# Characterization of the human antibody response to a novel neutralizing HIV-1 epitope

> **NIH NIH F30** · STANFORD UNIVERSITY · 2021 · $38,510

## Abstract

PROJECT SUMMARY
The HIV pandemic is one of the most profound global human health challenges of our time, with 75 million people
infected and 32 million dead from AIDS-related illnesses since 19811. Despite decades of dedicated efforts, an
effective vaccine has remained elusive. While the discovery and characterization of patient-derived broadly
neutralizing antibodies (bnAbs) to various epitopes of the HIV envelope protein (Env) demonstrate that inhibition
of the virus by human antibodies is possible, these antibodies have not yet been possible to elicit with a vaccine,
due in part to their extensive somatic hypermutation (SHM) or long heavy-chain third complementarity
determining regions (CDRH3s).
In recent unpublished work, our group has identified a novel epitope for antibody-mediated neutralization in the
prehairpin intermediate (PHI) of Env exposed during HIV viral fusion, demonstrating that a previously discovered
patient-derived antibody with 94% germline identity (A2) binds to the conserved, helical face of the CHR, and
after affinity maturation neutralizes tier-1B viruses across multiple clades in vitro. The limited degree of SHM of
the neutralizing antibody and the ability of a germline-inferred version to bind to the original epitope suggest that
it may be possible to elicit neutralizing antibodies to this epitope from the germline. In addition, we found that the
protein inhibitor 5-Helix, which binds and inhibits via the same helical CHR epitope, is capable of cross-clade
neutralization of tier-1, -2, and -3 HIV-1 viruses.
Taken together, these data inform the central hypothesis of this work: that higher-affinity antibodies to this
epitope, if identified, may be capable of effective cross-clade neutralization. Given that both A2 and 5-Helix inhibit
HIV fusion by binding to the CHR as a folded 𝛼-helix, this secondary structure is likely important in attempts to
identify additional CHR-directed neutralizing antibodies. Thus, I plan to use C34coil, a helical peptide mimetic of
the CHR comprising 19 amino acids from the CHR conserved face grafted onto one monomer of a GCN4 leucine
zipper dimer, to investigate antibody-mediated neutralization at this epitope. The long-term goal of this research
is to investigate the highly-conserved, helical face of the CHR as a potential HIV-1 immunogen capable of eliciting
broadly neutralizing antibodies. In the proposed work, I will (i) identify and characterize additional human-derived
monoclonal antibodies that bind to C34coil, (ii) investigate the serum and memory B cell response to C34coil in
HIV-1 infected individuals, and (iii) determine human naïve B cell reactivity to C34coil.
Collectively, this proposal aims to investigate the hypothesis that high-affinity antibodies to the helical CHR, if
identified, may be capable of effective cross-clade neutralization. These studies will inform the potential of a
scaffolded, helical mimetic of this epitope to elicit neutralizing antibodies towards an HIV va...

## Key facts

- **NIH application ID:** 10326698
- **Project number:** 1F30AI152943-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Maria Victoria Filsinger Interrante
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $38,510
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10326698

## Citation

> US National Institutes of Health, RePORTER application 10326698, Characterization of the human antibody response to a novel neutralizing HIV-1 epitope (1F30AI152943-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10326698. Licensed CC0.

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