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


METHODS
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.


CONCLUSIONS
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.
Department of Infectious Diseases; Aarhus University Hospital; Aarhus, Denmark.
Thomas Aagaard
TA
Rasmussen
Ole
O
Schmeltz Søgaard
Christel
C
Brinkmann
Fiona
F
Wightman
Sharon R
SR
Lewin
Jesper
J
Melchjorsen
Charles
C
Dinarello
Lars
L
Østergaard
Martin
M
Tolstrup
D019380:Anti-HIV Agents / Q000494:pharmacology*; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D002478:Cells, Cultured; D016655:HIV Core Protein p24 / Q000032:analysis; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development / Q000276:immunology / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D037181:Lectins, C-Type / Q000032:analysis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000821:virology; D008213:Lymphocyte Activation; D000077767:Panobinostat; D013601:T-Lymphocytes / Q000276:immunology*; D017735:Virus Latency / Q000187:drug effects*; D000099192:CD69 Antigens
D019380:Anti-HIV Agents; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D016655:HIV Core Protein p24; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D037181:Lectins, C-Type; D000077767:Panobinostat; D000099192:CD69 Antigens
HIV; HIV cure; HIV eradication; histone deacetylase inhibitors