# Developing Immunogens to Elicit Broadly Neutralizing anti-HIV-1 Antibodies

> **NIH NIH P01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2024 · $1,724,205

## Abstract

PROJECT SUMMARY
SHIV-infected rhesus macaques (RMs) develop HIV-1 broadly neutralizing antibodies (bNAbs) via Env-antibody
(Ab) co-evolutionary pathways that recapitulate events in HIV-1 infected humans. This includes the frequency of
bNAb induction, the viral epitopes targeted, and the immunogenetic and structural features of bNAbs, which are
all similar in RMs and humans. Thus, we hypothesize that SHIV-infected RMs can serve as a guide for HIV-1
immunogen design, allowing for an iterative analysis of Env-Ab coevolution and the design of lineage-based
immunogens in a way not previously possible. There are three main hurdles to inducing bNAbs in monkeys and
humans: (i) efficient priming of rare HIV bNAb germline (GL) B cells; (ii) immunofocused boosting of B cell
responses targeting conserved bNAb epitopes and away from off-target epitopes; and (iii) affinity-guided,
antigen-driven maturation of B cell lineages. We hypothesize that we can find solutions to all of these inter-
related challenges by using the SHIV animal model to guide the design of new priming and boosting immunogens
that target V3 glycan and CD4 binding site (CD4bs) bNAb epitopes. Specifically, we will work with the Bjorkman
laboratory and Core A to incorporate selective glycan deletions and other GL-targeted mutations into our SHIV
designs to immunofocus early B cell responses to the V3 glycan and CD4bs bNAb epitopes. We will also develop
lineage-maturing SHIVs designed to boost bNAb responses that are primed by GL-targeted Env trimer
nanoparticles or mRNA-LNPs vaccines and then allow the natural process of Env-Ab coevolution in the setting
of an evolving SHIV quasispecies to affinity-mature the primed bNAb lineages to neutralization breath. In both
instances, we will decipher SHIV Env-Ab co-evolution where, unlike in humans, we can analyze multiple animals
infected by the same SHIVs and identify maturation pathways that are shared among different outbred animals.
We hypothesize that such analyses, when combined with work by the Bjorkman and Nussenzweig laboratories,
can provide a “blueprint” for lineage-based immunogens by identifying key Env variants that bind bNAb
precursors and intermediate stage antibodies required for affinity maturation. In the last year of the Project, we
will determine the protective capacity of the best lineage-based protein and/or mRNA-LNP immunization regimen
against a heterologous tier 2 SHIV challenge. Throughout these studies, we will work closely with the Bjorkman
and Nussenzweig laboratories to assess the impact of antibody feedback on bNAb development in both
vaccinated and SHIV-infected RMs.

## Key facts

- **NIH application ID:** 10810306
- **Project number:** 2P01AI100148-11
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Pamela J Bjorkman
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,724,205
- **Award type:** 2
- **Project period:** 2013-02-10 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10810306

## Citation

> US National Institutes of Health, RePORTER application 10810306, Developing Immunogens to Elicit Broadly Neutralizing anti-HIV-1 Antibodies (2P01AI100148-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10810306. Licensed CC0.

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