# Molecular mechanisms of the CA-SP1 switch in HIV assembly and maturation

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2020 · $451,861

## Abstract

Project Summary/Abstract
HIV initially assembles as a non-infectious, immature particle that must undergo a maturation process to
become infectious. Assembly and maturation involve large-scale rearrangements of the viral capsid. These
large-scale rearrangements, in turn, are associated with programmed local conformational changes in capsid
protein segments termed molecular switches. In these studies, we will use structural, biophysical, and other
complementary approaches to understand the structure of the immature HIV-1 capsid and how a molecular
switch spanning the CA-SP1 region of the HIV-1 Gag protein controls immature virus assembly and
maturation. We propose to: (1) Test the hypothesis that the CA-SP1 junction folds into a 6-helix bundle that
undergoes reversible and cooperative unfolding and folding within immature virions to regulate access of the
viral protease during maturation. We will also determine how small molecule maturation inhibitors like bevirimat
disrupt this process by binding and stabilizing the 6-helix bundle. We will also initiate experiments to
understand how Gag-Gag interactions change during the early stages of maturation. (2) Elucidate the detailed
molecular organization of the immature HIV-1 Gag lattice. In particular, we will determine the high resolution
details of how the outermost set of Gag-Gag interactions (mediated by the CA-NTD domain) are organized
within the immature particle. We will also test the hypotheses that interactions between the CA-NTD layer and
the underlying CA-CTD layer are important for proper assembly and may be part of a structural network that
links two molecular switches that flank the CA region. Finally, we will also analyze the immature Gag lattices of
other retroviruses, in order to elucidate the general nature of switch-mediated Gag assembly. If successful,
these studies will lead to a thorough understanding of the immature capsid structure of retroviruses, how local
conformational transitions translate into large-scale capsid rearragenements during retroviral assembly and
maturation, and how small molecule inhibitors may be deployed to disrupt capsid rearrangement.

## Key facts

- **NIH application ID:** 9812837
- **Project number:** 5R01AI129678-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Barbie K. Ganser-Pornillos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $451,861
- **Award type:** 5
- **Project period:** 2016-11-01 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9812837

## Citation

> US National Institutes of Health, RePORTER application 9812837, Molecular mechanisms of the CA-SP1 switch in HIV assembly and maturation (5R01AI129678-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9812837. Licensed CC0.

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