# Harnessing SHIVs and Sequential Immunization to Elicit V3 Glycan-Targeted bNAbs against HIV-1

> **NIH NIH F30** · UNIVERSITY OF PENNSYLVANIA · 2024 · $36,512

## Abstract

PROJECT SUMMARY/ABSTRACT
Over 1.8 million people are newly infected with HIV each year, and despite decades of research since the onset
of the AIDS pandemic, we still do not have an efficacious vaccine. A major goal of vaccine design is the elicitation
of broadly neutralizing antibodies (bNAbs), which target highly conserved epitopes on the HIV Envelope
glycoprotein (Env) and block viral entry into host cells, thereby conferring protection against infection with a wide
variety of strains. One such conserved bNAb epitope is the V3-glycan patch, which is the focus of this application.
BNAbs arise naturally in some chronically infected patients as a result of prolonged antibody-virus coevolution
but have never been induced by vaccination in humans. A roadblock in previous vaccination studies was that
the heavy glycosylation of Env leads to concealment of bNAb epitopes, and as such, wildtype Env is not a viable
immunogen. To overcome this challenge, modified Envs have been engineered by removing several glycans in
an attempt to expose the underlying bNAb epitopes, and these have shown moderate success at stimulating
bNAb precursor B cells. However, these bNAb precursors generally have poor neutralization activity and thus
do not endow protective immunity. Attempts have been made to shepherd bNAb precursors into bona fide bNAbs
via immunization with a series of decreasingly engineered Env proteins, a concept termed sequential
immunization, though this has yielded inconsistent results. As such, the outstanding problem which this proposal
seeks to address is: how to boost V3-glycan-targeting bNAb precursors to guide their maturation into bNAbs with
high neutralization breadth and potency. An innovative two-pronged approach will be used to tackle this problem.
In Aim 1, the evolution of a bNAb precursor-like lineage will be rigorously dissected using an immunoglobulin
knockin mouse model. In Aim 2, antibody-virus coevolution will be studied in rhesus macaques immunized with
engineered Env immunogens and subsequently infected with a related chimeric Simian-Human
Immunodeficiency Virus. Together, the results will inform the design of novel immunogens and vaccination
regimens to elicit V3-glycan-targeted bNAbs in animals and potentially humans.
 This work will be performed by MD-PhD student Ashwin Skelly under the mentorship and guidance of Sponsor
Dr. Beatrice Hahn and Co-sponsor Dr. Amelia Escolano. The individualized training plan emphasizes gaining a
solid foundation in immunology and microbiology, developing written and oral scientific communication skills,
and engaging in clinical and professional development activities. The research will be conducted in the excellent
training environment of the University of Pennsylvania and the Wistar Institute, which are equipped with all the
cutting-edge resources and facilities needed for these projects including cores for flow cytometry, next-
generation sequencing, and bioinformatics. In sum, the vibrant resear...

## Key facts

- **NIH application ID:** 10921834
- **Project number:** 1F30AI179430-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ashwin Nicholas Skelly
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $36,512
- **Award type:** 1
- **Project period:** 2024-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10921834

## Citation

> US National Institutes of Health, RePORTER application 10921834, Harnessing SHIVs and Sequential Immunization to Elicit V3 Glycan-Targeted bNAbs against HIV-1 (1F30AI179430-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10921834. Licensed CC0.

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