title: Short communication: SAHA (vorinostat) induces CDK9 Thr-186 (T-loop) phosphorylation in resting CD4+ T cells: implications for reactivation of latent HIV.
abstract: The histone deacetylase inhibitor (HDACi) suberoylanilide hydroxyamic acid (SAHA), also known as vorinostat, has recently been reported to activate latent HIV-1 in patients undergoing antiretroviral therapy. It is possible that SAHA reactivation of latent viruses may involve effects on cellular transcription factors such as positive transcription elongation factor b (P-TEFb), a protein kinase whose core is composed of CDK9 and Cyclin T1. P-TEFb is recruited by the HIV-1 Tat protein to activate productive RNA polymerase II elongation of the integrated provirus. We found that SAHA treatment of isolated resting CD4(+) T cells induced CDK9 Thr-186 (T-loop) phosphorylation in six of eight healthy donors and increased Cyclin T1 expression in one donor; Thr-186 phosphorylation is required for P-TEFb function. Disulfiram, another small molecule currently under evaluation in clinical trials for reactivation of latent HIV-1, was also found capable of inducing CDK9 Thr-186 phosphorylation and Cyclin T1 levels in resting CD4(+) T cells from healthy donors. In a Jurkat CD4(+) T cells HIV-1 latency system, disulfiram reactivated the latent provirus and induced CDK9 Thr-186 phosphorylation. Our findings suggest that small molecules capable of reactivating latent HIV-1 in resting CD4(+) T cells may function in part by increasing CDK9 Thr-186 phosphorylation and perhaps Cyclin T1 expression, thereby up-regulating P-TEFb function.
authors: Department of Molecular Virology and Microbiology, Baylor College of Medicine , Houston, Texas.
authors: Rajesh
authors: R
authors: Ramakrishnan
authors: Hongbing
authors: H
authors: Liu
authors: Andrew P
authors: AP
authors: Rice
mesh_terms: D065086:Acetaldehyde Dehydrogenase Inhibitors / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002460:Cell Line; D056906:Cyclin T / Q000096:biosynthesis; D042863:Cyclin-Dependent Kinase 9 / Q000378:metabolism*; D004221:Disulfiram / Q000494:pharmacology*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D019169:Jurkat Cells; D010766:Phosphorylation / Q000187:drug effects; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D014775:Virus Activation / Q000187:drug effects; D017735:Virus Latency; D000077337:Vorinostat
chemical_list: D065086:Acetaldehyde Dehydrogenase Inhibitors; C503684:CCNT1 protein, human; D056906:Cyclin T; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D042925:Positive Transcriptional Elongation Factor B; C467969:CDK9 protein, human; D042863:Cyclin-Dependent Kinase 9; D004221:Disulfiram