Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 993 - 1001 |
| Number of pages | 9 |
| Journal | Human Vaccines & Immunotherapeutics |
| Volume | 9 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2013 |
Cite this
}
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 journal › Article › Research › peer-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
IS - 5
ER -