Discovery and Characterization of Latency-Reversing Compounds

潜伏期逆转化合物的发现和表征

基本信息

批准号：
9319622
负责人：
Louis R Barrows
金额：
$ 18.95万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9319622
关键词：
Address Adverse effects Agonist Anti-Retroviral Agents Biological Assay Botanicals Cell physiology Cells Chemical Structure Chemicals Chemistry Chromatin Structure Clinic Clinical Trials Drug Design Fractionation Generations Genetic Transcription Goals HIV HIV-1 Human Immune response In Vitro Individual Infection Inflammatory Interleukin-2 Mass Spectrum Analysis Medicinal Plants Modeling Monoclonal Antibody HuM291 Natural Products Nature Nuclear Magnetic Resonance Pathway interactions Patients Persons Pharmacologic Substance Plants Positive Transcriptional Elongation Factor B Process Protein Kinase C Recombinants Sampling Signal Pathway Source Stat5 protein T memory cell T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte Techniques Testing Therapeutic Transcription Factor AP-1 Transcriptional Activation Viral Viral reservoir Work base combat curative treatments cytokine drug discovery histone modification novel pharmacophore promoter public health relevance purge reactivation from latency research clinical testing small molecule transcription factor treatment strategy

项目摘要

DESCRIPTION (provided by applicant): The persistence of latent HIV in quiescent central memory T cells (Tcm) in individuals treated undergoing anti-retroviral therapy (ART) is well documented. It is this reservoir of virus that is thought to be the principal reason for the inabilty of current HIV treatment strategies to cure the infection. The possibility of reactivating latent HIV, and thus purging a person of latent HIV reservoirs, has prompted the search for HIV activating agents, but to date these efforts have not yielded tenable therapies. A clinical trial using a recombinant anti-CD3 antibody, and IL-2 to reactivate latent HIV was discontinued due to potent general T-cell activation and cytokine storm. Viral reactivation in the absence of global T cell activation is needed to avoid overproduction of inflammatory cytokines; not to mention the expansion of the latent HIV reservoir due to T cell proliferation. Plants are a rich source of molecules capable of modulating many human immunological responses, including activation of signaling pathways responsible for reactivation of latent HIV-1. We have identified 120 extracts from medicinal plants that are capable of reactivating latent HIV-1. Of these extracts, a significant proportion were found to spare T-cell activation and, therefore, constitute excellent candidates for viral eradication strategies. Based on these results, we conclude that the goal of identifying selective small molecule HIV activators with the desired qualities is possible. More importantly, exploration of these new latency reversing molecules will reveal mechanisms by which they can synergize with agents being explored in the clinic, and act to reactivate HIV in absence of general T cell activation. The mechanisms of action for these botanicals will be compared with the MOAs of known latency reversing agents for which signaling pathways resulting in transcriptional effects are characterized (such as protein kinase C and T-cell receptor agonists and others).

描述（由适用提供）：在抗逆转录病毒疗法（ART）治疗的个体中，静态中央记忆T细胞（TCM）中潜在艾滋病毒的持久性已得到充分记录。正是这种病毒储层被认为是治愈感染的当前艾滋病毒治疗策略不完整的主要原因。重新激活潜在艾滋病毒并因此清除潜伏的艾滋病毒储量的可能性促使人们寻找艾滋病毒激活剂，但至今，这些努力尚未产生可替代的疗法。由于潜在的一般T细胞激活和细胞因子风暴，使用了重组抗CD3抗体和IL-2进行重新激活HIV的临床试验。在没有全球的情况下，病毒重新激活需要T细胞激活以避免炎性细胞因子过量生产；更不用说由于T细胞增殖而导致潜在的HIV参与者的扩展。植物是能够调节许多人类免疫反应的丰富分子来源，包括激活负责潜在HIV-1的信号通路。我们已经从能够重新激活潜在HIV-1的药用植物中确定了120种提取物。在这些提取物中，发现很大一部分可以节省T细胞激活，因此构成了病毒辐射策略的出色候选者。基于这些结果，我们包括具有所需品质的选择性小分子HIV激活剂的目标。更重要的是，对这些新的潜伏期逆转分子的探索将揭示它们可以与诊所中探索的药物协同作用的机制，并在没有一般T细胞激活的情况下起作用HIV。这些植物学的作用机制将与已知潜伏期逆转剂的MOA进行比较，该剂量逆转剂的信号传导途径会导致转录效应（例如蛋白激酶C和T细胞受体激动剂等）。