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.
Highlights
Over the past three decades, great progress has been achieved in the fight against HIV/AIDS
Purified fractions derived from a collection of over 100 traditional Chinese medicinal herbs from a repository at Zhejiang University were individually incubated with C11 cells and HIV-1 expression was monitored by percentage of green fluorescent protein (GFP)-positive cells using flow cytometry
We found that the fractions from the dried root of Euphorbia kansui that co-eluted with methylene chloride and petroleum ether could potently activate the LTRdriven GFP production (Supplementary Fig. 1)
Summary
Over the past three decades, great progress has been achieved in the fight against HIV/AIDS. The reactivated viral infected cells might be cleared via cytopathic effects, immune clearance and cell death, thereby purging the latent reservoir[12, 14] This “shock and kill” strategy is currently considered one of the most promising strategies to accomplish an HIV-1 cure, and major research efforts are directed towards developing clinically effective latency-reversing agents (LRAs). Two procyanidin compounds isolated from the traditional medicinal plants Theobroma cacao[51] and Polygonum cuspidatum[52] have been reported recently to reactivate latent HIV-1 in cell line models Given this context, we attempted to examine active compounds from traditional Chinese medicinal herbs that may display HIV-1 latency-reversing activity. Our mechanistic studies indicate that it is a PKC agonist that can promote the transcription of HIV-1 by inducing both NF-κB and P-TEFb
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