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

2018 ◽  
Author(s):  
Tonya Kueck ◽  
Elena Cassella ◽  
Jessica Holler ◽  
Baek Kim ◽  
Paul D. Bieniasz
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Interferon Gamma ◽  
Transcriptional Repression ◽  
Cyclin Dependent Kinase ◽  
Antiviral Signaling ◽  
Aryl Hydrocarbon ◽  
Antiviral Effects ◽  
Ifn Γ ◽  
Hiv 1 ◽  
Hsv 1

SummaryThe 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-γ), 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-γ, respectively. Thus, distinct antiviral signaling pathways converge on CDK/cyclin repression, causing inhibition of viral DNA synthesis and replication.

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

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Tonya Kueck ◽  
Elena Cassella ◽  
Jessica Holler ◽  
Baek Kim ◽  
Paul D Bieniasz
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Interferon Gamma ◽  
Transcriptional Repression ◽  
Cyclin Dependent Kinase ◽  
Antiviral Signaling ◽  
Aryl Hydrocarbon ◽  
Antiviral Effects ◽  
Ifn Γ ◽  
Hiv 1 ◽  
Hsv 1

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-γ), 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-γ, respectively. Thus, distinct antiviral signaling pathways converge on CDK/cyclin repression, causing inhibition of viral DNA synthesis and replication.

scholarly journals Abnormal intracellular IL-2 and interferon-gamma (IFN-γ) production as HIV-1-associated markers of immune dysfunction

1998 ◽  
Vol 111 (2) ◽  
pp. 257-263 ◽  
Author(s):  
Westby ◽  
Marriott ◽  
Guckian ◽  
Cookson ◽  
Hay ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Immune Dysfunction ◽  
Ifn Γ ◽  
Hiv 1

scholarly journals Tryptophan Metabolism Activates Aryl Hydrocarbon Receptor-Mediated Pathway To Promote HIV-1 Infection and Reactivation

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Yan-Heng Zhou ◽  
Li Sun ◽  
Jun Chen ◽  
Wei-Wei Sun ◽  
Li Ma ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Aryl Hydrocarbon Receptor ◽  
Metabolic Pathways ◽  
Nuclear Translocation ◽  
Underlying Mechanism ◽  
Hiv Pathogenesis ◽  
Downstream Target ◽  
Potential Target ◽  
Aryl Hydrocarbon ◽  
Hiv 1

ABSTRACT Multiple cellular metabolic pathways are altered by HIV-1 infection, with an impact on immune activation, inflammation, and acquisition of non-AIDS comorbid diseases. The dysfunction of tryptophan (Trp) metabolism has been observed clinically in association with accelerated HIV-1 pathogenesis, but the underlying mechanism remains unknown. In this study, we demonstrated that the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, is activated by Trp metabolites to promote HIV-1 infection and reactivation. AHR directly binds to the HIV-1 5′ long terminal repeat (5′-LTR) at the molecular level to activate viral transcription and infection, and AHR activation by Trp metabolites increases its nuclear translocation and association with the HIV 5′-LTR; moreover, the binding of AHR with HIV-1 Tat facilitates the recruitment of positive transcription factors to viral promoters. These findings not only elucidate a previously unappreciated mechanism through which cellular Trp metabolites affect HIV pathogenesis but also suggest that a downstream target AHR may be a potential target for modulating HIV-1 infection. IMPORTANCE Cellular metabolic pathways that are altered by HIV-1 infection may accelerate disease progression. Dysfunction in tryptophan (Trp) metabolism has been observed clinically in association with accelerated HIV-1 pathogenesis, but the mechanism responsible was not known. This study demonstrates that Trp metabolites augment the activation of aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, to promote HIV-1 infection and transcription. These findings not only elucidate a previously unappreciated mechanism through which cellular Trp metabolites affect HIV pathogenesis but also suggest that a downstream target AHR may be a potential target for modulating HIV-1 infection.

Impact of aryl hydrocarbon receptor (AhR) knockdown on cell cycle progression in human HaCaT keratinocytes

2011 ◽  
Vol 392 (7) ◽  
Author(s):  
Michaela Kalmes ◽  
Jenny Hennen ◽  
Judith Clemens ◽  
Brunhilde Blömeke
Keyword(s):  
Cell Cycle ◽  
Aryl Hydrocarbon Receptor ◽  
Protein Level ◽  
Cell Cycle Progression ◽  
Physiological Function ◽  
Hacat Cells ◽  
Cyclin Dependent Kinase ◽  
Cycle Progression ◽  
Aryl Hydrocarbon ◽  
Exogenous Ligands

Abstract While activation of the aryl hydrocarbon receptor (AhR) by exogenous ligands is well investigated, its physiological function is less understood. By extending research in AhR biology, evidence appeared that the receptor generally plays an important role in cell physiology. In keratinocytes, little is known about endogenous functions of the AhR. In order to expand this knowledge, we analyzed the impact of AhR knockdown on cell cycle progression in HaCaT cells and showed that proliferation of siAhR HaCaT cells was significantly decreased. In line with that result, western blot analysis revealed that protein level of the cyclin dependent kinase inhibitor p27KIP1 was increased, whereas protein level of the cyclin dependent kinase (CDK) 2 was reduced. CDK4 and CDK6 protein levels remained unchanged, whereas protein level of the retinoblastoma protein (pRB) was reduced. By measuring ethoxyresorufin-O-deethylase (EROD) activity we showed that endogenous cytochrome P450 1 (CYP1), especially CYP1A1 is required for normal cell cycle in HaCaT cells, as well. To the best of our knowledge, we provide evidence for the first time in human skin cells, that in the absence of exogenous ligands, the AhR promotes cell cycle progression in HaCaT cells and one can speculate that this is the physiological function of this receptor in keratinocytes.

scholarly journals Role of the Aryl Hydrocarbon Receptor in the Immune Response Profile and Development of Pathology during Plasmodium berghei Anka Infection

2014 ◽  
Vol 82 (8) ◽  
pp. 3127-3140 ◽  
Author(s):  
Fatima Brant ◽  
Aline S. Miranda ◽  
Lisia Esper ◽  
David Henrique Rodrigues ◽  
Lucas Miranda Kangussu ◽  
...  
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Plasmodium Berghei ◽  
Transforming Growth Factor ◽  
Interleukin 17 ◽  
High Morbidity ◽  
Content Type ◽  
Aryl Hydrocarbon ◽  
Tnf Α ◽  
Ifn Γ ◽  
The Brain

ABSTRACTInfection withPlasmodium falciparummay result in severe disease affecting various organs, including liver, spleen, and brain, resulting in high morbidity and mortality.Plasmodium bergheiAnka infection of mice recapitulates many features of severe human malaria. The aryl hydrocarbon receptor (AhR) is an intracellular receptor activated by ligands important in the modulation of the inflammatory response. We found that AhR-knockout (KO) mice infected withP. bergheiAnka displayed increased parasitemia, earlier mortality, enhanced leukocyte-endothelial cell interactions in the brain microvasculature, and increased inflammation in brain (interleukin-17 [IL-17] and IL-6) and liver (gamma interferon [IFN-γ] and tumor necrosis factor alpha [TNF-α]) compared to infected wild-type (WT) mice. Infected AhR-KO mice also displayed a reduction in cytokines required for host resistance, including TNF-α, IL-1β, and IFN-γ, in the brain and spleen. Infection of AhR-KO mice resulted in an increase in T regulatory cells and transforming growth factor β, IL-6, and IL-17 in the brain. AhR modulated the basal expression of SOCS3 in spleen and brain, andP. bergheiAnka infection resulted in enhanced expression of SOCS3 in brain, which was absent in infected AhR-KO mice. These data suggest that AhR-mediated control of SOCS3 expression is probably involved in the phenotype seen in infected AhR-KO mice. This is, to our knowledge, the first demonstration of a role for AhR in the pathogenesis of malaria.

scholarly journals Expression of Interferon Gamma by a Recombinant Rabies Virus Strongly Attenuates the Pathogenicity of the Virus via Induction of Type I Interferon

2014 ◽  
Vol 89 (1) ◽  
pp. 312-322 ◽  
Author(s):  
Darryll A. Barkhouse ◽  
Samantha A. Garcia ◽  
Emily K. Bongiorno ◽  
Aurore Lebrun ◽  
Milosz Faber ◽  
...  
Keyword(s):  
Rabies Virus ◽  
Interferon Gamma ◽  
Virus Replication ◽  
Neutralizing Antibodies ◽  
Type I Interferon ◽  
Lethal Dose ◽  
Type I Interferons ◽  
Type I ◽  
Antiviral Effects ◽  
Ifn Γ

ABSTRACTPrevious animal model experiments have shown a correlation between interferon gamma (IFN-γ) expression and both survival from infection with attenuated rabies virus (RABV) and reduction of neurological sequelae. Therefore, we hypothesized that rapid production of murine IFN-γ by the rabies virus itself would induce a more robust antiviral response than would occur naturally in mice. To test this hypothesis, we used reverse engineering to clone the mouse IFN-γ gene into a pathogenic rabies virus backbone, SPBN, to produce the recombinant rabies virus designated SPBNγ. Morbidity and mortality were monitored in mice infected intranasally with SPBNγ or SPBN(−) control virus to determine the degree of attenuation caused by the expression of IFN-γ. Incorporation of IFN-γ into the rabies virus genome highly attenuated the virus. SPBNγ has a 50% lethal dose (LD50)more than 100-fold greater than SPBN(−).In vitroandin vivomouse experiments show that SPBNγ infection enhances the production of type I interferons. Furthermore, knockout mice lacking the ability to signal through the type I interferon receptor (IFNAR−/−) cannot control the SPBNγ infection and rapidly die. These data suggest that IFN-γ production has antiviral effects in rabies, largely due to the induction of type I interferons.IMPORTANCESurvival from rabies is dependent upon the early control of virus replication and spread. Once the virus reaches the central nervous system (CNS), this becomes highly problematic. Studies of CNS immunity to RABV have shown that control of replication begins at the onset of T cell entry and IFN-γ production in the CNS prior to the appearance of virus-neutralizing antibodies. Moreover, antibody-deficient mice are able to control but not clear attenuated RABV from the CNS. We find here that IFN-γ triggers the early production of type I interferons with the expected antiviral effects. We also show that engineering a lethal rabies virus to express IFN-γ directly in the infected tissue reduces rabies virus replication and spread, limiting its pathogenicity in normal and immunocompromised mice. Therefore, vector delivery of IFN-γ to the brain may have the potential to treat individuals who would otherwise succumb to infection with rabies virus.

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