# Determining the structural basis for ESCRT-mediated membrane scission in HIV-1 virion budding

> **NIH NIH F32** · UNIVERSITY OF CALIFORNIA BERKELEY · 2020 · $64,554

## Abstract

Project Summary
 The process of HIV-1 virion budding is essential for the completion of viral egress and intrinsically
linked to host cellular machinery, yet the structural mechanisms by which budding occurs remain poorly
understood. While the HIV-1 Gag polyprotein is capable of deforming host cells membranes and generate bud
structures, HIV-1 must hijack the host ESCRT proteins, which ultimately drive the membrane scission event
required for viral budding. This process begins with the recruitment of early-ESCRT factors (ESCRT-I, ESCRT-
II, and ALIX) to the viral bud site by HIV-1 Gag. These early ESCRTs are then responsible for the recruitment
of the late-ESCRT proteins, which form filamentous structures that are believed to drive scission through an
active remodeling process. Despite growing amounts of structural, biochemical, and biophysical data on these
proteins, the structural mechanism by which ESCRTs drive membrane scission is unknown, leaving a
significant gap in our understanding of how HIV-1 release is accomplished. In Aim 1, I will determine the
structures of 1:1 early-ESCRT complexes (ESCRT-I/ESCRT-II and ESCRT-I/ALIX) assembled on lipid
membranes, using single-particle cryo-electron microscopy. Recent structural work from the Hurley lab has
shown that ESCRT-I can self-associate to form spiral polymers through interactions within its core domain,
implying that ESCRT-I's interactions with ESCRT-II or ALIX may serve as an early template for organizing the
full ESCRT scission machinery. Results from this Aim will reveal the structures of these complexes in a native-
like context, providing valuable information to how the early-ESCRT components assemble at the membrane
and promote ESCRT-III recruitment. In Aim 2, a scission-competent, controllable in vitro viral budding system
will be developed and structures of the full ESCRT machinery at these viral bud necks will be determined using
cryo-electron tomography. The structures determined in this Aim will represent the first snapshots of on-
pathway membrane scission by the ESCRT machinery. Such structures will not only reveal the molecular
organization of the full ESCRT assembly, but also allow for the development, testing, and realization of the
exact structural mechanism behind ESCRT-mediate membrane scission. Detailed cryo-EM and cryo-ET
studies of these supramolecular complexes will reveal how HIV-1 hijacks and organizes the ESCRT machinery
to complete a vital aspect of the viral life cycle. This basic research proposal is significant for future
antiretroviral discovery, as our current incomplete mechanistic understanding of HIV-1 release has limited
investigations into its potential as a target for antiretroviral therapies. This work will result in a detailed `movie'
of—and biophysical insights into—the steps leading to virion budding and release. This contribution will be
significant because it will reveal the extent to which antivirals might successfully target HIV-1 release, inclu...

## Key facts

- **NIH application ID:** 10083062
- **Project number:** 1F32AI155226-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Kevin Larsen
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $64,554
- **Award type:** 1
- **Project period:** 2020-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10083062

## Citation

> US National Institutes of Health, RePORTER application 10083062, Determining the structural basis for ESCRT-mediated membrane scission in HIV-1 virion budding (1F32AI155226-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10083062. Licensed CC0.

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