title: The BET inhibitor OTX015 reactivates latent HIV-1 through P-TEFb.
abstract: None of the currently used anti-HIV-1 agents can effectively eliminate latent HIV-1 reservoirs, which is a major hurdle to a complete cure for AIDS. We report here that a novel oral BET inhibitor OTX015, a thienotriazolodiazepine compound that has entered phase Ib clinical development for advanced hematologic malignancies, can effectively reactivate HIV-1 in different latency models with an EC50 value 1.95-4.34 times lower than JQ1, a known BET inhibitor that can reactivate HIV-1 latency. We also found that OTX015 was more potent when used in combination with prostratin. More importantly, OTX015 treatment induced HIV-1 full-length transcripts and viral outgrowth in resting CD4(+) T cells from infected individuals receiving suppressive antiretroviral therapy (ART), while exerting minimal toxicity and effects on T cell activation. Finally, biochemical analysis showed that OTX015-mediated activation of HIV-1 involved an increase in CDK9 occupancy and RNAP II C-terminal domain (CTD) phosphorylation. Our results suggest that the BET inhibitor OTX015 may be a candidate for anti-HIV-1-latency therapies.
authors.affiliation: State Key Laboratory of Genetic Engineering, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Panpan
authors.initials: P
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Genetic Engineering, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Xiying
authors.initials: X
authors.lastname: Qu
authors.affiliation: Department of Infectious Diseases, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Yinzhong
authors.initials: Y
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Genetic Engineering, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Zhengtao
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Genetic Engineering, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Genetic Engineering, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Hanxian
authors.initials: H
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Genetic Engineering, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Ji
authors.affiliation: State Key Laboratory of Genetic Engineering, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Junxiao
authors.initials: J
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Genetic Engineering, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Genetic Engineering, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Infectious Diseases, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
authors.forename: Hongzhou
authors.initials: H
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Genetic Engineering, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: Huanzhang
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000083:Acetanilides / Q000378:metabolism* / Q000633:toxicity; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004347:Drug Interactions; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology*; D006575:Heterocyclic Compounds, 3-Ring / Q000378:metabolism* / Q000633:toxicity; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D010703:Phorbol Esters / Q000378:metabolism; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects*
chemical_list: D000083:Acetanilides; D006575:Heterocyclic Compounds, 3-Ring; C000605331:OTX015; D010703:Phorbol Esters; C070999:prostratin; D042925:Positive Transcriptional Elongation Factor B