# Env-Ab coevolution in SHIV infected RMs leading to V3 glycan bNAbs

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $1,405,625

## Abstract

PROJECT SUMMARY
 A major roadblock to rational HIV-1 vaccine design is the lack of a suitable primate model in which broadly
neutralizing antibodies (bNAbs) can be consistently induced and the underlying molecular, biological and
immunological mechanisms studied in an iterative fashion. Since most HIV-1 bNAbs have come from humans
infected by HIV-1, we hypothesized that one means to elicit bNabs in primates might be by infecting rhesus
macaques (RMs) with simian-human immunodeficiency virus (SHIV) strains that bear primary or
transmitted/founder HIV-1 Envs, including those that induced bNAbs in humans. SHIV infected RMs could then
be employed to assess the potential of different HIV-1 Envs to elicit bNAbs and to characterize the coevolutionary
pathways of bNAb lineages and cognate Envs that elicited them, thereby serving as a “molecular guide” for
rational vaccine design. Recent innovations in SHIV design by our lab have made this experimental strategy
testable. In this renewal application, we show that 24 of 150, or 16%, of RMs infected by SHIVs bearing different
primary HIV-1 Envs developed bNAbs targeting V3 glycan, V2 apex, CD4bs or fusion peptide epitopes. Nine of
these animals developed V3 glycan bNAbs. From this extensive dataset, we identified HIV-1 CH848 and
BG505.N332 Envs as immunogens that most consistently elicited V3 glycan bNAbs in RMs. We further showed
that by reducing the length of V1 and the number of potential N-linked glycans in V1 (designated CH848.dV1
and BG505.N332.dV1), we could enhance the frequency and speed of induction of V3 glycan bNAbs in SHIV
infected RMs. Based on these findings, we propose in this project to test the hypothesis that infection of RMs
by SHIV.CH848.dV1 or SHIV.BG505.N332.dV1 will selectively prime V3 glycan bNAb lineage B cell precursors,
and through a process of Env-Ab coevolution, mature these responses to achieve neutralization breadth.
Moreover, by identifying evolved Env intermediates that select for V3 glycan bNAb affinity maturation, we can
design lineage-based Env immunogens that, when constructed as SOSIP Env trimers and used to immunize
outbred RMs, will elicit V3 glycan bNAbs that are protective against heterologous virus challenge. Specific Aims
are: (i) to decipher molecular pathways of Env-Ab coevolution in SHIV-infected RMs that lead to the development
of V3 glycan bNAbs, including the identification of inferred germline bNAb precursors, bNAb lineage
intermediates and evolved Env intermediates that select for affinity maturation and neutralization breadth; (ii) to
evaluate the ability of nanoparticle-delivered, germline-targeted CH848.dV1 and BG505.N332.dV1 SOSIP Env
trimers to prime V3 glycan bNAb lineage precursors and for subsequent homologous SHIV infection to select for
affinity maturation and neutralization breadth; and (iii) to conduct a statistically-powered, proof-of-concept
vaccine trial in RMs testing the hypothesis that germline-targeted, B lineage-designed SOSIP Env trim...

## Key facts

- **NIH application ID:** 10370983
- **Project number:** 2P01AI131251-06
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** GEORGE M SHAW
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,405,625
- **Award type:** 2
- **Project period:** 2017-03-07 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10370983

## Citation

> US National Institutes of Health, RePORTER application 10370983, Env-Ab coevolution in SHIV infected RMs leading to V3 glycan bNAbs (2P01AI131251-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10370983. Licensed CC0.

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