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Sci Rep. 2017 Aug 25;7(1):9451. doi: 10.1038/s41598-017-07157-0.

Reactivation of HIV-1 from Latency by an Ingenol Derivative from Euphorbia Kansui.

Author information

1
State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China.
2
Department of Infectious Diseases, and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 200433, China.
3
Center for Infectious Diseases, Beijing You'an Hospital, Capital Medical University, Beijing, 100069, China.
4
Institute of Marine Biology, Ocean College, Zhejiang University, Hangzhou, 310058, China. mazj@zju.edu.cn.
5
State Key Laboratory of Genetic Engineering and Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Institute of Genetics, School of Life Sciences, Fudan University, Shanghai, 200438, China. hzzhu@fudan.edu.cn.

Abstract

Cells harboring latent HIV-1 pose a major obstacle to eradication of the virus. The 'shock and kill' strategy has been broadly explored to purge the latent reservoir; however, none of the current latency-reversing agents (LRAs) can safely and effectively activate the latent virus in patients. In this study, we report an ingenol derivative called EK-16A, isolated from the traditional Chinese medicinal herb Euphorbia kansui, which displays great potential in reactivating latent HIV-1. A comparison of the doses used to measure the potency indicated EK-16A to be 200-fold more potent than prostratin in reactivating HIV-1 from latently infected cell lines. EK-16A also outperformed prostratin in ex vivo studies on cells from HIV-1-infected individuals, while maintaining minimal cytotoxicity effects on cell viability and T cell activation. Furthermore, EK-16A exhibited synergy with other LRAs in reactivating latent HIV-1. Mechanistic studies indicated EK-16A to be a PKCγ activator, which promoted both HIV-1 transcription initiation by NF-κB and elongation by P-TEFb signal pathways. Further investigations aimed to add this compound to the therapeutic arsenal for HIV-1 eradication are in the pipeline.

PMID:
28842560
PMCID:
PMC5573388
DOI:
10.1038/s41598-017-07157-0
[Indexed for MEDLINE]
Free PMC Article

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