Antagonism of PP2A is an independent and conserved function of HIV-1 Vif and causes cell cycle arrest

Abstract

The seminal description of the cellular restriction factor APOBEC3G and its antagonism by HIV-1 Vif has underpinned two decades of research on the host-virus interaction. We recently reported that HIV-1 Vif is also able to degrade the PPP2R5 family of regulatory subunits of key cellular phosphatase PP2A (PPP2R5A-E; Greenwood et al., 2016; Naamati et al., 2019). We now identify amino acid polymorphisms at positions 31 and 128 of HIV-1 Vif which selectively regulate the degradation of PPP2R5 family proteins. These residues covary across HIV-1 viruses in vivo, favouring depletion of PPP2R5A-E. Through analysis of point mutants and naturally occurring Vif variants, we further show that degradation of PPP2R5 family subunits is both necessary and sufficient for Vif-dependent G2/M cell cycle arrest. Antagonism of PP2A by HIV-1 Vif is therefore independent of APOBEC3 family proteins, and regulates cell cycle progression in HIV-infected cells.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Proteomic datasets have been deposited to PRIDE, under the accession PXD018271, and are summarised in Source data files for Figures 2, 6 and 7.

The following data sets were generated

Article and author information

Author details

  1. Sara Marelli

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. James C Williamson

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Anna V Protasio

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Adi Naamati

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Edward JD Greenwood

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5224-0263
  6. Janet E Deane

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4863-0330
  7. Paul J Lehner

    Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9383-1054
  8. Nicholas J Matheson

    Department of Medicine, University of Cambridge, Cambridge, United Kingdom
    For correspondence
    njm25@cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3318-1851

Funding

Medical Research Council (MR/P008801/1)

  • Nicholas J Matheson

NHS Blood and Transplant (WPA15-02)

  • Nicholas J Matheson

Wellcome (210688/Z/18/Z)

  • Paul J Lehner

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

Ethics

Human subjects: Ethical permission for this study was granted by the University of Cambridge Human Biology Research Ethics Committee (HBREC.2017.20). Written informed consent was obtained from all volunteers prior to providing blood samples.

Reviewing Editor

  1. Frank Kirchhoff, Ulm University Medical Center, Germany

Publication history

  1. Received: October 31, 2019
  2. Accepted: March 17, 2020
  3. Accepted Manuscript published: April 15, 2020 (version 1)
  4. Version of Record published: March 1, 2021 (version 2)

Copyright

© 2020, Marelli 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. Sara Marelli
  2. James C Williamson
  3. Anna V Protasio
  4. Adi Naamati
  5. Edward JD Greenwood
  6. Janet E Deane
  7. Paul J Lehner
  8. Nicholas J Matheson
(2020)
Antagonism of PP2A is an independent and conserved function of HIV-1 Vif and causes cell cycle arrest
eLife 9:e53036.
https://doi.org/10.7554/eLife.53036

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