Histone deacetylase inhibitors induce reactivation of herpes simplex virus type 1 in a latency-associated transcript–independent manner in neuronal cells

Danaher, Robert J.; Jacob, Robert J. K.; Steiner, Marion R.; Allen, Will R; Hill, James M.; Miller, Craig S.

doi:10.1080/13550280590952817

Cited by 77 publications

(83 citation statements)

References 61 publications

(59 reference statements)

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“…This conclusion is reinforced by the observation that CTB, a drug that binds to p300/CBP and activates it by altering its conformation effectively, induced viral gene expression in ganglia incubated in medium containing NGF and EGF without prior or concurrent protein synthesis. iv) Studies reported elsewhere have shown that wide-spectrum HDAC inhibitor induced HSV reactivation (25). In this study we reaffirm the expectation that neurons harboring latent virus by inhibition of the HDACs do not require prior or concurrent protein synthesis.…”

Section: Discussionsupporting

confidence: 77%

“…Earlier studies have shown that HSV-1 can be reactivated from latently infected neurons by histone deacetylase (HDAC) inhibitors (25). The purpose of these studies was to verify that HDAC inhibitors, both broad spectrum and those with some degree of specificity, reactivate HSV-1 in latently infected TG maintained in organ culture incubated in medium containing NGF + EGF.…”

Section: Resultsmentioning

confidence: 99%

“…In this series of experiments, we tested three inhibitors. Trichostatin A (TSA) is a broad-spectrum HDAC inhibitor (25,26). Earlier studies have shown that it induces the reactivation of virus in neurons harboring latent virus (25).…”

Section: Resultsmentioning

confidence: 99%

“…Trichostatin A (TSA) is a broad-spectrum HDAC inhibitor (25,26). Earlier studies have shown that it induces the reactivation of virus in neurons harboring latent virus (25). pyridin-3-ylmethyl 4-(2-aminophenylcarbamoyl)benzylcarbamate (MS275) and 3-[5-(3-(3-Fluorophenyl)-3-oxopropen-1-yl)-1-methyl-1H-pyrrol-2-yl]-N-hydroxy-2-propenamide (MC1568) at low concentrations act as specific inhibitors of HDAC 1 and 4, respectively (27,28).…”

Section: Resultsmentioning

confidence: 99%

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Modulation of reactivation of latent herpes simplex virus 1 in ganglionic organ cultures by p300/CBP and STAT3

Zhou

Roizman

2013

Proc. Natl. Acad. Sci. U.S.A.

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A key property of herpes simplex viruses (HSVs) is their ability to establish latent infection in sensory or autonomic ganglia and to reactivate on physical, hormonal, or emotional stress. In latently infected ganglia, HSV expresses a long noncoding RNA and a set of microRNAs, but viral proteins are not expressed. The mechanism by which latent HSV reactivates is unknown. A key question is, what is the mechanism of reactivation in the absence of tegument proteins that enable gene expression in productive infection? Elsewhere we have reported the use of ganglionic organ cultures that enable rapid reactivation in medium containing antibody to NGF or delayed reactivation in medium containing NGF and EGF. We also reported that in the ganglionic organ cultures incubated in medium containing antibody to NGF, all viral genes are derepressed at once without requiring de novo protein synthesis within the time frame of a single replicative cycle. Here we report that latent HSV in ganglia immersed in medium containing NGF and EGF is reactivated by (i) broad spectrum as well as specific histone deacetylase 1 or histone deacetylase 4 inhibitors, (ii) activation of p300/CBP, and (iii) either STAT3 carrying the substitution of tyrosine 705 to phenylalanine or an inhibitor of STAT3. Conversely, reactivation of latent HSV was blocked by p300/CBP inhibitor in medium containing antibody to NGF. The results suggest that (i) STAT3 is required for the maintenance of the latent state and interference with its functions leads to reactivation and (ii) p300/CBP is essential for HSV reactivation.latency-associated transcript | nerve growth factor

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Section: Discussionsupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Modulation of reactivation of latent herpes simplex virus 1 in ganglionic organ cultures by p300/CBP and STAT3

Zhou

Roizman

2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Note that in this experiment, three of the mice inoculated with R112 succumbed to infection between days 9 and 14. that fails to repress the genome in nonneuronal cells. Consistent with this hypothesis are reports that virus reactivation from latent state is enhanced by HDAC inhibitors (15)(16)(17). To test the hypothesis, we inserted a gene encoding REST devoid of both Nand C-terminal repressor domains into the wild-type HSV-1 genome.…”

Section: Discussionmentioning

confidence: 72%

Disruption of HDAC/CoREST/REST repressor by dnREST reduces genome silencing and increases virulence of herpes simplex virus

Zhou

Khan

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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In nonneuronal cells, herpes simplex virus 1 overcomes host defenses, replicates, and ultimately kills the infected cell. Among the host defenses suppressed by the virus is a repressor complex whose key components are histone deacetylase (HDAC) 1 or 2, RE-1 silencing transcription factor (REST), corepressor of REST (CoREST), and lysinespecific demethylase (LSD) 1. In neurons innervating cells at the portal of entry into the body, the virus establishes a "latent" infection in which viral DNA is silenced with the exception of a family of genes. The question posed here is whether the virus hijacks this repressor complex to silence itself in neurons during the latent state. To test this hypothesis, we inserted into the wild-type virus genome a wild-type REST [recombinant (R) 111], a dominant-negative REST (dnREST) lacking the N-and C-terminal repressor domains (R112), or an insertion control consisting of tandem repeats of stop codons (R113). The recombinant virus R112 carrying the dnREST replicated better and was more virulent than the wild-type parent or the other recombinant viruses when administered by the corneal or i.p. routes. Moreover, in contrast to other recombinants, corneal route inoculation by R112 recombinant virus resulted in higher DNA copy numbers, higher levels of infectious virus in eye, trigeminal ganglion, or brain, and virtually complete destruction of trigeminal ganglia in mice that may ultimately succumb to infection. These results support an earlier conclusion that the HDAC/CoREST/REST/LSD1 repressor complex is a significant component of the host innate immunity and are consistent with the hypothesis that HSV-1 hijacks the repressor to silence itself during latent infection.chromatin remodeling | herpesviruses | latency H erpes simplex virus 1 (HSV-1) replicates at the portal of entry into the body, infects sensory nerve endings, and is transported retrograde to the neuronal nucleus (reviewed in ref. 1). In mice, a common animal model system, the virus replicates in some neurons but is silenced and establishes a latent infection in other neurons. Thus, infectious virus is readily detected during the first 10-15 d after infection at a peripheral site. It then disappears, and by day 28 only latent virus is present in the ganglia. One explanation for the two different outcomes of infection is that on release of the viral DNA into the nucleus, the cell attempts to silence the DNA. This attempt leads to a silent, latent infection in neurons but not in cells at the portal of entry into the body or in cell cultures in which the virus replicates. The fundamental question posed in the studies reported here is whether the silencing system suppressed by the virus in productively infected cells is enabled to establish a silent, "latent" infection in neurons.Specifically, several lines of evidence indicate that in infected cells, ICP0, an α (immediate-early) protein, plays a crucial role in enabling viral replication at low multiplicities of infection. At the portal of entry, the genes encoding α protein...

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The histone deacetylase inhibitor Entinostat enhances polymer‐mediated transgene expression in cancer cell lines

Elmer

Christensen

Barua

et al. 2015

Biotech & Bioengineering

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Eukaryotic cells maintain an immense amount of genetic information by tightly wrapping their DNA around positively charged histones. While this strategy allows human cells to maintain more than 25,000 genes, histone binding can also block gene expression. Consequently, cells express histone acetyl transferases (HATs) to acetylate histone lysines and release DNA for transcription. Conversely, histone deacetylases (HDACs) are employed for restoring the positive charge on the histones, thereby silencing gene expression by increasing histone-DNA binding. It has previously been shown that histones bind and silence viral DNA, while hyperacetylation of histones via HDAC inhibition restores viral gene expression. In this study, we demonstrate that treatment with Entinostat, an HDAC inhibitor, enhances transgene (luciferase) expression by up to 25-fold in human prostate and murine bladder cancer cell lines when used with cationic polymers for plasmid DNA delivery. Entinostat treatment altered cell cycle progression, resulting in a significant increase in the fraction of cells present in the G0/G1 phase at low micromolar concentrations. While this moderate G0/G1 arrest disappeared at higher concentrations, a modest increase in the fraction of apoptotic cells and a decrease in cell proliferation were observed, consistent with the known anticancer effects of the drug. DNase accessibility studies revealed no significant change in plasmid transcriptional availability with Entinostat treatment. However, quantitative PCR studies indicated that Entinostat treatment, at the optimal dose for enhancing transgene expression, led to an increase in the amount of plasmid present in the nucleus in two cancer cell lines. Taken together, our results show that Entinostat enhances polymer-mediated transgene expression and can be useful in applications related to transient protein expression in mammalian cells.

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Histone deacetylase inhibitors induce reactivation of herpes simplex virus type 1 in a latency-associated transcript–independent manner in neuronal cells

Cited by 77 publications

References 61 publications

Modulation of reactivation of latent herpes simplex virus 1 in ganglionic organ cultures by p300/CBP and STAT3

Modulation of reactivation of latent herpes simplex virus 1 in ganglionic organ cultures by p300/CBP and STAT3

Disruption of HDAC/CoREST/REST repressor by dnREST reduces genome silencing and increases virulence of herpes simplex virus

The histone deacetylase inhibitor Entinostat enhances polymer‐mediated transgene expression in cancer cell lines

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