# HIV-1 membrane fusion and inhibition

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2024 · $772,175

## Abstract

Summary
Virus entry begins with the first encounter between the virus and the cell surface and ends with delivery of the
contents of the virus into the host cell. HIV-1 membrane fusion is the first key delivery step, mediated by the
virus-encoded envelope glycoprotein [Env; trimeric (gp160)3 cleaved to (gp120/gp41)3], which belongs to the
group of class I viral fusion proteins including influenza hemagglutinin, SARS-CoV-2 spike protein and Ebola
glycoprotein. A mature Env spike has three copies each of noncovalently-associated receptor-binding subunit
gp120 and fusion subunit gp41. Sequential binding of gp120 to the primary receptor CD4 and a coreceptor
(chemokine receptor CCR5 or CXCR4) leads to large, irreversible structural rearrangements in gp41, which drive
fusion. This picture, derived largely from structural studies of the soluble fragments and from cellular studies with
inhibitors and antibodies, is still incomplete because it lacks extension to a high-resolution picture of the complete
Env trimer in the context of a lipid-bilayer membrane, which is the substrate of the fusion reaction. We have
determined by NMR the structures of the HIV-1 Env transmembrane domain (TMD), membrane proximal external
region (MPER), and cytoplasmic tail (CT) in bicelles that mimic lipid bilayers. These regions all form well-ordered,
trimeric clusters in a lipid bilayer. Disruption of any of them can reduce membrane fusion efficiency and alter the
antigenic structure of the entire Env, suggesting that they have structural and functional roles in fusion and in
trimer conformational stabilization. Very recently, we have completed a high-resolution structure of the intact
SARS-CoV-2 postfusion spike in membrane, showing how the functionally critical membrane-interacting regions
interact with membrane and with each other. These findings are the basis of our overall hypothesis that that
structures of the HIV-1 fusion complex either alone or bound with fusion inhibitors in membrane will reveal new
structural features of the membrane-interacting regions and substantially advance our mechanistic
understanding of the viral fusion and its inhibition, thereby informing future development of intervention
strategies. We will apply advanced technologies in cryogenic electron microscopy (cryo-EM) and tomography
(cryo-ET) to study structural and functional properties of the HIV-1 fusion complex, as reconstituted in
membranes and on the surface of a virus particle. We will also investigate molecular mechanisms of HIV-1
inhibition by two distinct types of fusion inhibitors. Our goal is a "molecular movie" of HIV-1 fusion, to inform
development of new intervention strategies. We propose the following Specific Aims to address our hypothesis:
1) We will determine structure of the HIV-1 fusion complex containing intact Env, CD4 and CCR5 in the context
of a lipid bilayer. 2) We will investigate molecular mechanism of HIV-1 fusion inhibition by anti-CD4 antibody
ibalizumab. 3) We wil...

## Key facts

- **NIH application ID:** 10838787
- **Project number:** 1R01AI181618-01
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Bing Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $772,175
- **Award type:** 1
- **Project period:** 2024-05-20 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838787

## Citation

> US National Institutes of Health, RePORTER application 10838787, HIV-1 membrane fusion and inhibition (1R01AI181618-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10838787. Licensed CC0.

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