HIV-1 Vpu is a potent transcriptional suppressor of NF-κB-elicited antiviral immune responses

  1. Simon Langer
  2. Christian Hammer
  3. Kristina Hopfensperger
  4. Lukas Klein
  5. Dominik Hotter
  6. Paul D De Jesus
  7. Kristina M Herbert
  8. Lars Pache
  9. Nikaïa Smith
  10. Johannes A van der Merwe
  11. Sumit K Chanda
  12. Jacques Fellay
  13. Frank Kirchhoff
  14. Daniel Sauter  Is a corresponding author
  1. Sanford Burnham Prebys Medical Discovery Institute, United States
  2. École Polytechnique Fédérale de Lausanne, Switzerland
  3. Ulm University Medical Center, Germany

Abstract

Many viral pathogens target innate sensing cascades and/or cellular transcription factors to suppress antiviral immune responses. Here, we show that the accessory viral protein U (Vpu) of HIV-1 exerts broad immunosuppressive effects by inhibiting activation of the transcription factor NF-κB. Global transcriptional profiling of infected CD4+ T-cells revealed that vpu-deficient HIV-1 strains induce substantially stronger immune responses than the respective wild type viruses. Gene set enrichment analyses and cytokine arrays showed that Vpu suppresses the expression of NF-κB targets including interferons and restriction factors. Mutational analyses demonstrated that this immunosuppressive activity of Vpu is independent of its ability to counteract the restriction factor and innate sensor tetherin. However, Vpu-mediated inhibition of immune activation required an arginine residue in the cytoplasmic domain that is critical for blocking NF-κB signaling downstream of tetherin. In summary, our findings demonstrate that HIV-1 Vpu potently suppresses NF-κB-elicited antiviral immune responses at the transcriptional level.

Data availability

RNA sequencing data have been uploaded to the Gene Expression Omnibus (GEO) database (accession number #GSE117655).

The following data sets were generated

Article and author information

Author details

  1. Simon Langer

    Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Christian Hammer

    School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4548-7548
  3. Kristina Hopfensperger

    Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Lukas Klein

    Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Dominik Hotter

    Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Paul D De Jesus

    Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Kristina M Herbert

    Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Lars Pache

    Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Nikaïa Smith

    Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Johannes A van der Merwe

    Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Sumit K Chanda

    Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Jacques Fellay

    School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8240-939X
  13. Frank Kirchhoff

    Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  14. Daniel Sauter

    Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
    For correspondence
    daniel.sauter@uni-ulm.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7665-0040

Funding

Deutsche Forschungsgemeinschaft (SPP 1923)

  • Frank Kirchhoff
  • Daniel Sauter

European Research Council

  • Frank Kirchhoff

International Graduate School in Molecular Medicine Ulm

  • Simon Langer
  • Kristina Hopfensperger
  • Dominik Hotter

Deutsche Forschungsgemeinschaft (404687549)

  • Simon Langer

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

Ethics

Human subjects: The use of human PBMCs was approved by the Ethics Committee of the Ulm University Medical Center (application #50/16). All donors were anonymized and provided informed written consent.

Copyright

© 2019, Langer 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. Simon Langer
  2. Christian Hammer
  3. Kristina Hopfensperger
  4. Lukas Klein
  5. Dominik Hotter
  6. Paul D De Jesus
  7. Kristina M Herbert
  8. Lars Pache
  9. Nikaïa Smith
  10. Johannes A van der Merwe
  11. Sumit K Chanda
  12. Jacques Fellay
  13. Frank Kirchhoff
  14. Daniel Sauter
(2019)
HIV-1 Vpu is a potent transcriptional suppressor of NF-κB-elicited antiviral immune responses
eLife 8:e41930.
https://doi.org/10.7554/eLife.41930

Share this article

https://doi.org/10.7554/eLife.41930

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