BET inhibitors RVX-208 and PFI-1 reactivate HIV-1 from latency

• Published in: Scientific reports 2017-11, Vol.7 (1), p.16646-12, Article 16646
• Main Authors: Lu, Panpan, Shen, Yinzhong, Yang, He, Wang, Yanan, Jiang, Zhengtao, Yang, Xinyi, Zhong, Yangcheng, Pan, Hanyu, Xu, Jianqing, Lu, Hongzhou, Zhu, Huanzhang
• Format: Article
• Language: English
• Subjects: 13; 13/31; 631/154/1435/2417; 631/250/255/1901; 631/326/596/2564; CD4 antigen; CD4 Antigens - metabolism; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; Cell activation; Clinical trials; Cyclin-Dependent Kinase 9 - metabolism; Gene regulation; HIV Infections - drug therapy; HIV Infections - virology; HIV-1 - drug effects; HIV-1 - physiology; Humanities and Social Sciences; Humans; Inhibitors; Jurkat Cells; Latency; Latent infection; Lymphocytes; Lymphocytes T; multidisciplinary; Phosphorylation; Quinazolinones - chemistry; Quinazolinones - pharmacology; Receptors, CCR5 - metabolism; Science; Science (multidisciplinary); tat Gene Products, Human Immunodeficiency Virus - metabolism; Transcription; Tumor Necrosis Factor-alpha - metabolism; Virus Activation - drug effects; Virus Latency - drug effects
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-017-16816-1

Persistent latent reservoir in resting CD4+ T cells is a major obstacle in curing HIV-1 infection. Effective strategies for eradication of the HIV-1 reservoir are urgently needed. We report here for the first time that two BET inhibitors, RVX-208, which has entered phase II clinical trials for diverse cardiovascular disorders, and PFI-1, which has been widely studied in oncology, can reactivate HIV-1 from latency. RVX-208 and PFI-1 treatment alone or in combination with other latency reversing agents efficiently reactivated HIV-1 transcription through an up-regulation of P-TEFb by increasing CDK9 Thr-186 phosphorylation in latently infected Jurkat T cells in vitro . The two BET inhibitors also reactivated HIV-1 transcription in cART treated patient-derived resting CD4+ T cells ex vivo , without influence on global immune cell activation. Our findings, in combination with previous reports, further confirm that BET inhibitors are a group of leading compounds for combating HIV-1 latency for viral eradication.