title: Short Communication: The Broad-Spectrum Histone Deacetylase Inhibitors Vorinostat and Panobinostat Activate Latent HIV in CD4(+) T Cells In Part Through Phosphorylation of the T-Loop of the CDK9 Subunit of P-TEFb.
abstract: Cessation of highly active antiretroviral therapy (HAART) in HIV-infected individual leads to a rebound of viral replication due to reactivation of a viral reservoir composed largely of latently infected memory CD4(+) T cells. Efforts to deplete this reservoir have focused on reactivation of transcriptionally silent latent proviruses. HIV provirus transcription depends critically on the positive transcription elongation factor b (P-TEFb), whose core components are cyclin-dependent kinase 9 (CDK9) and cyclin T1. In resting CD4(+) cells, the functional levels of P-TEFb are extremely low. Cellular activation upregulates cyclin T1 protein levels and CDK9 T-loop (T186) phosphorylation. The broad-spectrum histone deacetylase inhibitors (HDACis) vorinostat and panobinostat have been shown to reactivate latent virus in vivo in HAART-treated individuals. In this study, we have found that vorinostat and panobinostat activate P-TEFb in resting primary CD4(+) T cells through induction of CDK9 T-loop phosphorylation. In contrast, tacedinaline and romidepsin, HDAC 1 and 2 inhibitors, were unable to activate CDK9 T-loop phosphorylation. We used a CCL19 primary CD4(+) T-cell model HIV latency to assess the correlation between induction of CDK9 T-loop phosphorylation and reactivation of latent HIV virus by HDACis. Vorinostat and panobinostat treatment of cells harboring latent HIV increased CDK9 T-loop phosphorylation and reactivation of latent virus, whereas tacedinaline and romidepsin failed to induce T-loop phosphorylation or reactivate latent virus. We conclude that the ability of vorinostat and panobinostat to induce latent HIV is, in part, likely due to the ability of the broad-spectrum HDACis to upregulate P-TEFb through increased CDK9 T-loop phosphorylation.
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine , Houston, Texas.
authors.forename: Md Saha
authors.initials: MS
authors.lastname: Jamaluddin
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine , Houston, Texas.
authors.forename: Pei-Wen
authors.initials: PW
authors.lastname: Hu
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine , Houston, Texas.
authors.forename: Yih
authors.initials: Y
authors.lastname: Jan
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine , Houston, Texas.
authors.forename: Edward B
authors.initials: EB
authors.lastname: Siwak
authors.affiliation: Department of Molecular Virology and Microbiology, Baylor College of Medicine , Houston, Texas.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Rice
mesh_terms: D023241:Antiretroviral Therapy, Highly Active; D001549:Benzamides; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002478:Cells, Cultured; D056906:Cyclin T / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D004789:Enzyme Activation; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D000077767:Panobinostat; D010655:Phenylenediamines / Q000494:pharmacology*; D010766:Phosphorylation; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D011533:Proviruses / Q000187:drug effects; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency; D014779:Virus Replication / Q000187:drug effects; D000077337:Vorinostat
chemical_list: D001549:Benzamides; C503684:CCNT1 protein, human; D056906:Cyclin T; D047630:Depsipeptides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D010655:Phenylenediamines; D000077337:Vorinostat; D000077767:Panobinostat; C087123:romidepsin; D042925:Positive Transcriptional Elongation Factor B; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; C081895:tacedinaline