Discovering New HIV-1 Latency Reversal Agents from Euphorbia Species

从大戟属物种中发现新的 HIV-1 潜伏期逆转剂

基本信息

批准号：
10649761
负责人：
Adam Mitchell Spivak
金额：
$ 77.46万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-25 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10649761
关键词：
Actinic keratosis Adverse effects Affect Africa Agonist Behavior CD4 Positive T Lymphocytes Cathartics Cell Compartmentation Cell Line Cells Chemicals Chinese Traditional Medicine Chronic Clinical Trials Clinical Trials Design Constipation Data Disease Drug Kinetics Drug or chemical Tissue Distribution Euphorbia Euphorbiaceae Evaluation FDA approved Family Far East Fluid overload HIV-1 High Pressure Liquid Chromatography Histone Deacetylase Inhibitor Human Immune Immune Targeting Immunocompetent In Vitro Individual Infection Intervention Knowledge Libraries Medicinal Plants Methods Modeling Mus Natural Products Outcome Participant Persons Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase I Clinical Trials Plant Extracts Plant Roots Plants Powder dose form Process Protein Kinase C Proviruses RNA Reporting Research Rest Safety Structure-Activity Relationship T-Cell Activation T-Lymphocyte Tea Testing Toxic effect Traditional Medicine Transcript Viral Cytopathogenic Effect Viremia Virus Virus Latency Virus Replication Work antiretroviral therapy aqueous chemical synthesis clinical development cytotoxicity design first-in-human immune activation in vitro testing in vivo latent HIV reservoir liquid chromatography mass spectrometry member memory CD4 T lymphocyte mouse model nonhuman primate novel novel strategies pre-clinical restoration screening

项目摘要

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.

项目概要抗逆转录病毒疗法 (ART) 使 HIV-1 感染成为一种可治疗的疾病，但 ART 并不能治愈，因为长寿命静息 T 细胞中具有复制能力的非转录原病毒。直接针对这些目标的策略潜伏感染细胞对于根除 HIV-1 感染者 (PLWH) 中的病毒是必要的。使用化合物逆转病毒潜伏期的药理学方法（称为潜伏期逆转剂或 LRA），通过病毒细胞病变效应使储存库受到免疫靶向或清除，已被研究在临床试验中。然而，迄今为止还没有任何试验对潜在的储存库产生显着的干扰。一大障碍阻碍 HIV-1 根除进展的因素是对能够消灭 HIV-1 的 LRA 的识别和表征重新激活潜伏储库的很大一部分，并且不会产生限制体内的不利影响使用。潜伏期逆转的一种机制，即蛋白激酶 C 激活，已在体外和在体内显示出前景。 HIV-1潜伏期的小鼠和非人类灵长类动物模型。鉴于尚未满足的迫切需要，可扩展的 HIV-1 治疗策略，PKC 激动剂在体内诱导的有效潜伏期逆转呈现出一种有吸引力的方法。我们和其他人已经确定了 PKC 激动剂的潜伏期逆转潜力，称为巨大戟二萜醇是大戟科药用植物中常见的天然化合物。例如，甘水大戟原产于东亚，含有 14 种独特的巨大戟二萜醇化合物，具有 PKC 激动剂活性。甘遂桉的根粉制成茶，在中药中用作药物泻药，治疗液体过多和便秘。我们一直在进行首次人体 I 期临床评估甘遂茶对感染者的安全性、抗潜伏期和免疫刺激作用的试验（NCT02531295）已被证明是安全且耐受性良好的。巨大戟二萜醇甲丁酸酯，一种天然存在的巨大戟二萜醇存在于 E. peplus 中，经 FDA 批准可局部用于治疗光化性角化病。最近的一份报告描述了 HIV-1 使用巨大戟二甲酚甲丁酸酯在感染者体内逆转潜伏期。许多大戟属物种原产于东非受 HIV-1 影响尤为严重的地区，正在积极将其用作传统药物。然而，鲜为人知关于这些天然产物或其化学物质的潜在抗 HIV-1 或免疫调节活性选民。我们假设大戟属物种的化学成分作为传统药物被积极使用药物具有有效的 HIV-1 潜伏逆转活性。我们提出了完整的临床前表征从原产于东非的药用大戟属植物中分离出天然存在的生物活性化合物，关于潜伏逆转潜力、免疫扰动以及体外和体内潜在的脱靶效应 HIV-1 持久性小鼠模型。这项工作将产生新知识，为旨在实现以下目标的战略提供信息：消除 HIV-1 潜伏病毒库。