# HIV-1 Q23.17 Env: Engineering a novel immunogen to elicit broadly neutralizing antibodies

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $804,299

## Abstract

PROJECT SUMMARY
In humans, neutralizing antibodies elicited by HIV-1 coevolve with viral Envs in distinctive patterns, in some
cases acquiring substantial breadth. We found that primary HIV-1 Envs, when expressed by simian-human
immunodeficiency viruses (SHIVs) in 22 rhesus macaques (RMs), elicited patterns of Env-Ab coevolution
strikingly similar to those in humans (Science 371:eabd2638, 2021). This included conserved immunogenetic,
structural and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions and
deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a
208-strain panel, revealed a V2-apex mode of recognition like that of human bNAbs PGT145 and PCT64. We
subsequently expanded this study to include 150 RMs infected by SHIVs bearing any of 15 different primary
HIV-1 Envs; 24 (16%) of these animals developed bNAbs targeting conserved V2 apex, V3 glycan, CD4bs or
fusion peptide epitopes. The V2 apex was the most common bNAb epitope targeted in RMs. We concluded that
Env-Ab coevolution in RMs recapitulates developmental features of human bNAbs and may serve to guide and
accelerate HIV-1 immunogen design for humans. From these preclinical data, we identified HIV-1 Q23.17 Env
as the immunogen that most consistently elicited V2 apex bNAbs. Here, we propose to elucidate the Env-Ab
coevolutionary pathways by which HIV-1 Q23.17 Env selectively primes, boosts and affinity-matures V2 apex
bNAb responses and to translate these findings into an all-SOSIP Env trimer vaccine regimen consisting of a
germline-targeted Q23.17 Env prime followed by boosts with lineage-designed Q23.17 Env “imunotypes”
capable of affinity-maturing B cells to achieve breadth. Specific aims are: (i) to decipher molecular pathways of
Env-Ab coevolution in SHIV.Q23.17 infected RMs that lead to the development of V2 apex bNAbs, including the
identification of inferred germline bNAb precursors and lineage intermediates and corresponding Env
immunotypes that bind to them; (ii) to use mammalian display saturation mutagenesis to generate Q23.17 Env
variants that exhibit enhanced binding affinity to multiple rhesus germline V2 apex bNAb B cell precursors and
to engineer these Envs as nanoparticle-delivered SOSIP trimers; (iii) to test the immunogenicity of germline-
targeted and lineage-designed Q23.17 Env SOSIP trimers in V2 apex bNAb UCA knockin mice and outbred
RMs and to advance the most promising combinations to a proof-of-concept preclinical vaccine trial in RMs; and
(iv) to conduct an appropriately powered preclinical vaccine trial in 28 RMs to test the hypothesis that reverse-
engineered, B lineage-designed Q23.17 SOSIP Env trimers can prime, boost and affinity mature V2 apex bNAb
responses in RMs to an extent that is superior to conventional SOSIP Env immunogens and that protects RMs
from heterologous virus challenge. The significance of these studies could be far-reaching: if we can d...

## Key facts

- **NIH application ID:** 10828374
- **Project number:** 5R01AI165080-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** GEORGE M SHAW
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $804,299
- **Award type:** 5
- **Project period:** 2021-06-23 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10828374

## Citation

> US National Institutes of Health, RePORTER application 10828374, HIV-1 Q23.17 Env: Engineering a novel immunogen to elicit broadly neutralizing antibodies (5R01AI165080-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10828374. Licensed CC0.

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