OBJECTIVE: To investigate the effect of the histone deacetylase inhibitor panobinostat on HIV-associated inflammation. DESIGN: Sub-study of a single-arm, phase I/II clinical trial. METHODS: HIV-infected adults on suppressive antiretroviral therapy received oral panobinostat 20 mg three times per week, every other week, for 8 weeks, that is, four cycles of treatment. Plasma levels of high-sensitivity C-reactive protein, matrix metalloproteinase 9, soluble CD40 ligand and interleukin-6 were determined using human ELISA kits. Soluble endothelia selectin (E-selectin) was measured by a multiplex immunoassay. Total monocyte count, phenotype changes on monocytes and monocyte histone acetylation were analyzed using flow cytometry. Whole-genome expression in peripheral blood mononuclear cells was analyzed at baseline and on-panobinostat employing the Affymetrix Human Transcriptome Array 2.0 microarray assay. Changes from baseline were analyzed using Wilcoxon signed-rank test. For the gene-expression analyses, fold-changes, P values and false detection rate were computed using TAC software. RESULTS: Panobinostat treatment led to significant reductions in multiple established plasma markers of inflammation. Notably, high-sensitivity C-reactive protein decreased by a median of 58% during treatment and this change persisted for 4 weeks after treatment. Plasma levels of interleukin-6, matrix metalloproteinase 9, E-selectin and soluble CD40 ligand also significantly decreased on and/or postpanobinostat. Additionally, we observed a significant reduction in the proportions of intermediate monocytes and tissue factor-positive monocytes. This suppression of cardiovascular risk biomarkers was associated with a prominent reduction in the expression of genes related to inflammation and atherosclerosis. CONCLUSION: Collectively, these data indicate that panobinostat may have therapeutic potential to target excess inflammation in HIV patients with high cardiovascular risk.
OBJECTIVE: To investigate the effect of the histone deacetylase inhibitor panobinostat on HIV-associated inflammation. DESIGN: Sub-study of a single-arm, phase I/II clinical trial. METHODS:HIV-infected adults on suppressive antiretroviral therapy received oral panobinostat 20 mg three times per week, every other week, for 8 weeks, that is, four cycles of treatment. Plasma levels of high-sensitivity C-reactive protein, matrix metalloproteinase 9, soluble CD40 ligand and interleukin-6 were determined using human ELISA kits. Soluble endothelia selectin (E-selectin) was measured by a multiplex immunoassay. Total monocyte count, phenotype changes on monocytes and monocyte histone acetylation were analyzed using flow cytometry. Whole-genome expression in peripheral blood mononuclear cells was analyzed at baseline and on-panobinostat employing the Affymetrix Human Transcriptome Array 2.0 microarray assay. Changes from baseline were analyzed using Wilcoxon signed-rank test. For the gene-expression analyses, fold-changes, P values and false detection rate were computed using TAC software. RESULTS:Panobinostat treatment led to significant reductions in multiple established plasma markers of inflammation. Notably, high-sensitivity C-reactive protein decreased by a median of 58% during treatment and this change persisted for 4 weeks after treatment. Plasma levels of interleukin-6, matrix metalloproteinase 9, E-selectin and soluble CD40 ligand also significantly decreased on and/or postpanobinostat. Additionally, we observed a significant reduction in the proportions of intermediate monocytes and tissue factor-positive monocytes. This suppression of cardiovascular risk biomarkers was associated with a prominent reduction in the expression of genes related to inflammation and atherosclerosis. CONCLUSION: Collectively, these data indicate that panobinostat may have therapeutic potential to target excess inflammation in HIVpatients with high cardiovascular risk.
Authors: Wouter A van der Heijden; Lisa Van de Wijer; Farid Keramati; Wim Trypsteen; Sofie Rutsaert; Rob Ter Horst; Martin Jaeger; Hans Jpm Koenen; Hendrik G Stunnenberg; Irma Joosten; Paul E Verweij; Jan van Lunzen; Charles A Dinarello; Leo Ab Joosten; Linos Vandekerckhove; Mihai G Netea; André Jam van der Ven; Quirijn de Mast Journal: JCI Insight Date: 2021-04-08
Authors: Ane Bjerg Christensen; Anders Dige; Johan Vad-Nielsen; Christel R Brinkmann; Mia Bendix; Lars Østergaard; Martin Tolstrup; Ole S Søgaard; Thomas A Rasmussen; Jens Randel Nyengaard; Jørgen Agnholt; Paul W Denton Journal: Mediators Inflamm Date: 2015-12-01 Impact factor: 4.711
Authors: Vanita Chopra; Luisa Quinti; Prarthana Khanna; Paolo Paganetti; Rainer Kuhn; Anne B Young; Aleksey G Kazantsev; Steven Hersch Journal: J Huntingtons Dis Date: 2016-12-15
Authors: 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 Journal: mSphere Date: 2018-02-14 Impact factor: 4.389
Authors: Martina Korfei; Daniel Stelmaszek; BreAnne MacKenzie; Sylwia Skwarna; Shashipavan Chillappagari; Anna C Bach; Clemens Ruppert; Shigeki Saito; Poornima Mahavadi; Walter Klepetko; Ludger Fink; Werner Seeger; Joseph A Lasky; Soni S Pullamsetti; Oliver H Krämer; Andreas Guenther Journal: PLoS One Date: 2018-11-27 Impact factor: 3.240