HIV-1 Assembly is Assisted by IRSp53 Through an Interaction that Extends Gag Conformation
- 1University of Chicago
Abstract
Budding of the immature virion is an essential part of the HIV-1 life cycle. However, understanding and inhibiting this process has been challenging, as both simulations and theoretical studies suggest that the energy required to bend the membrane is too high for the complete assembly of a spherical viral particle at the plasma membrane without the assistance of cellular host factors. Recent results suggest that the I-BAR protein IRSp53 may be one such host factor, but the molecular mechanism by which the Gag-IRSp53 interaction promotes HIV-1 assembly and budding remains poorly understood. We employ molecular dynamics simulations, starting from AlphaFold models, to show that the SH3 domain of IRSp53 interacts directly with the MACANTD domain of Gag and we experimentally validate this interaction. Our simulations show that the specificity of the interaction with IRSp53 arises from its ability to extend the MACANTD Gag conformation in a manner similar to RNA binding, which is known to activate Gag assembly. We then computationally design HIV-1 Gag mutants that, as confirmed by simulations, do not undergo conformational changes upon interaction with theIRSp53 SH3 domain. Experimentally, these Gag mutants are tested and shown to accumulate in cells. In addition, for these mutants we observe large quantities of Gag assembling at the plasma membrane but exhibiting large budding defects. These results validate the proposed mechanism by which the Gag-IRSp53 interaction promotes completion of HIV-1 budding and suggest new routes for inhibiting viral assembly or budding.
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BibTeX
@misc{waltmann2026hiv1,
title = {{HIV-1 Assembly is Assisted by IRSp53 Through an Interaction that Extends Gag Conformation}},
author = {C. Waltmann and P. Merida and P. Banerjee and K. Buresova and C. Poussineau and J. Burlaud-Gaillard and R. Gurram and J. Beiter and C. Favard and D. Muriaux and G. A. Voth},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.756744},
url = {https://www.biorxiv.org/content/10.64898/2026.10.05.756744v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - HIV-1 Assembly is Assisted by IRSp53 Through an Interaction that Extends Gag Conformation
AU - C. Waltmann
AU - P. Merida
AU - P. Banerjee
AU - K. Buresova
AU - C. Poussineau
AU - J. Burlaud-Gaillard
AU - R. Gurram
AU - J. Beiter
AU - C. Favard
AU - D. Muriaux
AU - G. A. Voth
PY - 2026
DA - 2026/10/05
PB - bioRxiv
DO - 10.64898/2026.10.05.756744
UR - https://www.biorxiv.org/content/10.64898/2026.10.05.756744v1
AB - Budding of the immature virion is an essential part of the HIV-1 life cycle. However, understanding and inhibiting this process has been challenging, as both simulations and theoretical studies suggest that the energy required to bend the membrane is too high for the complete assembly of a spherical viral particle at the plasma membrane without the assistance of cellular host factors. Recent results suggest that the I-BAR protein IRSp53 may be one such host factor, but the molecular mechanism by which the Gag-IRSp53 interaction promotes HIV-1 assembly and budding remains poorly understood. We employ molecular dynamics simulations, starting from AlphaFold models, to show that the SH3 domain of IRSp53 interacts directly with the MACANTD domain of Gag and we experimentally validate this interaction. Our simulations show that the specificity of the interaction with IRSp53 arises from its ability to extend the MACANTD Gag conformation in a manner similar to RNA binding, which is known to activate Gag assembly. We then computationally design HIV-1 Gag mutants that, as confirmed by simulations, do not undergo conformational changes upon interaction with theIRSp53 SH3 domain. Experimentally, these Gag mutants are tested and shown to accumulate in cells. In addition, for these mutants we observe large quantities of Gag assembling at the plasma membrane but exhibiting large budding defects. These results validate the proposed mechanism by which the Gag-IRSp53 interaction promotes completion of HIV-1 budding and suggest new routes for inhibiting viral assembly or budding.
ER -