Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
The histone deacetylase inhibitor panobinostat lowers biomarkers of cardiovascular risk and inflammation in HIV patients. / Høgh Kølbæk Kjær, Anne Sofie; Brinkmann, Christel Rothe; Dinarello, Charles A; Olesen, Rikke; Østergaard, Lars Jørgen; Søgaard, Ole Schmeltz; Tolstrup, Martin; Rasmussen, Thomas Aagaard.
In: AIDS, 13.04.2015.Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
}
TY - JOUR
T1 - The histone deacetylase inhibitor panobinostat lowers biomarkers of cardiovascular risk and inflammation in HIV patients
AU - Høgh Kølbæk Kjær, Anne Sofie
AU - Brinkmann, Christel Rothe
AU - Dinarello, Charles A
AU - Olesen, Rikke
AU - Østergaard, Lars Jørgen
AU - Søgaard, Ole Schmeltz
AU - Tolstrup, Martin
AU - Rasmussen, Thomas Aagaard
PY - 2015/4/13
Y1 - 2015/4/13
N2 - 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.
AB - 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.
U2 - 10.1097/QAD.0000000000000678
DO - 10.1097/QAD.0000000000000678
M3 - Journal article
C2 - 25870990
JO - AIDS
JF - AIDS
SN - 0269-9370
ER -