Pandeló José Diego, Bartholomeeusen Koen, da Cunha Rodrigo Delvecchio, Abreu Celina Monteiro, Glinski Jan, da Costa Thais Barbizan Ferreira, Bacchi Rabay Ana Flávia Mello, Pianowski Filho Luiz Francisco, Dudycz Lech W, Ranga Udaykumar, Peterlin Boris Matija, Pianowski Luiz Francisco, Tanuri Amilcar, Aguiar Renato Santana
Departamento de Genética, Instituto de Biologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil.
Department of Medicine, Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94143-0703, United States.
Virology. 2014 Aug;462-463:328-39. doi: 10.1016/j.virol.2014.05.033. Epub 2014 Jul 9.
The ability of HIV to establish long-lived latent infection is mainly due to transcriptional silencing of viral genome in resting memory T lymphocytes. Here, we show that new semi-synthetic ingenol esters reactivate latent HIV reservoirs. Amongst the tested compounds, 3-caproyl-ingenol (ING B) was more potent in reactivating latent HIV than known activators such as SAHA, ingenol 3,20-dibenzoate, TNF-α, PMA and HMBA. ING B activated PKC isoforms followed by NF-κB nuclear translocation. As virus reactivation is dependent on intact NF-κB binding sites in the LTR promoter region ING B, we have shown that. ING B was able to reactivate virus transcription in primary HIV-infected resting cells up to 12 fold and up to 25 fold in combination with SAHA. Additionally, ING B promoted up-regulation of P-TEFb subunits CDK9/Cyclin T1. The role of ING B on promoting both transcription initiation and elongation makes this compound a strong candidate for an anti-HIV latency drug combined with suppressive HAART.
HIV建立长期潜伏感染的能力主要归因于静息记忆T淋巴细胞中病毒基因组的转录沉默。在此，我们表明新型半合成大戟醇酯可重新激活潜伏的HIV储存库。在所测试的化合物中，3-己酰基大戟醇（ING B）在重新激活潜伏HIV方面比已知激活剂如SAHA、大戟醇3,20-二苯甲酸酯、TNF-α、PMA和HMBA更有效。ING B激活PKC亚型，随后导致NF-κB核转位。由于病毒重新激活依赖于ING B在LTR启动子区域中完整的NF-κB结合位点，我们已经证明，ING B能够在原代HIV感染的静息细胞中重新激活病毒转录，最高可达12倍，与SAHA联合使用时最高可达25倍。此外，ING B促进P-TEFb亚基CDK9/细胞周期蛋白T1的上调。ING B在促进转录起始和延伸方面的作用使该化合物成为与抑制性高效抗逆转录病毒疗法联合使用的抗HIV潜伏药物的有力候选者。
