# Targeting Immunogenicity to the MPER Hinge and C-helix for BNAb Elicitation

> **NIH NIH P01** · DANA-FARBER CANCER INST · 2020 · $1,744,691

## Abstract

Project Summary - Overall
 While there is an obvious need for vaccines eliciting broadly neutralizing antibodies (BNAbs) against the
highly mutable retrovirus HIV-1 to stem person-to-person and global spread, the means to achieve this goal
have remained elusive. Antibodies produced against trimeric gp160 sites of vulnerability during natural
infection drive retroviral mutation further, diversifying quasispecies in individuals. One apparent exception is
the membrane proximal external region (MPER) site, which is stealth, largely immersed in lipid and only
revealed during hemifusion/fusion. Hence, immune pressures are not confounding or contributing to viral
escape. However, a paucity of naturally arising antibodies has been postulated to be a consequence of
deletion at the earliest B cell checkpoints in view of lipid reactivity, polyspecificity and even autoreactivity of
certain anti-MPER mAbs. To the contrary, our recent mouse immunogenicity studies have generated germinal
center-derived and T cell-dependent, affinity-matured anti-MPER antibodies using liposome-arrayed MPER
segments without clinical sequelae or significant anti-lipid reactivity. These findings are consistent with the re-
evaluated greater prevalence of naturally arising human anti-MPER antibodies in HIV-1 patients. This PO1
focuses on engendering anti-MPER responses with potent BNAb specificities, creating immunogens that
capture native MPER conformational states arising during transitions of trimer unwinding, going from the
compact torus-like gp160 base to conformers on the flat viral membrane with maximum MPER exposure. This
goal shall be achieved using molecular immunology approaches of the Reinherz group (DFCI) in Project 1 in
conjunction with the biomaterials expertise of the Irvine group (MIT) in Project 2 and utilizing technology
components A-D, NMR (Wagner, Harvard), electron microscopy (EM) (Walz, Rockefeller), EPR (Song,
NHMFL) and microengraving (Love, MIT), respectively. Optimization of immunogen design will be achieved by
orientation of the MPER on lipid membranes in nanovaccines through the use of synthetic peptide nucleic acid
(PNA) stalks, acyl chain and TM segment linkers and vetted by NMR, EPR, EM and BIAcore measurements. In
addition, optimal nanoscale MPER segment spacing and organization will engage uncommitted common
ancestors (UCAs) of BNAbs. Vector space of antibody attachment will be controlled by biomaterial formulation
of polymer poly(ethylene glycol) (PEG) "steric clouds" and utilization of nanodisc-embedded gp160 in
heterologous immunization strategies. Approach angles of elicited mAbs rescued by single-cell microengraving
will be assessed and compared with those of naturally arising BNAbs. Co-delivery of chemical adjuvants to
activate the STING and ICOS pathways shall augment CD4 TFH in germinal centers to drive somatic
hypermutation. Assessment of vaccine-induced long-term plasma cell development by analysis of bulk serum
IgG and single bone marrow ...

## Key facts

- **NIH application ID:** 9982752
- **Project number:** 5P01AI126901-05
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** ELLIS L REINHERZ
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,744,691
- **Award type:** 5
- **Project period:** 2016-08-05 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982752

## Citation

> US National Institutes of Health, RePORTER application 9982752, Targeting Immunogenicity to the MPER Hinge and C-helix for BNAb Elicitation (5P01AI126901-05). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9982752. Licensed CC0.

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