State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology, Ministry of Education, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China.
Department of Infectious Diseases, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
Antiviral Res. 2019 Sep;169:104555. doi: 10.1016/j.antiviral.2019.104555. Epub 2019 Jul 9.
The latent reservoir of HIV-1 in resting memory CD4 T cells serves as a major barrier to curing HIV-1 infection. Reactivation of latent HIV-1 is proposed as a promising strategy for the clearance of the viral reservoirs. Because of the limitations of current latency reversal agents (LRAs), identification of new LRAs is urgently required. Here, we analyzed Euphorbia kansui extracts and obtained three ingenol derivative compounds named EK-1A, EK-5A and EK-15A. We found that ingenol derivatives can effectively reactivate latent HIV-1 at very low (nanomolar) concentrations in HIV latency model in vitro. Furthermore, ingenol derivatives exhibited synergy with other LRAs in reactivating latent HIV-1. We verified that EK-15A can promote latent HIV-1 reactivation in the ex vivo resting CD4 T cells isolated from the peripheral blood of HIV-infected individuals on suppressive antiretroviral therapy. In addition, ingenol derivatives down-regulated the expression of cell surface HIV co-receptors CCR5 and CXCR4, therefore potentially preventing new infection of HIV-1. Our results indicated that the ingenol derivatives extracted from Euphorbia kansui have dual functions: reactivation of latent HIV-1 and inhibition of HIV-1 infection.
HIV-1 潜伏在静止记忆 CD4 T 细胞中的储库是治愈 HIV-1 感染的主要障碍。潜伏 HIV-1 的激活被提出作为清除病毒储库的一种有前途的策略。由于当前潜伏逆转剂 (LRA) 的局限性，迫切需要鉴定新的 LRA。在这里，我们分析了大戟属植物甘遂的提取物，得到了三种 10-去乙酰巴卡丁 III 衍生物化合物，分别命名为 EK-1A、EK-5A 和 EK-15A。我们发现，在体外 HIV 潜伏模型中，这些 10-去乙酰巴卡丁 III 衍生物化合物可以在非常低（纳摩尔）浓度下有效激活潜伏的 HIV-1。此外，10-去乙酰巴卡丁 III 衍生物化合物在激活潜伏 HIV-1 方面表现出与其他 LRA 的协同作用。我们验证了 EK-15A 可以促进抑制性抗逆转录病毒治疗的 HIV 感染者外周血分离的静止 CD4 T 细胞中潜伏 HIV-1 的重新激活。此外，10-去乙酰巴卡丁 III 衍生物化合物下调了细胞表面 HIV 共受体 CCR5 和 CXCR4 的表达，因此可能预防 HIV-1 的新感染。我们的研究结果表明，从甘遂中提取的 10-去乙酰巴卡丁 III 衍生物具有双重功能：激活潜伏的 HIV-1 和抑制 HIV-1 感染。
