# Project 2 - B cell antigen receptor structure and antigen-BCR interaction dynamics

> **NIH NIH U54** · DUKE UNIVERSITY · 2022 · $428,073

## Abstract

Project Summary/Abstract – Project 2
Structural analysis of how HIV-1 Envelope (Env) interacts with antigen receptor on B cells (BCR) to initiate B cell
signaling and activation is key to understanding antibody responses against HIV protein immunogens. Recent
studies of the organization of the BCR complex on the cell membrane supports a model in which BCRs exist in
different signaling states that require definition in structural terms. We hypothesize the following distinct states
of the BCR complex – 1) “signaling-inhibited’, 2) signaling-competent and 3) ‘signaling-disrupted’. Advances in
HIV-1 Env design including those that target germline precursors have led to the development of Env
immunogens as potential candidates for HIV vaccines. How BCRs of distinct specificities and signaling-states
interact with Env protein immunogens that trigger signaling and activate these cells are not clearly understood.
The overall goal of the project is to define BCR-antigen structures with specificity of broadly neutralizing
antibodies (bnAb), non-canonical glycan-binding bnAbs and to-be isolated autologous neutralizing antibodies
(anAb). In this project, we will perform biophysical/biochemical, structural and immunological analyses to define
properties of HIV Env-BCR interactions for activation of B cells expressing bnAb or germline precursor BCRs. In
Aim 1, we will perform Cryo-EM and molecular dynamic simulation analyses to define structures of antigen-
liganded BCR complex with specificities of autologous or broadly neutralizing HIV-1 antibodies. In addition, we
will define the structures of BCRs with specificities of glycan-binding bnAbs that present non-canonical Fab
configurations (I-shaped versus Y-shaped). In Aim 2, we will study specificity of bnAb precursors with disrupted
proximal signaling and determine whether such BCRs show distinct cell surface interaction dynamics with Env
proteins. Studies in Aim 3 will define antigen-BCR interaction parameters that enhance B cell signaling, antigen
internalization and MHC class II-peptide presentation of Env protein eptiopes. The proposed studies will bridge
high-resolution structures and antigen-BCR interaction dynamics to B cell signaling and activation. The long-
range goals of these studies are to provide the mechanistic basis for understanding the humoral response to
HIV-1 vaccines and guide development of strategies to enhance vaccine efficacy.

## Key facts

- **NIH application ID:** 10506668
- **Project number:** 1U54AI170752-01
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** S. Munir ALAM
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $428,073
- **Award type:** 1
- **Project period:** 2022-06-14 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10506668

## Citation

> US National Institutes of Health, RePORTER application 10506668, Project 2 - B cell antigen receptor structure and antigen-BCR interaction dynamics (1U54AI170752-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10506668. Licensed CC0.

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