Lu Panpan, Yang Jinlong, Yang Xinyi, Liang Zhiming, Wang Jing, Wang Yanan, Zhao Lin, Pan Hanyu, Shen Xiaoting, Zhu Yuqi, Xun Jingna, Lu Hongzhou, Zhu Huanzhang
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, China.
Department of Infectious Disease, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, China.
Nanotheranostics. 2022 Mar 21;6(3):325-336. doi: 10.7150/ntno.69259. eCollection 2022.
Numbers of HIV latency reversal agents (LRAs) have been tested in clinical trials, but with limited effect. EK-16A is an ingenol derivative that isolated from . Our prior studies have suggested that it could reactivate latent HIV and meanwhile inhibit HIV infection . Here, we further advanced the research . , the activity of EK-16A liposomes was measured in HIV latently infected cells. In serum pharmacology test, BALB/c mice were orally administered with EK-16A liposomes, serum was separated and co-cultured with cells, HIV reactivation was measured. , NSG mice were transplanted with human cells for 3 weeks and then administered with EK-16A liposomes for 3 days. In ACH2 cell engrafted NSG mice, P24 in plasma and cell-associated HIV RNA in tissues was measured. In J-Lat 10.6 cell engrafted NSG mice, GFP expression of J-Lat 10.6 cells in diverse tissues was measured. Hematoxylin and eosin (HE) staining was carried out for histopathological examination in both mice. EK-16A liposomes can reactivate latent HIV in ACH2 and J-Lat 10.6 cells. Serum pharmacological test showed that EK-16A retained activity after oral administration. Importantly, in ACH2 cell engrafted NSG mice, EK-16A liposomes increased the secretion of P24 in plasma and the expression of cell-associated HIV RNA in tissues. In J-Lat 10.6 cell engrafted NSG mice, EK-16A liposomes increased the GFP expression of J-Lat 10.6 cells in diverse tissues, including the bone marrow, spleen, liver, lung and peripheral blood. Furthermore, there was no obvious histopathological change associated with the use of EK-16A liposomes in both mice. Our results confirmed the enhancing HIV replication activity and preliminary security of EK-16A in human cell engrafted NSG mice, laying the foundation for research in clinical trials.
多种HIV潜伏逆转剂（LRAs）已在临床试验中进行了测试，但效果有限。EK-16A是一种从……中分离出的 Ingenol 衍生物。我们之前的研究表明，它可以重新激活潜伏的HIV，同时抑制HIV感染。在此，我们进一步推进了该研究。首先，在HIV潜伏感染细胞中测量了EK-16A脂质体的活性。在血清药理学试验中，给BALB/c小鼠口服EK-16A脂质体，分离血清并与细胞共培养，测量HIV的重新激活情况。其次，将人细胞移植到NSG小鼠体内3周，然后给予EK-16A脂质体3天。在植入ACH2细胞的NSG小鼠中，测量血浆中的P24以及组织中与细胞相关的HIV RNA。在植入J-Lat 10.6细胞的NSG小鼠中，测量不同组织中J-Lat 10.6细胞的GFP表达。对两只小鼠均进行苏木精和伊红（HE）染色以进行组织病理学检查。EK-16A脂质体可以在ACH2和J-Lat 10.6细胞中重新激活潜伏的HIV。血清药理学试验表明，EK-16A口服后仍保留活性。重要的是，在植入ACH2细胞的NSG小鼠中，EK-16A脂质体增加了血浆中P24的分泌以及组织中与细胞相关的HIV RNA的表达。在植入J-Lat 10.6细胞的NSG小鼠中，EK-16A脂质体增加了不同组织（包括骨髓、脾脏、肝脏、肺和外周血）中J-Lat 10.6细胞的GFP表达。此外，在两只小鼠中，使用EK-16A脂质体均未观察到明显的组织病理学变化。我们的结果证实了EK-16A在植入人细胞的NSG小鼠中增强HIV复制的活性以及初步安全性为临床试验研究奠定了基础。
