# Antigen recognition and activation of HIV-specific B cell antigen receptors

> **NIH NIH R01** · DUKE UNIVERSITY · 2024 · $1,106,519

## Abstract

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.

## Key facts

- **NIH application ID:** 11007935
- **Project number:** 2R01AI145656-06
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** S. Munir ALAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,106,519
- **Award type:** 2
- **Project period:** 2019-03-20 → 2029-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11007935

## Citation

> US National Institutes of Health, RePORTER application 11007935, Antigen recognition and activation of HIV-specific B cell antigen receptors (2R01AI145656-06). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11007935. Licensed CC0.

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