Structure of the HIV immature lattice allows for essential lattice remodeling within budded virions

  1. Sikao Guo
  2. Ipsita Saha
  3. Saveez Saffarian
  4. Margaret E Johnson  Is a corresponding author
  1. Johns Hopkins University, United States
  2. National Cancer Institute, United States
  3. University of Utah, United States

Abstract

For HIV virions to become infectious, the immature lattice of Gag polyproteins attached to the virion membrane must be cleaved. Cleavage cannot initiate without the protease formed by the homo-dimerization of domains linked to Gag. However, only 5% of the Gag polyproteins, termed Gag-Pol, carry this protease domain, and they are embedded within the structured lattice. The mechanism of Gag-Pol dimerization is unknown. Here, we use spatial stochastic computer simulations of the immature Gag lattice as derived from experimental structures, showing that dynamics of the lattice on the membrane is unavoidable due to the missing 1/3 of the spherical protein coat. These dynamics allow for Gag-Pol molecules carrying the protease domains to detach and reattach at new places within the lattice. Surprisingly, dimerization timescales of minutes or less are achievable for realistic binding energies and rates despite retaining most of the large-scale lattice structure. We derive a formula allowing extrapolation of timescales as a function of interaction free energy and binding rate, thus predicting how additional stabilization of the lattice would impact dimerization times. We further show that during assembly, dimerization of Gag-Pol is highly likely and therefore must be actively suppressed to prevent early activation. By direct comparison to recent biochemical measurements within budded virions, we find that only moderately stable hexamer contacts (-12kBT<∆G<-8kBT) retain both the dynamics and lattice structures that are consistent with experiment. These dynamics are likely essential for proper maturation, and our models quantify and predict lattice dynamics and protease dimerization timescales that define a key step in understanding formation of infectious viruses.

Data availability

All software used for simulations is available open source at https://github.com/mjohn218/NERDSS, and executable model files and instructions for running them are freely available at https://github.com/mjohn218/NERDSS/sample_inputs/gagLatticeRemodeling.

Article and author information

Author details

  1. Sikao Guo

    TC Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Ipsita Saha

    Laboratory of Cell and Developmental Signaling, National Cancer Institute, Frederick, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Saveez Saffarian

    Center for Cell and Genome Science, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Margaret E Johnson

    TC Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, United States
    For correspondence
    margaret.johnson@jhu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9881-291X

Funding

National Science Foundation (1753174)

  • Margaret E Johnson

National Institutes of Health (R01 AI150474)

  • Saveez Saffarian

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Laura Ruth Delgui, National Scientific and Technical Research Council, Argentina

Version history

  1. Received: November 12, 2022
  2. Preprint posted: November 21, 2022 (view preprint)
  3. Accepted: July 12, 2023
  4. Accepted Manuscript published: July 12, 2023 (version 1)
  5. Version of Record published: July 21, 2023 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Sikao Guo
  2. Ipsita Saha
  3. Saveez Saffarian
  4. Margaret E Johnson
(2023)
Structure of the HIV immature lattice allows for essential lattice remodeling within budded virions
eLife 12:e84881.
https://doi.org/10.7554/eLife.84881

Share this article

https://doi.org/10.7554/eLife.84881

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