The aryl hydrocarbon receptor and interferon gamma generate antiviral states via transcriptional repression.
Tonya KueckElena CassellaJessica HollerBaek KimPaul D BieniaszPublished in: eLife (2018)
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.
Keyphrases
- cell cycle
- transcription factor
- dendritic cells
- antiretroviral therapy
- hiv positive
- hiv infected
- hepatitis c virus
- induced apoptosis
- human immunodeficiency virus
- hiv testing
- cell cycle arrest
- signaling pathway
- immune response
- poor prognosis
- hiv aids
- cell proliferation
- men who have sex with men
- genome wide identification
- pi k akt
- single molecule
- protein kinase
- endoplasmic reticulum stress
- herpes simplex virus
- cell free
- circulating tumor
- protein protein