# Approaches to inducing broadly neutralizing antibodies with immunogens mimicking steric occlusion of the MPER as configured on the HIV-1virion surface

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2022 · $445,000

## Abstract

ABSTRACT
Development of a preventive AIDS vaccine is a daunting task given the structural complexity of the HIV-1
envelope (Env) protein as well as extensive antigenic variation among viral quasispecies driven by immune
escape mechanisms. Moreover, immunodominance toward non-neutralizing epitopes on the Env trimer, the
sole viral antigen on the virion surface, makes the elicitation of broadly neutralizing antibody (bnAb) by
vaccination particularly difficult. Nonetheless, immunological and structural characterizations of isolated bnAbs
from HIV-1 infected donors have guided additional neutralizing target epitopes along with new approaches in
vaccine strategies. The membrane proximal external region (MPER) of gp41 subunit is an attractive bnAb
target given its linear and conserved epitope sequences as exemplified by 4E10, 10E8 and DH511 and 2F5
mAbs. However, MPER immunogen vaccines including peptides, protein scaffolds or MPER/liposomes have
all failed to elicit neutralizing activities, suggesting incomplete mimicry of the quaternary structure on the virion
surface. Furthermore, the accessibility of the MPER is limited, being shielded by gp160 trimer ectodomain from
above and the viral membrane from below, contributing to the poor immunogenicity of the MPER elicited by
trimer immunogens. A closed rather than open configuration of gp140 trimer immunogens has proven to be
important for elicitation of bnAbs directed to epitopes in gp120. Likewise, our recent MPER/liposome results
suggest that the unrestricted approach angle afforded to the B cell receptor with current vaccine formulation is
problematic, resulting in induction of a majority of Abs without neutralizing activity or gp160 trimer reactivity.
Therefore, MPER immunogens must mimic spatial occlusion and enforce limited Ab accessibility to the MPER
in a manner analogous to that imposed by the quaternary structural configuration of gp160 on the virion
surface. Given sequence variations in the N-terminal region of the MPER, we will develop strategies to
augment subdominant Ab responses directed to the MPER C-terminal region in Aim 1. A knock-in (KI) mouse
model generating antibodies with long CDRH3 loops, extrinsic factors such as cyclic di-GMP adjuvant, ICOSL
and persistent antigen supply will be tested independently or in combination for their impact on augmenting
MPER C-terminal region-specific Abs. In Aim 2, we shall exploit nanodisc technology that serves as a platform
for the assembly of gp160 into a native membrane-like environment to prime or boost MPER-specific Ab
responses with a desirable approach angle and to eliminate off-target vector responses. In conjunction with
optimized vaccine regimen in Aim 1, we shall pursue complementary heterologous immunization strategies in
mouse and rabbit models to foster the induction of 4E10/10E8-like bnAbs. DNA C-particle and
MPERTM/liposome immunogens will further disfavor expansion of gp120-41 directed dominant undesirable
Ab responses elicited...

## Key facts

- **NIH application ID:** 10452514
- **Project number:** 5R01AI145509-04
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Mikyung Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $445,000
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452514

## Citation

> US National Institutes of Health, RePORTER application 10452514, Approaches to inducing broadly neutralizing antibodies with immunogens mimicking steric occlusion of the MPER as configured on the HIV-1virion surface (5R01AI145509-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10452514. Licensed CC0.

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