IP6 is an HIV pocket factor that prevents capsid collapse and promotes DNA synthesis

  1. Donna L Mallery
  2. Chantal L Márquez
  3. William A McEwan
  4. Claire Dickson
  5. David A Jacques
  6. Madhanagopal Anandapadamanaban
  7. Katsia Bichel
  8. Gregory J Towers
  9. Adolfo Saiardi
  10. Till Böcking  Is a corresponding author
  11. Leo C James  Is a corresponding author
  1. Medical Research Council Laboratory of Molecular Biology, United Kingdom
  2. University of New South Wales, Australia
  3. University College London, United Kingdom

Abstract

The HIV capsid is semi-permeable and covered in electropositive pores that are essential for viral DNA synthesis and infection. Here we show that these pores bind the abundant cellular polyanion IP6, transforming viral stability from minutes to hours and allowing newly synthesised DNA to accumulate inside the capsid. An arginine ring within the pore coordinates IP6, which strengthens capsid hexamers by almost 10°C. Single molecule measurements demonstrate that this renders native HIV capsids highly stable and protected from spontaneous collapse. Moreover, encapsidated reverse transcription assays reveal that, once stabilised by IP6, the accumulation of new viral DNA inside the capsid increases > 100-fold. Remarkably, isotopic labelling of inositol in virus producing cells reveals that HIV selectively packages over 300 IP6 molecules per infectious virion. We propose that HIV recruits IP6 to regulate capsid stability and uncoating, analogous to picornavirus pocket factors.

Data availability

Diffraction data have been deposited in PDB under the accession code 6ERM, 6ERN and 6ES8.

The following data sets were generated

Article and author information

Author details

  1. Donna L Mallery

    Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. Chantal L Márquez

    EMBL Australia Node in Single Molecule Science, University of New South Wales, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
  3. William A McEwan

    Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4408-0407
  4. Claire Dickson

    Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. David A Jacques

    EMBL Australia Node in Single Molecule Science, University of New South Wales, Sydney, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6426-4510
  6. Madhanagopal Anandapadamanaban

    Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Katsia Bichel

    Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Gregory J Towers

    Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Adolfo Saiardi

    Medical Research Council (MRC) Laboratory for Molecular Cell Biology, University College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Till Böcking

    EMBL Australia Node in Single Molecule Science, University of New South Wales, Sydney, Australia
    For correspondence
    till.boecking@unsw.edu.au
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1165-3122
  11. Leo C James

    Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
    For correspondence
    lcj@mrc-lmb.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2131-0334

Funding

Medical Research Council (U105181010)

  • Leo C James

Wellcome

  • Leo C James

National Health and Medical Research Council (339223)

  • Till Böcking

National Health and Medical Research Council (GNT1036521)

  • David A Jacques

Wellcome (206248/Z/17/Z)

  • William A McEwan

Wellcome

  • Gregory J Towers

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

Reviewing Editor

  1. Wesley I Sundquist, University of Utah School of Medicine, United States

Publication history

  1. Received: January 23, 2018
  2. Accepted: May 29, 2018
  3. Accepted Manuscript published: May 31, 2018 (version 1)
  4. Version of Record published: July 10, 2018 (version 2)

Copyright

© 2018, Mallery et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Donna L Mallery
  2. Chantal L Márquez
  3. William A McEwan
  4. Claire Dickson
  5. David A Jacques
  6. Madhanagopal Anandapadamanaban
  7. Katsia Bichel
  8. Gregory J Towers
  9. Adolfo Saiardi
  10. Till Böcking
  11. Leo C James
(2018)
IP6 is an HIV pocket factor that prevents capsid collapse and promotes DNA synthesis
eLife 7:e35335.
https://doi.org/10.7554/eLife.35335

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