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

• 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
• 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

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.

项目摘要 抗逆转录病毒疗法（ART）已使HIV-1感染成为可治疗的疾病，但ART由于 在长寿命的静息T细胞中复制能力未转录的前病毒。直接针对这些目标的战略 潜伏感染的细胞将是根除HIV-1（PLWH）感染者体内病毒所必需的。 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库受到免疫靶向或清除，已经进行了研究 在临床试验阶段然而，迄今为止，还没有任何试验对潜在的水库产生重大影响。一个主要障碍 阻碍HIV-1根除进展的是LRA的鉴定和表征， 重新激活相当大一部分的潜伏性储库，并且不会产生限制体内 使用.潜伏期逆转的一种机制，蛋白激酶C激活，已经在体外和体内显示出希望。 HIV-1潜伏期的鼠和非人灵长类动物模型。鉴于有效的需求尚未实现且迫切， 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， 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， 巨大戟醇是已知为大戟科的药用植物家族中常见的天然化合物。 例如，甘遂原产于东亚，含有14种独特的巨大戟醇化合物， 激动剂活性E.甘遂，配制成茶，在传统中医中用作 治疗体液过多和便秘的泻药。我们一直在进行第一次人体试验， 评价E.甘遂茶 （NCT 02531295），已证明安全且耐受性良好。巨大戟醇甲基丁酸酯，一种天然存在的巨大戟醇 存在于E. PEPLUS是FDA批准的用于治疗光化性角化病的局部使用。最近的一份报告描述了HIV-1 使用巨大戟醇甲基丁酸酯在PLWH中的体内潜伏期逆转。许多原产于东非的大戟属物种， 在受艾滋病毒-1影响最严重的地区，作为传统药物被积极使用。然而， 关于这些天然产物或其化学品的潜在抗HIV-1或免疫调节活性， 选民。我们假设，化学成分的大戟属物种在积极使用的传统， 药物具有强效的HIV-1潜伏逆转活性。我们提出了一个完整的临床前表征 从原产于东非的药用大戟属植物物种中分离的天然存在的生物活性化合物， 关于潜伏期逆转潜力、免疫干扰和体外和体内潜在脱靶效应， HIV-1持续存在的鼠模型。这项工作将产生新的知识，为战略提供信息， 消除HIV-1潜伏库。