# Expansion and targeted maturation of germline HIV-1 bNAb-associated BCRs

> **NIH NIH P01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $1,803,472

## Abstract

ABSTRACT
The elicitation of potent and broad HIV-1 neutralizing antibodies (bNAbs) by immunization has been one of the
major goals of HIV-1 vaccine research since the beginning of the HIV/AIDS epidemic. During the past decade,
significant technical and conceptual advances have enabled the isolation and detailed characterization of a
plethora of new bNAbs from HIV-1-infected subjects. The structural characterization of such antibodies,
combined with information on their ontogenies, has vastly improved our understanding of how such antibodies
are generated during natural infection, leading to new hypotheses regarding how to elicit them by
immunization. Our HIVRAD Program grant aims at testing novel reagents and prime-boost immunization
schemes to elicit VRC01-class bNAbs, which are among the most broad and potent HIV-1 neutralizing
antibodies known and display impressive protective potential in animal studies. However, the development of
VRC01-class bNAbs by immunization will necessitate overcoming several obstacles. A successful
immunization scheme will likely require, at a minimum, the availability of novel immunogens to initiate and
guide the bNAb maturation process, the development of strategies that will minimize the expansion of
competing off-target B cells, the development of optimal ‘boost’ Env immunogens to guide the appropriate
antibody maturation, and the supply of sustained T helper responses. Here we propose to test concepts, not
tested previously, that we have developed to directly address these issues. One new strategy we will evaluate
is based on the use of anti-idiotypic monoclonal antibodies (aiMAbs) we generated against germline VRC01-
class BCRs. Our preliminary data suggest that these aiMAbs specifically expand naive B cells that express
germline VRC01-class B cell receptors (BCRs) and that these cells enter the germinal center (GC) reaction
and expand even further upon Env immunization. One obvious advantage is a greater expansion in GC of
desired B cells over ‘off target’ B cells, thus improving our chance to induce the correct set of somatic
hypermutations during the boost immunizations. Thus, immunizations with aiMAbs will be followed by booster
immunizations with an Env specifically designed to engage germline VRC01-class BCRs (426c Core) and then
with Envs expressing key steric blocks for VRC01-class antibodies. In this regard we highlight the fact that
since our initial submission we generated new information which indicates that the 426c Core elicits antibodies
that bypass glycans on the conserved N-linked glycosylation site N276, which are one of the major obstacles
preventing germline VRC01-class antibodies from becoming broadly neutralizing. We will test our proposed
strategy by an iterative approach with well-integrated experiments. The preliminary data we present support
our overall approach.

## Key facts

- **NIH application ID:** 9832175
- **Project number:** 5P01AI138212-02
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Leonidas Stamatatos
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,803,472
- **Award type:** 5
- **Project period:** 2018-12-06 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9832175

## Citation

> US National Institutes of Health, RePORTER application 9832175, Expansion and targeted maturation of germline HIV-1 bNAb-associated BCRs (5P01AI138212-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9832175. Licensed CC0.

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