The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression
- The Rockefeller University, United States
- Emory University, United States
- Kyung Hee University, South Korea
Figures
Figure 1 with 2 supplements
AhR activation inhibits HIV-1 replication in macrophages.
(A and B) HIV-1NLYU2 replication in CD4+ T cells (A) or macrophages (B) treated with AhR agonist or antagonist. Representative of at least three different donors. (C) Numbers of infected macrophages …
Figure 1—figure supplement 1
Effect of AhR activation on HIV-1 replication.
(A–H) HIV-1 replication in CD4+ T cells (A) PBMCs (B–D) or macrophages (E–H), using strain HIV-1NLYU2 or HIV-189.6, as indicated. (I) Comparison of HIV-1 supernatant reverse transcriptase levels, at …
Figure 1—figure supplement 2
Effect of AhR activation on STAT1, cell-cycle and gene expression in macrophages.
(A) FACS analysis of macrophages stained for classical macrophage markers (CD14, CD208) and M1 and M2 macrophage markers (CD80 and CD168, respectively). The shaded histograms represents unstained …
Figure 2 with 1 supplement
Reduced CDK/cyclin, phospho-SAMHD1 and dTNP levels in macrophages following activation of AhR.
(A) Quantitative PCR analysis of CDK1, cyclin A2, CDK2, cyclin E2 and CYP1B1 mRNA levels in macrophages treated with carrier (DMSO), AhR agonist or AhR antagonist. Values indicate fold-change, error …
Figure 2—figure supplement 1
Effects of AhR activation in PBMC and purified CD4+ T cells.
(A) Levels of SAMHD1, phosphorylated SAMHD1, CDK1 and CDK2 proteins in activated or unsimulated, unfractionated PBMCs treated with carrier, AhR agonist or antagonist. (B) Levels of SAMHD1, …
Figure 3 with 1 supplement
AhR activation inhibits HIV-1, and HSV-1 replication, but SIVmac Vpx confers resistance.
(A) Western blot analysis of HSV-1 glycoprotein D (gD) levels over time in infected macrophages treated with AhR agonist or antagonist. Numbers represent relative band intensities. Representative of …
Figure 3—figure supplement 1
Vpx-induced degradation of SAMHD1 abolishes AhR-mediated inhibition in macrophages.
(A) Western blot analysis of SAMHD1 and phosphorylated SAMHD1 in macrophages treated with increasing concentrations of SIV3+ or SIV3+ ΔVpx virus like particles. (B and C) Virus replication assays in …
Figure 4 with 2 supplements
IFN-γ inhibits HIV-1 replication in macrophages.
(A and B) HIV-1NLYU2 replication in macrophages (A) or PBMCs (B) treated with increasing concentrations of IFN-γ. Representative of 3 different donors. (C) Comparison of HIV-1 supernatant reverse …
Figure 4—figure supplement 1
Effect of IFN-γ on HIV-1 replication and microarray analysis of IFN-γ-induced changes in mRNA levels.
(A and B) HIV-1NLYU2 replication in macrophages or PBMCs treated with increasing concentrations of IFN-γ. (C and D) Microarray analysis of RNA extracted from macrophages, from two different donors, …
Figure 4—figure supplement 2
IDO1-mediated Tryptophan catabolism does not mediate the IFN-γ induced replication block.
(A) Western blot analysis of HSP90 (loading control) and IDO1 expression in IFN-γ treated macrophages. (B, C) Single round infection in macrophages treated with increasing concentrations of …
Figure 5
IFN-γ-mediated inhibition of viral replications is mechanistically similar to AhR.
(A) Quantitative PCR analysis of CDK1, cyclin A2, CDK2, cyclin E2 and CYP1B1 mRNA levels in macrophages that were untreated or treated with IFN-γ. Numbers indicate fold-change, error bars represent …
Figure 6
IFN-γ inhibits HIV-1 and HSV-1 replication, but SIVmac Vpx confers resistance.
(A) Western blot analysis of HSV-1 glycoprotein D (gD) over time in infected macrophages that were either untreated or treated with IFN-γ. (B) HSV-1 infectious virion yield during replication in …
Figure 7
CDK1 mRNA stability is not affected by AhR and IFN-γ.
(A) Decay of CDK1, TNFα and IL-1β following transcriptional blockage with actinomycin D, monitored over time by qPCR and normalized to GAPDH. Representative example from three different donors. (B) …
Figure 8
Summary depiction of the convergent mechanisms by which AhR agonists and IFN-γ inhibit on HIV-1 and HSV-1 replication.
AhR agonist and IFN-γ mediated signaling both cause transcriptional repression of CDK1/2 and associated cyclins. This repression results in a reduction in SAMHD1 phosphorylation and, therefore, …
Additional files
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Supplementary file 1
Top 100 upregulated genes in AhR activated macrophages.
The fold change in mRNA levels, relative to carrier treated cells, for the top 100 AhR-activation-induced genes is given.
- https://doi.org/10.7554/eLife.38867.016
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Supplementary file 2
Top 100 downregulated genes in AhR activated macrophages.
The fold change in mRNA levels, relative to carrier treated cells, for the top 100 AhR-activation-repressed genes is given.
- https://doi.org/10.7554/eLife.38867.017
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Supplementary file 3
Pathway analysis of top 100 downregulated genes in (i) AhR activated macrophages and (ii) IFN-γ stimulated macrophages
- https://doi.org/10.7554/eLife.38867.018
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Supplementary file 4
Top 100 upregulated genes in IFN-γ treated macrophages.
The fold change in mRNA levels, relative to carrier treated cells, for the top 100 IFN-γ-induced genes is given.
- https://doi.org/10.7554/eLife.38867.019
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Supplementary file 5
Top 100 downregulated genes in IFN-γ treated macrophages.
The fold change in mRNA levels, relative to carrier treated cells, for the top 100 IFN-γ-repressed genes is given.
- https://doi.org/10.7554/eLife.38867.020
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Transparent reporting form
- https://doi.org/10.7554/eLife.38867.021
