Discovering New HIV-1 Latency Reversal Agents from Euphorbia Species

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PROJECT SUMMARY Antiretroviral therapy (ART) has rendered HIV-1 infection a treatable illness, however ART is not curative due to replication-competent untranscribed provirus in long-lived resting T cells. Strategies to directly target these latently infected cells will be necessary to eradicate the virus in people living with HIV-1 (PLWH). Pharmacologic approaches using compounds to reverse viral latency (known as latency reversal agents or LRAs), to subject the reservoir to immune-targeting or clearance via viral cytopathic effects, have been studied in clinical trials. No trial to date, however, has significantly perturbed the latent reservoir. One major barrier impeding progress toward HIV-1 eradication is the identification and characterization of LRAs that are able to reactivate a significant fraction of the latent reservoir and do not have adverse effects that would limit in vivo use. One mechanism of latency reversal, protein kinase C activation, has shown promise in vitro, as well as in murine and non-human primate models of HIV-1 latency. Given the unfulfilled and urgent need for effective, scalable HIV-1 cure strategies, the potent latency reversal induced by PKC agonists in vivo presents an attractive approach. We and others have identified the latency reversal potential of PKC agonists known as ingenols, naturally-occurring compounds common to a family of medicinal plants known as Euphorbiaceae. Euphorbia kansui, for example, is native to east Asia and contains 14 unique ingenol compounds with PKC agonist activity. The root powder of E. kansui, formulated as tea, is used in Traditional Chinese Medicine as a cathartic to treat fluid overload and constipation. We have been conducting a first-in-human, phase I clinical trial evaluating safety, anti-latency and immune stimulatory effects of E. kansui tea among PLWH (NCT02531295) that has proven to be safe and well-tolerated. Ingenol mebutate, a naturally-occurring ingenol present in E. peplus, is FDA-approved for topical use to treat actinic keratosis. A recent report described HIV-1 latency reversal in vivo among PLWH using ingenol mebutate. Many Euphorbia species native to East Africa, a region disproportionately affected by HIV-1, are in active use as traditional medicines. However, little is known regarding potential anti-HIV-1 or immune modulatory activities of these natural products or their chemical constituents. We hypothesize that chemical components of Euphorbia species in active use as traditional medicines have potent HIV-1 latency reversal activity. We propose a complete pre-clinical characterization of naturally-occurring bioactive compounds isolated from medicinal Euphorbia plant species native to East Africa, with regard to latency reversing potential, immune perturbation, and potential off-target effects in vitro and in a murine model of HIV-1 persistence. This work will generate new knowledge to inform strategies aimed at elimination of the HIV-1 latent reservoir.