim 3, we will define priming and boosting immunogen activation ranges for bnAb
lineages to multiple Envelope targets and develop lineage-specific prime/boost combinations for testing in
physiologically relevant mouse models. The overall objective of this grant is to bridge quantitative measurements
of antigen-activated biophysical/biochemical events and B cell surface organization/interactions to optimal B cell
priming and boosting in relevant ex-vivo and in-vivo B cell activation models, and to use this information for
facilitating design and selection of immunogens for HIV-1 vaccine development.
Istituzione: DUKE UNIVERSITY
PI: S. Munir ALAM, Laurent Karl Verkoczy
Progetto: 5R01AI145656-08
Settori: National Institute of Allergy and Infectious Diseases
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