Discovering New HIV-1 Latency Reversal Agents from Euphorbia Species

项目总结 抗逆转录病毒疗法(ART)使hiv-1感染成为一种可治疗的疾病，但抗逆转录病毒疗法并不能治愈。 到长寿静息T细胞中具有复制能力的未转录前病毒。直接针对这些客户的策略 潜伏感染细胞将是根除HIV-1感染者(PLWH)病毒所必需的。 使用化合物逆转病毒潜伏期的药物方法(称为潜伏期反转剂或 LRAS)，通过病毒的细胞病变效应使储存库受到免疫靶向或清除 在临床试验中。然而，到目前为止，还没有一项试验显著扰乱了潜在的储集层。一大障碍 阻碍根除艾滋病毒-1的进展的是识别和表征能够 重新激活相当一部分潜伏储存库，并且不会产生限制体内的不良反应 使用。潜伏期逆转的一种机制，即蛋白激酶C激活，在体外和临床上都显示出了希望。 小鼠和非人类灵长类动物HIV-1潜伏期模型。鉴于对有效的、未得到满足的迫切需要， 可扩展的HIV-1治愈策略，PKC激动剂在体内诱导的有效潜伏期逆转呈现 吸引人的方法。我们和其他人已经确定了PKC激动剂的潜伏期逆转潜力，称为 一种天然存在的化合物，常见于一科药用植物，称为大戟科。 例如，甘遂原产于东亚，含有14种独特的具有pkc的吲哚化合物。 激动剂活性。甘遂根粉，制成茶，在中药中作为一种 用于治疗液体超载和便秘的泻药。我们一直在进行首例人类第一期临床试验 甘遂茶的安全性、抗潜伏期和免疫刺激作用 (NCT02531295)，这已被证明是安全和耐受性良好的。美丁酸吲哚，一种自然产生的吲哚 存在于E.peplus，是FDA批准用于局部治疗光化性角化病的药物。最近的一份报告描述了HIV-1 使用吲哚美丁酸酯的PLWH患者体内潜伏期逆转。许多大戟物种原产于东非，一种 在受艾滋病毒-1影响较大的地区，这些药物正被作为传统药物积极使用。然而，人们对此知之甚少 关于这些天然产品或其化学物质潜在的抗HIV-1或免疫调节活性 选民。我们假设活跃使用的大戟属植物的化学成分是传统的 药物具有强大的HIV-1潜伏期逆转活性。我们提出了一个完整的临床前特征 从原产于东非的药用大戟属植物中分离出的天然生物活性化合物， 关于潜伏期逆转潜力、免疫扰动和潜在的体外和在 HIV-1持续感染的小鼠模型。这项工作将产生新的知识，为旨在 消除HIV-1潜伏的蓄水池。

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.