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Larragoite ET, Nell RA, Martins LJ, et al. Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation. Biochem Pharmacol. 2021;195:114844doi: 10.1016/j.bcp.2021.114844.
Larragoite, E. T., Nell, R. A., Martins, L. J., Barrows, L. R., Planelles, V., & Spivak, A. M. (2022). Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation. Biochemical pharmacology, 195114844. https://doi.org/10.1016/j.bcp.2021.114844
Larragoite, Erin T, et al. "Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation." Biochemical pharmacology vol. 195 (2022): 114844. doi: https://doi.org/10.1016/j.bcp.2021.114844
Larragoite ET, Nell RA, Martins LJ, Barrows LR, Planelles V, Spivak AM. Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation. Biochem Pharmacol. 2022 Jan;195:114844. doi: 10.1016/j.bcp.2021.114844. Epub 2021 Nov 18. PMID: 34801521.
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Biochem Pharmacol. 2022 Jan;195:114844. doi: 10.1016/j.bcp.2021.114844. Epub 2021 Nov 18.

Histone deacetylase inhibition reduces deleterious cytokine release induced by ingenol stimulation.

Biochemical pharmacology

Erin T Larragoite, Racheal A Nell, Laura J Martins, Louis R Barrows, Vicente Planelles, Adam M Spivak

Affiliations

  1. Department of Pathology, University of Utah, Salt Lake City, United States. Electronic address: [email protected].
  2. Department of Medicine, University of Utah School of Medicine, Salt Lake City, United States.
  3. Department of Pathology, University of Utah, Salt Lake City, United States. Electronic address: [email protected].
  4. Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, United States. Electronic address: [email protected].
  5. Department of Pathology, University of Utah, Salt Lake City, United States. Electronic address: [email protected].
  6. Department of Medicine, University of Utah School of Medicine, Salt Lake City, United States. Electronic address: [email protected].

PMID: 34801521 DOI: 10.1016/j.bcp.2021.114844

Abstract

Latency reversing agents (LRAs), such as protein kinase C (PKC) agonists, constitute a promising strategy for exposing and eliminating the HIV-1 latent reservoir. PKC agonists activate NF-κB and induce deleterious pro-inflammatory cytokine production. Adjuvant pharmacological agents, such as ruxolitinib, a JAK inhibitor, have previously been combined with LRAs to reduce deleterious pro-inflammatory cytokine secretion without inhibiting HIV-1 reactivation in vitro. Histone deacetylase inhibitors (HDACi) are known to dampen pro-inflammatory cytokine secretion in the context of other diseases and synergize with LRAs to reactivate latent HIV-1. This study investigates whether a panel of epigenetic modifiers, including HDACi, could dampen PKC-induced pro-inflammatory cytokine secretion during latency reversal. We screened an epigenetic modifier library for compounds that reduced intracellular IL-6 production induced by the PKC agonist Ingenol-3,20-dibenzoate. We further tested the most promising epigenetic inhibitor class, HDACi, for their ability to reduce pro-inflammatory cytokines and reactivate latent HIV-1 ex vivo. We identified nine epigenetic modulators that reduced PKC-induced intracellular IL-6. In cells from aviremic individuals living with HIV-1, the HDAC1-3 inhibitor, suberohydroxamic acid (SBHA), reduced secretion of pro-inflammatory cytokines TNF-α, IL-5, IL-2r, and IL-17 but did not significantly reactivate latent HIV-1 when combined with Ingenol-3,20-dibenzoate. Combining SBHA and Ingenol-3,20-dibenzoate reduces deleterious cytokine production during latency reversal but does not induce significant viral reactivation in aviremic donor PBMCs. The ability of SBHA to reduce PKC-induced pro-inflammatory cytokines when combined with Ingenol-3,20-dibenzoate suggests SBHA can be used to reduced PKC induced pro-inflammatory cytokines but not to achieve latency reversal in the context of HIV-1.

Copyright © 2021 Elsevier Inc. All rights reserved.

Keywords: Cytokine; HDACi; HIV-1; Ingenol-3,20-dibenzoate; Latency reversing agent; Suberohydroxamic acid

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