Treatment of HIV-infected individuals with the histone deacetylase inhibitor panobinostat results in increased numbers of regulatory T cells and limits Ex vivo lipopolysaccharide-induced inflammatory responses

Christel Rothe Brinkmann, Jesper Falkesgaard Højen, Thomas Aagaard Rasmussen, Anne Sofie Kjær, Rikke Olesen, Paul W. Denton, Lars Østergaard, Zhengyu Ouyang, Mathias Lichterfeld, Xu Yu, Ole Schmeltz Søgaard, Charles Dinarello, Martin Tolstrup

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Histone deacetylase inhibitors (HDACi) modulate the transcriptional activity of all cells, including innate and adaptive immune cells. Therefore, we aimed to evaluate immunological effects of treatment with the HDACi panobinostat in HIV-infected patients during a clinical phase IIa latency reversal trial. Using flow cytometry, we investigated changes in T cell activation (CD69, CD38, HLA-DR) and the expression of CD39 and CTLA4 on regulatory T cells (Tregs). Whole-blood stimulations were performed and cytokine responses measured using Luminex. Gene expression in purified peripheral blood mononuclear cells (PBMCs) was evaluated using an Affymetrix HTA 2.0 gene chip. We found that proportions of CD4+ and CD8+ T cells expressing CD69 increased 24 h after initial panobinostat administration (P < 0.01), followed by an increase in the proportions of CD38+ HLA-DR+-coexpressing CD4+ T cells on day 4 (P = 0.02). Concurrently, proportions of Tregs increased by 40% (P = 0.003). Treg CTLA4 median fluorescent intensity (MFI) increased by 25% (P = 0.007), and CD39 MFI on CD39+ Treg increased by 12% (P = 0.02). Lipopolysaccharide (LPS)-induced inflammatory responses (interleukin-1β [IL-1β], IL-6, IL-12p40, and tumor necrosis factor alpha [TNF-α]) in whole blood were significantly downregulated 4 days after initial dosing. Lastly, panobinostat induced significant changes in the overall gene expression pattern (fold change, >1.5; false-discovery-rate [FDR]-corrected P, < 0.05). Importantly, measures of immune function returned to baseline after panobinostat treatment and follow-up revealed no sustained effect on overall gene expression.

Original languageEnglish (US)
Article numbere00616-17
JournalmSphere
Volume3
Issue number1
DOIs
StatePublished - Jan 1 2018
Externally publishedYes

Keywords

  • Clinical trials
  • Gene expression
  • Histone deacetylase inhibitors
  • Human immunodeficiency virus
  • Inflammation
  • T-cell immunity

ASJC Scopus subject areas

  • Microbiology
  • Molecular Biology

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