Background: HIV eradication strategies aim to combine agents that reverse viral latency with therapies that boost the host immune response. We performed a non-human primate study evaluating the safety and in vivo biological response to an herbal supplement, Euphorbia kansui, containing compounds in the potent class of latency reversal agents, ingenols.
Methods: Six juvenile rhesus macaques (RM) were infected with SIVmac251 and treated with once daily subcutaneous 20 mg/kg tenofovir, 50 mg/kg emtricitabine, and 3.25 mg/kg dolutegravir for 15 weeks. Three animals were administered oral kansui, starting with a test dose, followed by a dose equivalent to that used in traditional Chinese medicine, given for an increasing number of consecutive days: (1) 5 mg/kg x 1, (2) 20 mg/kg x 1, (3) 20 mg/kg x 2 days, and (4) 20 mg/kg x 3 days. Each dose was followed by a 2-week washout period, and blood was drawn at the end of each dosing period. Markers of T-cell, NK-cell, and monocyte activation were characterized by flow cytometry, and SIV total DNA and unspliced RNA from PBMCs were quantified by real-time PCR. Data were analyzed using multivariate mixed effects regression.
Results: There were no adverse events observed at any given dose/frequency of kansui administered. There was a trend for increased activation levels in treated vs. control monkeys over time. Statistically significant kansui effects on CD8+ T (HLA-DR+CD38+; 8.5-fold increase, P=0.015), NK cell (CD3-CD8+; 6.0-fold, P=0.001), and monocyte (HLA-DR+CD14^hiCD16+CD80+; 27-fold, P=0.023) activation were observed at time point 4. Comparisons by treatment group were uninformative for SIV DNA and RNA, because 2 control animals had SIV RNA and DNA levels below the limit of detection, providing limited information on relative changes over time. Within treated animals, there was no statistically significant association between timepoint and SIV RNA or DNA.
Conclusions: Kansui was well tolerated in three ART-suppressed, SIVmac251-infected RM. Statistically significant increases in CD8+ T-cell, NK-cell, and monocyte activation markers were observed at the highest dose/frequency of kansui compared to controls. These are important preliminary data for a currently enrolling human clinical trial of Euphorbia kansui and support a potential role for ingenols in future HIV cure strategies.