The BET inhibitor OTX015 reactivates latent HIV-1 through P-TEFb

• Published in: Scientific reports 2016-04, Vol.6 (1), p.24100-24100, Article 24100
• Main Authors: Lu, Panpan, Qu, Xiying, Shen, Yinzhong, Jiang, Zhengtao, Wang, Pengfei, Zeng, Hanxian, Ji, Haiyan, Deng, Junxiao, Yang, Xinyi, Li, Xian, Lu, Hongzhou, Zhu, Huanzhang
• Format: Article
• Language: English
• Subjects: 13; 13/109; 13/31; 38/90; 45/15; 45/77; 631/250/1619/554; 692/699/255/1901; 82/1; 82/80; Acetanilides - metabolism; Acetanilides - toxicity; Acquired immune deficiency syndrome; AIDS; Antiretroviral agents; Antiretroviral therapy; Antiviral agents; Biochemical analysis; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - virology; Cell activation; Cell Survival - drug effects; Cells, Cultured; Cyclin-dependent kinases; Drug dosages; Drug Interactions; Drug therapy; Gene expression; Heterocyclic Compounds, 3-Ring - metabolism; Heterocyclic Compounds, 3-Ring - toxicity; HIV; HIV-1 - drug effects; HIV-1 - physiology; Human immunodeficiency virus; Humanities and Social Sciences; Humans; Kinases; Laboratories; Latency; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes T; multidisciplinary; Phorbol Esters - metabolism; Phosphorylation; Positive Transcriptional Elongation Factor B - metabolism; Science; Toxicity; Virology; Virus Activation - drug effects; Virus Latency - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep24100

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 EC 50 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.