The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression
- The Rockefeller University, United States
- 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.
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All data generated or analysed during this study are included in the manuscript and supporting files
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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.
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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The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression
eLife 7:e38867.
https://doi.org/10.7554/eLife.38867
