The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV-1 without producing a T cell response

Bernhard, Wendy; Barreto, Kris; Saunders, Amy E.; Dahabieh, Matthew S.; Johnson, Pauline; Sadowski, Ivan

doi:10.1016/j.febslet.2011.10.018

Cited by 80 publications

(65 citation statements)

References 25 publications

(41 reference statements)

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“…HDACis and HMT inhibitors (HMTis) have been reported to synergistically enhance the expression of the latent HIV genome, although most of these studies were limited by the use of transformed cell line model systems and nonselective inhibitors (16,18,19,45). As we found little effect on latent proviral expression following demethylation induced by exposure to GSK343 (Fig.…”

Section: Prc1 and Prc2 Occupy The Hiv Promoter In 2d10 Cells Thementioning

confidence: 73%

“…This activity of these enzymes was further validated by using pharmacological inhibitors such as BIX01294 (19), chaetocin (16,45), and 3-deazaneplanocin A (DZNep) (18), alone or in combination with HDACis (16,18,19,45,51). However, these studies have serious limitations, as they were performed in either cycling, transformed T-cell line models of HIV latency (16,18,19,45) or bulk PBMCs and resting CD4 ϩ T cells isolated from HIV-positive (HIV ϩ ) aviremic patients (45), and the inhibitors used in these studies were either not highly selective or used at concentrations that allowed nonselective effects.…”

Section: Discussionmentioning

confidence: 99%

“…Epigenetic modifications such as histone methylation and deacetylation appear to play a role in maintaining HIV latency. Latent HIV-1 proviruses display a defined nucleosomal structure featuring a key nucleosome near the transcription start site (11,12), with local occupancy of histone deacetylases (HDACs), deacetylated histones (13)(14)(15), and methylated histones (16)(17)(18)(19)(20). HDAC inhibitors (HDACis) have been extensively studied for their potential to reactivate latent virus in cultured-cell models of latency, ex vivo in resting CD4 ϩ T cells from patients, and in vivo in patients with ART-suppressed viremia (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32).…”

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confidence: 99%

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H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells

Tripathy

McManamy

Burch

et al. 2015

J Virol

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Histone methyltransferase inhibitors (HMTis) and histone deacetylase inhibitors (HDACis) are reported to synergistically induce the expression of latent human immunodeficiency virus type 1 (HIV-1), but studies have largely been performed with cell lines. As specific and potent HMTis directed at EZH1 (enhancer of zeste 2 Polycomb repressive complex 2 subunit 1)/EZH2 are now in human testing, we wished to rigorously test such an inhibitor in a primary resting T-cell model of HIV latency. We found that GSK343, a potent and selective EZH2/EZH1 inhibitor, reduced trimethylation of histone 3 at lysine 27 (H3K27) of the HIV provirus in resting cells. Remarkably, this epigenetic change was not associated with increased proviral expression in latently infected resting cells. However, following the reduction in H3K27 at the HIV long terminal repeat (LTR), subsequent exposure to the HDACi suberoylanilide hydroxamic acid or vorinostat (VOR) resulted in increases in HIV gag RNA and HIV p24 antigen production that were up to 2.5-fold greater than those induced by VOR alone. Therefore, in primary resting CD4 ؉ T cells, true mechanistic synergy in the reversal of HIV latency may be achieved by the combination of HMTis and HDACis. Although other cellular effects of EZH2 inhibition may contribute to the sensitization of the HIV LTR to subsequent exposure to VOR, and to increase viral antigen production, this synergistic effect is directly associated with H3K27 demethylation at nucleosome 1 (Nuc-1). Based upon our findings, the combination of HMTis and HDACis should be considered for testing in animal models or clinical trials. IMPORTANCEDemethylation of H3K27 mediated by the histone methyltransferase inhibitor GSK343 in primary resting T cells is slow, occurring over 96 h, but by itself does not result in a significant upregulation of cell-associated HIV RNA expression or viral antigen production. However, following H3K27 demethylation, latent viral expression within infected primary resting CD4 ؉ T cells is synergistically increased upon exposure to the histone deacetylase inhibitor vorinostat. Demethylation at H3K27 sensitizes the HIV promoter to the effects of an HDACi and provides a proof-of-concept for the testing of combination epigenetic approaches to disrupt latent HIV infection, a necessary step toward the eradication of HIV infection. C urrent antiretroviral therapy (ART) potently suppresses human immunodeficiency virus type 1 (HIV-1) replication; however, HIV infection persists (1, 2). The primary reservoir of persistent infection is a small pool of latently infected resting central memory CD4 ϩ T cells (3-5). This reservoir must be targeted in any attempt to eradicate HIV-1 infection. Latent HIV infection is defined as dormant, nonreplicating virus that can be recovered following activation of the latently infected cell. However, a recent study found that a single exposure to latency-reversing agents, even a broad mitogenic signal, does not reverse latency universally throughout a population of infected cells,...

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Section: Prc1 and Prc2 Occupy The Hiv Promoter In 2d10 Cells Thementioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells

Tripathy

McManamy

Burch

et al. 2015

J Virol

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“…Chaetocin belongs to the 3-6-epi-dithio-diketopiperazines, which have been suggested to participate in immunosuppression [55] and anti-inflammation [56] . As a specific SUV39H1 inhibitor, chaetocin was observed to cause a 25-fold increase in latent HIV expression without significant toxicity or global T cell activation in Jurkat T cells [57] . Subsequently, another group observed that chaetocin induced HIV-1 recovery in 50% of CD8-depleted PBMC cultures and in 86% of resting CD4 + T cell cultures isolated from HIV-1-infected, HAARTtreated patients [32] .…”

Section: Histone Methyltransferase Inhibitors (Hmti)mentioning

confidence: 97%

Progress and challenges in the use of latent HIV-1 reactivating agents

Shang

Ding

et al. 2015

Acta Pharmacol Sin

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Highly active antiretroviral therapy (HAART) can effectively suppress the replication of human immunodeficiency virus-1 (HIV-1) and block disease progression. However, chronic HIV-1 infection remains incurable due to the persistence of a viral reservoir, including the transcriptionally silent provirus in CD4 + memory T cells and the sanctuary sites that are inaccessible to drugs. Reactivation and the subsequent elimination of latent virus through virus-specific cytotoxic effects or host immune responses are critical strategies for combating the disease. Indeed, a number of latency reactivating reagents have been identified through mechanism-directed approaches and large-scale screening, including: (1) histone deacetylase inhibitors (HDACi); (2) cytokines and chemokines; (3) DNA methyltransferase inhibitors (DNMTI); (4) histone methyltransferase inhibitors (HMTI); (5) protein kinase C (PKC) activators; (6) P-TEFb activators; and (7) unclassified agents, such as disulfram. They have proved to be efficacious in latent cell line models and CD4 + T lymphocytes from HIV-1-infected patients. This review comprehensively summarizes the recent progress and relative challenges in this field.

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“…Disruption of chromatin organization at the HIV-1 LTR promoter sets a threshold for transcription factor activation and eventually reversal of the state of chromatin that is responsible for the repression of HIV proviral DNA within the host genome. Interestingly, proof-of-concept studies using various combinations of HDAC or histone methyltransferase (HMT) inhibitors showed that purging of latent proviruses from latently infected cells is practically attainable (40,41).…”

Section: Hiv Latency As a Critical Obstacle To The Eradication Of Hivmentioning

confidence: 99%

Interaction between Endogenous Bacterial Flora and Latent HIV Infection

Victoriano

Imai

Okamoto

2013

Clin Vaccine Immunol

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bHuman commensal bacteria do not normally cause any diseases. However, in certain pathological conditions, they exhibit a number of curious behaviors. In HIV infection, these bacteria exhibit bidirectional relationships: whereas they cause opportunistic infections based on immunological deterioration, they also augment HIV replication, in particular, viral replication from latently infected cells, which is attributable to the effect of butyric acid produced by certain anaerobic bacteria by modifying the state of chromatin. Here, we review recent evidence supporting the contributory role of such endogenous microbes in disrupting HIV latency and its potential link to the clinical progression of AIDS.

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The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV-1 without producing a T cell response

Cited by 80 publications

References 25 publications

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells

Progress and challenges in the use of latent HIV-1 reactivating agents

Interaction between Endogenous Bacterial Flora and Latent HIV Infection

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The Suv39H1 methyltransferase inhibitor chaetocin causes induction of integrated HIV-1 without producing a T cell response

Cited by 80 publications

References 25 publications

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 + T Cells

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 + T Cells

Progress and challenges in the use of latent HIV-1 reactivating agents

Interaction between Endogenous Bacterial Flora and Latent HIV Infection

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Product

Resources

About

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells

H3K27 Demethylation at the Proviral Promoter Sensitizes Latent HIV to the Effects of Vorinostat in Ex Vivo Cultures of Resting CD4 ⁺ T Cells