Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation

Thomas Aagaard Rasmussen, Ole Schmeltz Sogaard, Christel Brinkmann, Fiona Wightman, Sharon Ruth Lewin, Jesper Melchjorsen, Charles Dinarello, Lars Ostergaard, Martin Tolstrup

Research output: Contribution to journalArticleResearchpeer-review

124 Citations (Scopus)

Abstract

Objective: We aimed to compare the potential for inducing HIV production and the effect on T-cell activation of potent HDAC inhibitors undergoing clinical investigation. Design: In vitro study. Results: The various HDAC inhibitors displayed significant potency differences in stimulating HIV-1 expression from the latently infected cell lines with panobinostat > givinostat ? belinostat > vorinostat > valproic acid. Panobinostat was significantly more potent than all other HDAC inhibitors and induced virus production even in the very low concentration range 8-31 nM. The proportion of primary T-cells expressing the early activation marker CD69 increased moderately in all HDAC inhibitor-treated cells compared with untreated cells. Finally, proof was obtained that panobinostat, givinostat and belinostat induce virus production in latently infected primary cells at therapeutic concentrations with panobinostat being the most potent stimulator. Methods: The latently infected cell lines ACH2 and U1 were treated with the HDAC inhibitors panobinostat, givinostat, belinostat, vorinostat and valproic acid. Viral induction was estimated by p24 production. Peripheral blood mononuclear cells from uninfected donors were treated with the HDAC inhibitors and the expression of activation markers on T-cell phenotypes was measured using flow cytometry. Finally, the ability of givinostat, belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4+ T cell infection model. Conclusion: At therapeutic concentrations panobinostat stimulate HIV-1 expression in latently infected cells with greater potency than other HDAC inhibitors undergoing clinical investigation. These findings warrant further investigation and panobinostat is now being advanced into clinical testing against latent HIV infection. ? 2013 Landes Bioscience
Original languageEnglish
Pages (from-to)993 - 1001
Number of pages9
JournalHuman Vaccines & Immunotherapeutics
Volume9
Issue number5
DOIs
Publication statusPublished - 2013

Cite this

Rasmussen, Thomas Aagaard ; Sogaard, Ole Schmeltz ; Brinkmann, Christel ; Wightman, Fiona ; Lewin, Sharon Ruth ; Melchjorsen, Jesper ; Dinarello, Charles ; Ostergaard, Lars ; Tolstrup, Martin. / Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. In: Human Vaccines & Immunotherapeutics. 2013 ; Vol. 9, No. 5. pp. 993 - 1001.
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abstract = "Objective: We aimed to compare the potential for inducing HIV production and the effect on T-cell activation of potent HDAC inhibitors undergoing clinical investigation. Design: In vitro study. Results: The various HDAC inhibitors displayed significant potency differences in stimulating HIV-1 expression from the latently infected cell lines with panobinostat > givinostat ? belinostat > vorinostat > valproic acid. Panobinostat was significantly more potent than all other HDAC inhibitors and induced virus production even in the very low concentration range 8-31 nM. The proportion of primary T-cells expressing the early activation marker CD69 increased moderately in all HDAC inhibitor-treated cells compared with untreated cells. Finally, proof was obtained that panobinostat, givinostat and belinostat induce virus production in latently infected primary cells at therapeutic concentrations with panobinostat being the most potent stimulator. Methods: The latently infected cell lines ACH2 and U1 were treated with the HDAC inhibitors panobinostat, givinostat, belinostat, vorinostat and valproic acid. Viral induction was estimated by p24 production. Peripheral blood mononuclear cells from uninfected donors were treated with the HDAC inhibitors and the expression of activation markers on T-cell phenotypes was measured using flow cytometry. Finally, the ability of givinostat, belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4+ T cell infection model. Conclusion: At therapeutic concentrations panobinostat stimulate HIV-1 expression in latently infected cells with greater potency than other HDAC inhibitors undergoing clinical investigation. These findings warrant further investigation and panobinostat is now being advanced into clinical testing against latent HIV infection. ? 2013 Landes Bioscience",
author = "Rasmussen, {Thomas Aagaard} and Sogaard, {Ole Schmeltz} and Christel Brinkmann and Fiona Wightman and Lewin, {Sharon Ruth} and Jesper Melchjorsen and Charles Dinarello and Lars Ostergaard and Martin Tolstrup",
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Rasmussen, TA, Sogaard, OS, Brinkmann, C, Wightman, F, Lewin, SR, Melchjorsen, J, Dinarello, C, Ostergaard, L & Tolstrup, M 2013, 'Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation', Human Vaccines & Immunotherapeutics, vol. 9, no. 5, pp. 993 - 1001. https://doi.org/10.4161/hv.23800

Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation. / Rasmussen, Thomas Aagaard; Sogaard, Ole Schmeltz; Brinkmann, Christel; Wightman, Fiona; Lewin, Sharon Ruth; Melchjorsen, Jesper; Dinarello, Charles; Ostergaard, Lars; Tolstrup, Martin.

In: Human Vaccines & Immunotherapeutics, Vol. 9, No. 5, 2013, p. 993 - 1001.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Comparison of HDAC inhibitors in clinical development: effect on HIV production in latently infected cells and T-cell activation

AU - Rasmussen, Thomas Aagaard

AU - Sogaard, Ole Schmeltz

AU - Brinkmann, Christel

AU - Wightman, Fiona

AU - Lewin, Sharon Ruth

AU - Melchjorsen, Jesper

AU - Dinarello, Charles

AU - Ostergaard, Lars

AU - Tolstrup, Martin

PY - 2013

Y1 - 2013

N2 - Objective: We aimed to compare the potential for inducing HIV production and the effect on T-cell activation of potent HDAC inhibitors undergoing clinical investigation. Design: In vitro study. Results: The various HDAC inhibitors displayed significant potency differences in stimulating HIV-1 expression from the latently infected cell lines with panobinostat > givinostat ? belinostat > vorinostat > valproic acid. Panobinostat was significantly more potent than all other HDAC inhibitors and induced virus production even in the very low concentration range 8-31 nM. The proportion of primary T-cells expressing the early activation marker CD69 increased moderately in all HDAC inhibitor-treated cells compared with untreated cells. Finally, proof was obtained that panobinostat, givinostat and belinostat induce virus production in latently infected primary cells at therapeutic concentrations with panobinostat being the most potent stimulator. Methods: The latently infected cell lines ACH2 and U1 were treated with the HDAC inhibitors panobinostat, givinostat, belinostat, vorinostat and valproic acid. Viral induction was estimated by p24 production. Peripheral blood mononuclear cells from uninfected donors were treated with the HDAC inhibitors and the expression of activation markers on T-cell phenotypes was measured using flow cytometry. Finally, the ability of givinostat, belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4+ T cell infection model. Conclusion: At therapeutic concentrations panobinostat stimulate HIV-1 expression in latently infected cells with greater potency than other HDAC inhibitors undergoing clinical investigation. These findings warrant further investigation and panobinostat is now being advanced into clinical testing against latent HIV infection. ? 2013 Landes Bioscience

AB - Objective: We aimed to compare the potential for inducing HIV production and the effect on T-cell activation of potent HDAC inhibitors undergoing clinical investigation. Design: In vitro study. Results: The various HDAC inhibitors displayed significant potency differences in stimulating HIV-1 expression from the latently infected cell lines with panobinostat > givinostat ? belinostat > vorinostat > valproic acid. Panobinostat was significantly more potent than all other HDAC inhibitors and induced virus production even in the very low concentration range 8-31 nM. The proportion of primary T-cells expressing the early activation marker CD69 increased moderately in all HDAC inhibitor-treated cells compared with untreated cells. Finally, proof was obtained that panobinostat, givinostat and belinostat induce virus production in latently infected primary cells at therapeutic concentrations with panobinostat being the most potent stimulator. Methods: The latently infected cell lines ACH2 and U1 were treated with the HDAC inhibitors panobinostat, givinostat, belinostat, vorinostat and valproic acid. Viral induction was estimated by p24 production. Peripheral blood mononuclear cells from uninfected donors were treated with the HDAC inhibitors and the expression of activation markers on T-cell phenotypes was measured using flow cytometry. Finally, the ability of givinostat, belinostat and panobinostat to reactivate latent HIV-1 expression in primary T-cells was investigated employing a CCL19-induced latent primary CD4+ T cell infection model. Conclusion: At therapeutic concentrations panobinostat stimulate HIV-1 expression in latently infected cells with greater potency than other HDAC inhibitors undergoing clinical investigation. These findings warrant further investigation and panobinostat is now being advanced into clinical testing against latent HIV infection. ? 2013 Landes Bioscience

UR - http://www.ncbi.nlm.nih.gov/pubmed/23370291

U2 - 10.4161/hv.23800

DO - 10.4161/hv.23800

M3 - Article

VL - 9

SP - 993

EP - 1001

JO - Human Vaccines & Immunotherapeutics

JF - Human Vaccines & Immunotherapeutics

SN - 2164-5515

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ER -