Nanotheranostics 2022; 6(3):325-336. doi:10.7150/ntno.69259 This issue

Research Paper

EK-16A liposomes enhance HIV replication in ACH2 or J-Lat 10.6 cell engrafted NSG mice

Panpan Lu1, Jinlong Yang1, Xinyi Yang1, Zhiming Liang1, Jing Wang1, Yanan Wang1, Lin Zhao1, Hanyu Pan1, Xiaoting Shen1, Yuqi Zhu1, Jingna Xun1,2, Hongzhou Lu2, Huanzhang Zhu1✉

1. 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.
2. 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.

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Citation:
Lu P, Yang J, Yang X, Liang Z, Wang J, Wang Y, Zhao L, Pan H, Shen X, Zhu Y, Xun J, Lu H, Zhu H. EK-16A liposomes enhance HIV replication in ACH2 or J-Lat 10.6 cell engrafted NSG mice. Nanotheranostics 2022; 6(3):325-336. doi:10.7150/ntno.69259. Available from https://www.ntno.org/v06p0325.htm

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Abstract

Graphic abstract

Background: 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 Euphorbia kansui. Our prior studies have suggested that it could reactivate latent HIV and meanwhile inhibit HIV infection in vitro. Here, we further advanced the research in vivo.

Methods: In vitro, 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. In vivo, 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.

Results: 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.

Conclusions: 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.

Keywords: HIV, LRAs, Euphorbia kansui, EK-16A, NSG mouse model