The thioacetate-ω(γ-lactam carboxamide) HDAC inhibitor ST7612AA1 as HIV-1 latency reactivation agent.
Antiretroviral therapy (ART) is unable to cure HIV infection. The ability of HIV to establish a subset of latent infected CD4(+) T cells, which remain undetectable to the immune system, becomes a major roadblock to achieve viral eradication. Histone deacetylase inhibitors (HDACi) have been shown to potently induce the reactivation of latent HIV. Here, we show that a new thiol-based HDACi, the thioacetate-ω(γ-lactam carboxamide) derivative ST7612AA1, is a potent inducer of HIV reactivation. We evaluated HIV reactivation activity of ST7612AA1 compared to panobinostat (PNB), romidepsin (RMD) and vorinostat (VOR) in cell culture models of HIV-1 latency, in latently infected primary CD4(+) T lymphocytes and in PBMCs from HIV(+) patients. ST7612AA1 potently induced HIV-1 reactivation at submicromolar concentrations with comparable potency to panobinostat or superior to vorinostat. The presence of known antiretrovirals did not affect ST7612AA1-induced reactivation and their activity was not affected by ST7612AA1. Cell proliferation and cell activation were not affected by ST7612AA1, or any other HDACi used. In conclusion, our results indicate that ST7612AA1 is a potent activator of latent HIV and that reactivation activity of ST7612AA1 is exerted without activation or proliferation of CD4(+) T cells. ST7612AA1 is a suitable candidate for further studies of HIV reactivation strategies and potential new therapies to eradicate the viral reservoirs.
AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
Roger
R
Badia
AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
Judith
J
Grau
AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
Eva
E
Riveira-Muñoz
AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
Ester
E
Ballana
R&D Sigma-Tau Industrie Farmaceutiche Riunite SpA, Via Pontina km30, 400, I-00040 Pomezia, Italy.
Giuseppe
G
Giannini
AIDS Research Institute - IrsiCaixa and Health Research Institute Germans Trias i Pujol (IGTP), Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain. Electronic address: jaeste@irsicaixa.es.
José A
JA
Esté
D000813:Anilides / Q000378:metabolism*; D044966:Anti-Retroviral Agents / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D047630:Depsipeptides / Q000378:metabolism; D004347:Drug Interactions; D015497:HIV-1 / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D007211:Indoles / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008297:Male; D000077767:Panobinostat; D011760:Pyrrolidinones / Q000378:metabolism*; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*; D000077337:Vorinostat
D000813:Anilides; D044966:Anti-Retroviral Agents; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D011760:Pyrrolidinones; C000597472:thioacetic acid S-(6-((5-oxopyrrolidine-2-carbonyl)amino)-6-phenylcarbamoylhexyl) ester; D000077337:Vorinostat; D000077767:Panobinostat; C087123:romidepsin
HDAC; HIV; Latency; Reactivation; Shock-and-kill