The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression

  1. Tonya Kueck
  2. Elena Cassella
  3. Jessica Holler
  4. Baek Kim
  5. Paul D Bieniasz  Is a corresponding author
  1. The Rockefeller University, United States
  2. Emory University, United States

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor whose activation induces the expression of numerous genes, with many effects on cells. However, AhR activation is not known to affect the replication of viruses. We show that AhR activation in macrophages causes a block to HIV-1 and HSV-1 replication. We find that AhR activation transcriptionally represses cyclin-dependent kinase (CDK)1/2 and their associated cyclins, thereby reducing SAMHD1 phosphorylation, cellular dNTP levels and both HIV-1 and HSV-1 replication. Remarkably, a different antiviral stimulus, interferon gamma (IFN-g), that induces a largely non-overlapping set of genes, also transcriptionally represses CDK1, CDK2 and their associated cyclins, resulting in similar dNTP depletion and antiviral effects. Concordantly, the SIV Vpx protein provides complete and partial resistance to the antiviral effects of AhR and IFN-g, respectively. Thus, distinct antiviral signaling pathways converge on CDK/cyclin repression, causing inhibition of viral DNA synthesis and replication.

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. Tonya Kueck

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Elena Cassella

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jessica Holler

    Department of Pediatrics, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Baek Kim

    Department of Pediatrics, Emory University, Atlanta, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Paul D Bieniasz

    Laboratory of Retrovirology, The Rockefeller University, New York, United States
    For correspondence
    pbieniasz@rockefeller.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2368-3719

Funding

Howard Hughes Medical Institute

  • Paul D Bieniasz

National Institute of Allergy and Infectious Diseases (R37AI64003)

  • Paul D Bieniasz

National Institute of General Medical Sciences (R01 GM104198)

  • Baek Kim

National Institute of Allergy and Infectious Diseases (R01 AI136581)

  • Baek Kim

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

Reviewing Editor

  1. Satyajit Rath, Agharkar Research Institute (ARI) and Indian Institute of Science Education and Research (IISER), India

Publication history

  1. Received: June 2, 2018
  2. Accepted: August 21, 2018
  3. Accepted Manuscript published: August 22, 2018 (version 1)
  4. Version of Record published: September 3, 2018 (version 2)

Copyright

© 2018, Kueck 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. Tonya Kueck
  2. Elena Cassella
  3. Jessica Holler
  4. Baek Kim
  5. Paul D Bieniasz
(2018)
The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression
eLife 7:e38867.
https://doi.org/10.7554/eLife.38867
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