Euphorbia Kansui Reactivates Latent HIV

Abstract

While highly active anti-retroviral therapy has greatly improved the lives of HIV infected individuals, these treatments are unable to eradicate the virus. Current approaches to reactivate the virus have been limited by toxicity, lack of an orally available therapy, and limited responses in primary CD4+ T cells and in clinical trials. The PKC agonist ingenol, purified from Euphorbia plants, is a potent T cell activator and reactivates latent HIV. Euphorbia kansui itself has been used for centuries in traditional Chinese medicine to treat ascites, fluid retention, and cancer. We demonstrate that an extract of this plant, Euphorbia kansui, is capable of recapitulating T cell activation induced by the purified ingenol. Indeed, Euphorbia kansui induced expression of the early T cell activation marker CD69 and P-TEFb in a dose-dependent manner. Furthermore, Euphorbia kansui reactivated latent HIV in a CD4+ T cell model of latency and in HIV+ HAART suppressed PBMC. When combined with the other latency reversing agents, the effective dose of Euphorbia kansui required to reactive HIV was reduced 10-fold and resulted in synergistic reactivation of latent HIV. We conclude that Euphorbia Euphorbia kansui reactivates latent HIV and activates CD4+ T cells. When used in combination with a latency reversing agent, the effective dose of Euphorbia kansui is reduced; which suggests its application as a combination strategy to reactivate latent HIV while limiting the toxicity due to global T cell activation. As a natural product, which has been used in traditional medicine for thousands of years, Euphorbia kansui is attractive as a potential treatment strategy, particularly in resource poor countries with limited treatment options. Further clinical testing will be required to determine its safety with current anti-retroviral therapies.

Novel Latency Reversal Agents for HIV-1 Cure

“…Euphorbia kansui has been used as part of traditional Chinese medicine as a cathartic and contains twelve ingenol compounds(53). Kansui plant extracts have been shown to reactivate HIV-1 in both cell lines in vitro and in patient cells ex vivo (54). Kansui is safe and has oral bioavailability as a tea.…”

Synthetic Ingenols Maximize Protein Kinase C-Induced HIV-1 Latency Reversal

“…We next sought to test the PKC activity and cytotoxicity of synthetic ingenols in resting CD4 ϩ T cells in vitro as a means to explore the therapeutic windows of these compounds. Cell surface expression of CD69, a biomarker of early T cell activation, is well known to directly correlate with PKC activity (46)(47)(48). Recent studies with bryostatin-1 and bryostatin analogs have demonstrated a direct correlation between CD69 expression and HIV-1 latency reversal in vitro (48,49).…”

P-TEFb as A Promising Therapeutic Target

“…Therefore, a combination of a P-TEFb-releaser and a PKC agonist elicits a potent induction of HIV transcription in latently infected cells [161,171,274]. Interestingly, extracts from Euphorbia kansui, a plant used in Chinese traditional medicine for treatment of fluid retention, cancer, or ascites, contains a high concentration of various ingenol derivatives, and exhibits potent HIV reactivation in combination with HDACis or BETis [276]. P-TEFb-releasers/activators are also effective as anti-cancer agents.…”