HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF- κB/IRF3 nuclear transport

Abstract

HIV-1 must replicate in cells that are equipped to defend themselves from infection through intracellular innate immune systems. HIV-1 evades innate immune sensing through encapsidated DNA synthesis and encodes accessory genes that antagonize specific antiviral effectors. Here we show that both particle associated, and expressed HIV-1 Vpr, antagonize the stimulatory effect of a variety of pathogen associated molecular patterns by inhibiting IRF3 and NF-κB nuclear transport. Phosphorylation of IRF3 at S396, but not S386, was also inhibited. We propose that, rather than promoting HIV-1 nuclear import, Vpr interacts with karyopherins to disturb their import of IRF3 and NF-κB to promote replication in macrophages. Concordantly, we demonstrate Vpr dependent rescue of HIV-1 replication in human macrophages from inhibition by cGAMP, the product of activated cGAS. We propose a model that unifies Vpr manipulation of nuclear import and inhibition of innate immune activation to promote HIV-1 replication and transmission.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Hataf Khan

    Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  2. Rebecca P Sumner

    Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  3. Jane Rasaiyaah

    Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  4. Choon Ping Tan

    Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  5. Maria Teresa Rodriguez-Plata

    Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    Maria Teresa Rodriguez-Plata, Maria Teresa Rodriguez-Plata is affiliated with Black Belt TX Ltd. The author has no financial interests to declare..
  6. Chris Van Tulleken

    Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  7. Douglas Fink

    Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  8. Lorena Zuliani-Alvarez

    Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4682-4043
  9. Lucy Thorne

    Division of Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  10. David Stirling

    Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  11. Richard S B Milne

    Infection and Immunity, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  12. Greg J Towers

    Infection and Immunity, University College London, London, United Kingdom
    For correspondence
    g.towers@ucl.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7707-0264

Funding

Wellcome Trust (Senior Biomedical Research Fellowship)

  • Greg J Towers

H2020 European Research Council (Advanced Grant HIVinnate)

  • Greg J Towers

Medical Research Council (PhD studentship)

  • Hataf Khan

Medical Research Council (Clinical training fellowship)

  • Chris Van Tulleken

Wellcome Trust (Collaborative Award)

  • Greg J Towers

National Institute of Health Research (University College London Hospitals Biomedical Research Centre)

  • Greg J Towers

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

Ethics

Human subjects: This study was approved by the UCL/UCLH Committees on the Ethics of Human Research, Committee Alpha reference (06/Q0502/92). All participants provided written informed consent and consent for publication.

Reviewing Editor

  1. John W Schoggins, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: July 7, 2020
  2. Accepted: December 9, 2020
  3. Accepted Manuscript published: December 10, 2020 (version 1)
  4. Accepted Manuscript updated: December 12, 2020 (version 2)
  5. Version of Record published: December 24, 2020 (version 3)

Copyright

© 2020, Khan 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. Hataf Khan
  2. Rebecca P Sumner
  3. Jane Rasaiyaah
  4. Choon Ping Tan
  5. Maria Teresa Rodriguez-Plata
  6. Chris Van Tulleken
  7. Douglas Fink
  8. Lorena Zuliani-Alvarez
  9. Lucy Thorne
  10. David Stirling
  11. Richard S B Milne
  12. Greg J Towers
(2020)
HIV-1 Vpr antagonizes innate immune activation by targeting karyopherin-mediated NF- κB/IRF3 nuclear transport
eLife 9:e60821.
https://doi.org/10.7554/eLife.60821

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