Interferon Dependent Immune Memory during HSV-1 Neuronal Latency via Increased H3K9me3 and Restriction by ATRX
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE306427 | GEO | 2025/10/14
REPOSITORIES: GEO
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Project description:The establishment of latent herpes simplex virus 1 (HSV-1) infection is controlled by promyelocytic leukemia nuclear bodies (PML NBs). Viral genomes are recruited to PML NBs structures and chromatinized by repressive H3.3K9me3 modified H3.3 histone variant to form viral DNA-containing PML-NBs (vDCP NBs). Exactly how this occurs is unclear. Here we identify an essential role for the HUSH complex and its SETDB1 and MORC2 effectors in the establishment and maintenance of latent herpes simplex virus 1 (HSV-1) infection. ChIP-seq analyses conducted on latently/quiescently infected primary human fibroblasts highlight the association of the H3K9me3 mark with the entire viral genome. We demonstrate the necessity of HUSH, SETDB1, and MORC2 in the establishment of repressive heterochromatin in vDCP NBs. Depletion of these components prior to viral infection results in reduced H3K9me3 levels across the entirety of latent/quiescent HSV-1 genomes, with minimal impact on the cellular genome as a whole. Once latency is established, depletion of HUSH, SETDB1, or MORC2 by shRNAs or the HIV-2ROD Vpx protein, induces the reactivation of HSV-1 in infected primary human fibroblasts as well as in human induced pluripotent stem cell-derived sensory neurons (hiPSDN). We discovered that the viral protein ICP0 induces MORC2 degradation via the proteasome machinery. This process is concurrent with ICP0 capability to initiate full HSV-1 reactivation, as well as the significant reactivation of HSV-1 upon MORC2 depletion in hiPSDN. Our data demonstrate the potent antiviral restriction activity of the HUSH/SETDB1/MORC2 complex to a non-integrated human herpesvirus, its close association with PML NBs, and introduces a new target for anti-herpesvirus therapy.
2024-09-24 | GSE263436 | GEO
Project description:Herpes simplex virus 1 (HSV-1) transcribes its genome in a highly coordinated temporal cascade, utilizing the host RNA polymerase II (Pol II). Repression of transcription precedes the cascade's progression in a process requiring viral immediate early (IE) genes, in a phenomenon termed Transient Immediate Early gene Mediated Repression (TIEMR). Given that components of promyelocytic leukaemia nuclear bodies (PML-NBs) are known to rapidly engage incoming HSV-1 genomes, we investigated their potential role in TIEMR regulation. Using siRNA knockdown of PML-NB constituents (PML, DAXX, and ATRX), we unexpectedly observed that ATRX depletion resulted in a significant reduction in nascent viral transcription on viral IE promoters at 1.5 hours post-infection (hpi). ChIP-Seq analysis indicated ATRX is associated with both highly transcriptionally active and transcriptionally restricted regions, indicating that ATRX has diverse functions in the viral genome. We show here that ATRX association with active transcription on IE genes is correlated to the presence of G-quadruplexes (G4s). Drug stabilization of G4s mimicked the effects of ATRX knockdown, significantly reducing transcription initiation on IE genes. These findings suggest that ATRX promotes transcriptional initiation of HSV-1 IE genes by preventing G4 formation. In sum, our results reveal a previously unrecognized pro-transcriptional role for ATRX early in HSV-1 infection.
2025-08-26 | GSE293675 | GEO
Project description:Herpes simplex virus 1 (HSV-1) transcribes its genome in a highly coordinated temporal cascade, utilizing the host RNA polymerase II (Pol II). Repression of transcription precedes the cascade's progression in a process requiring viral immediate early (IE) genes, in a phenomenon termed Transient Immediate Early gene Mediated Repression (TIEMR). Given that components of promyelocytic leukaemia nuclear bodies (PML-NBs) are known to rapidly engage incoming HSV-1 genomes, we investigated their potential role in TIEMR regulation. Using siRNA knockdown of PML-NB constituents (PML, DAXX, and ATRX), we unexpectedly observed that ATRX depletion resulted in a significant reduction in nascent viral transcription on viral IE promoters at 1.5 hours post-infection (hpi). ChIP-Seq analysis indicated ATRX is associated with both highly transcriptionally active and transcriptionally restricted regions, indicating that ATRX has diverse functions in the viral genome. We show here that ATRX association with active transcription on IE genes is correlated to the presence of G-quadruplexes (G4s). Drug stabilization of G4s mimicked the effects of ATRX knockdown, significantly reducing transcription initiation on IE genes. These findings suggest that ATRX promotes transcriptional initiation of HSV-1 IE genes by preventing G4 formation. In sum, our results reveal a previously unrecognized pro-transcriptional role for ATRX early in HSV-1 infection.
2025-08-26 | GSE293674 | GEO
Project description:Herpes simplex virus 1 (HSV-1) transcribes its genome in a highly coordinated temporal cascade, utilizing the host RNA polymerase II (Pol II). Repression of transcription precedes the cascade's progression in a process requiring viral immediate early (IE) genes, in a phenomenon termed Transient Immediate Early gene Mediated Repression (TIEMR). Given that components of promyelocytic leukaemia nuclear bodies (PML-NBs) are known to rapidly engage incoming HSV-1 genomes, we investigated their potential role in TIEMR regulation. Using siRNA knockdown of PML-NB constituents (PML, DAXX, and ATRX), we unexpectedly observed that ATRX depletion resulted in a significant reduction in nascent viral transcription on viral IE promoters at 1.5 hours post-infection (hpi). ChIP-Seq analysis indicated ATRX is associated with both highly transcriptionally active and transcriptionally restricted regions, indicating that ATRX has diverse functions in the viral genome. We show here that ATRX association with active transcription on IE genes is correlated to the presence of G-quadruplexes (G4s). Drug stabilization of G4s mimicked the effects of ATRX knockdown, significantly reducing transcription initiation on IE genes. These findings suggest that ATRX promotes transcriptional initiation of HSV-1 IE genes by preventing G4 formation. In sum, our results reveal a previously unrecognized pro-transcriptional role for ATRX early in HSV-1 infection.
2025-08-26 | GSE293673 | GEO
Project description:Herpes simplex virus 1 (HSV-1) transcribes its genome in a highly coordinated temporal cascade, utilizing the host RNA polymerase II (Pol II). Repression of transcription precedes the cascade's progression in a process requiring viral immediate early (IE) genes, in a phenomenon termed Transient Immediate Early gene Mediated Repression (TIEMR). Given that components of promyelocytic leukaemia nuclear bodies (PML-NBs) are known to rapidly engage incoming HSV-1 genomes, we investigated their potential role in TIEMR regulation. Using siRNA knockdown of PML-NB constituents (PML, DAXX, and ATRX), we unexpectedly observed that ATRX depletion resulted in a significant reduction in nascent viral transcription on viral IE promoters at 1.5 hours post-infection (hpi). ChIP-Seq analysis indicated ATRX is associated with both highly transcriptionally active and transcriptionally restricted regions, indicating that ATRX has diverse functions in the viral genome. We show here that ATRX association with active transcription on IE genes is correlated to the presence of G-quadruplexes (G4s). Drug stabilization of G4s mimicked the effects of ATRX knockdown, significantly reducing transcription initiation on IE genes. These findings suggest that ATRX promotes transcriptional initiation of HSV-1 IE genes by preventing G4 formation. In sum, our results reveal a previously unrecognized pro-transcriptional role for ATRX early in HSV-1 infection.
2025-08-26 | GSE293672 | GEO
Project description:Host innate immune defences play a critical role in restricting the intracellular propagation and pathogenesis of invading viral pathogens. Here we show that the histone H3.3 chaperone HIRA (histone cell cycle regulator) associates with promyelocytic leukaemia nuclear bodies (PML-NBs) to stimulate the induction of innate immune defences against herpes simplex virus 1 (HSV-1) infection. Following the activation of innate immune signalling, HIRA localized at PML-NBs in a Janus-Associated Kinase (JAK), Cyclin Dependent Kinase (CDK), and Sp100-dependent manner. RNA-seq analysis revealed that HIRA promoted the transcriptional upregulation of a broad repertoire of host genes that regulate innate immunity to HSV-1 infection, including those involved in MHC-I antigen presentation, cytokine signalling, and interferon stimulated gene (ISG) expression. ChIP-seq analysis revealed that PML, the principle scaffolding protein of PML-NBs, was required for the enrichment of HIRA onto ISGs, identifying a role for PML in the HIRA-dependent regulation of innate immunity to virus infection. Our data identifies independent roles for HIRA in the intrinsic silencing of viral gene expression and the induction of innate immune defences to restrict the initiation and propagation of HSV-1 infection, respectively. These intracellular host defences are antagonized by the HSV-1 ubiquitin ligase ICP0, which disrupts the stable recruitment of HIRA to infecting viral genomes and PML-NBs at spatiotemporally distinct phases of infection. Our study highlights the importance of histone chaperones to regulate multiple phases of intracellular immunity to virus infection, findings that are likely to be highly pertinent in the cellular restriction of many clinically important viral pathogens.
2019-03-12 | GSE128173 | GEO
Project description:Chronic viral infections are difficult to treat and new approaches, particularly those involving enhancing immune responses are needed. Herpes simplex virus (HSV) establishes latency, reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus-specific T cells are important to control HSV, and activated T cells require increased metabolism of glutamine for their proliferation. We found that treatment of HSV-1 latently infected mice and HSV-2 infected guinea pigs with supplemental oral glutamine reduced virus reactivation. Transcriptome analysis of mice treated with glutamine showed that several interferon (IFN)-γ inducible genes were upregulated. Unlike wild-type mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in IFN-γ knock-out mice. Mice treated with glutamine had higher numbers of HSV-specific IFN-γ producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-γ-associated immune response and reduce the rate of reactivation of latent virus infection.
2017-08-30 | GSE95714 | GEO
Project description:Chronic viral infections are difficult to treat and new approaches, particularly those involving enhancing immune responses are needed. Herpes simplex virus (HSV) establishes latency, reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus-specific T cells are important to control HSV, and activated T cells require increased metabolism of glutamine for their proliferation. We found that treatment of HSV-1 latently infected mice and HSV-2 infected guinea pigs with supplemental oral glutamine reduced virus reactivation. Transcriptome analysis of mice treated with glutamine showed that several interferon (IFN)-γ inducible genes were upregulated. Unlike wild-type mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in IFN-γ knock-out mice. Mice treated with glutamine had higher numbers of HSV-specific IFN-γ producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-γ-associated immune response and reduce the rate of reactivation of latent virus infection.
2017-08-30 | GSE95713 | GEO
Project description:Chronic viral infections are difficult to treat and new approaches, particularly those involving enhancing immune responses are needed. Herpes simplex virus (HSV) establishes latency, reactivates frequently, and breakthrough reactivation can occur despite suppressive antiviral therapy. Virus-specific T cells are important to control HSV, and activated T cells require increased metabolism of glutamine for their proliferation. We found that treatment of HSV-1 latently infected mice and HSV-2 infected guinea pigs with supplemental oral glutamine reduced virus reactivation. Transcriptome analysis of mice treated with glutamine showed that several interferon (IFN)-γ inducible genes were upregulated. Unlike wild-type mice, supplemental glutamine was ineffective in reducing the rate of HSV-1 reactivation in IFN-γ knock-out mice. Mice treated with glutamine had higher numbers of HSV-specific IFN-γ producing CD8 T cells in latently infected ganglia. Thus, glutamine may enhance the IFN-γ-associated immune response and reduce the rate of reactivation of latent virus infection.
2017-08-30 | GSE95715 | GEO
Project description:Herpes simplex virus type 1 (HSV-1) is a 152 Kb double stranded DNA alpha-herpesvirus, which establishes long life latent infection in sensory neurons. Most of our knowledge regarding HSV-1 latency comes from in vivo studies using small animal models, mainly rodents and rabbits, which are not naturally infected by HSV-1. Furthermore, these animal models do not fully recapitulate the species specific effects of human HSV-1 infection. Human cellular models utilize trigeminal ganglia removed from cadavers or, alternatively, neuron-like cells derived from cancerous cell lines that do not fully reflect effects on normal human neurons. This limitation poses the need to develop an in vitro model to investigate molecular details of the mechanisms underlying latency and reactivation in human neurons. Induced pluripotent stem (iPS) cell technologies offer an unprecedented opportunity to generate unlimited supplies of neurons and the facility to manipulate such cells in vitro. In this study, we developed an in vitro HSV-1 infection model in human iPS-derived neural progenitor cells (NPCs) and neurons, which displays the main hallmarks of latency defined in animal models and in humans. Induced pluripotent stem (iPS) cells were generated from human skin biopsy samples
2014-05-02 | E-GEOD-46041 | biostudies-arrayexpress