Development of Nef antagonists to enhance CTL clearance of HIV reservoirs

开发 Nef 拮抗剂以增强 HIV 病毒库的 CTL 清除

• 批准号: 9291589
• 负责人: Kathleen L. Collins
• 金额: $ 45.88万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9291589
• 关键词: Affect; Animals; Antigen Presentation; Bacteria; Biological Assay; Biology; Cells; Clear Cell; Combined Modality Therapy; Complex; Cytotoxic T-Lymphocytes; Development; Disease; Drug effect disorder; Drug usage; Gene Expression; Genes; Goals; HIV; HIV-1; Immune response; Immune system; Immunoprecipitation; Immunotherapeutic agent; Infection; Lead; Life; Marines; Mediating; Microsomes; Modeling; Molecular Weight; Natural Products; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Property; Scheme; Structure; Therapeutic; Toxic effect; Transcription Factor AP-1; United States; Viral Antigens; Viral Genes; Virus; Virus Diseases; Work; cytotoxicity; drug candidate; improved; in vivo; inhibitor/antagonist; killings; pandemic disease; pharmacophore; public health relevance; research study

 DESCRIPTION: HIV-1 causes a persistent infection due to long-lived reservoirs of latently infected cells that present a barrier to achieving a cure. There are active efforts ongoing to eliminate the latently infected cells by using drugs that antagonize latency and activate viral gene expression. To date, the antagonists that have been identified tend to reactivate viral gene expression without efficiently killing the infected cells and clearing the reservoirs. Therefore, i may be necessary to develop immunotherapeutic approaches to ultimately clear the virus and cure disease. Cytotoxic T lymphocytes, which can recognize actively infected cells may aid in the clearance of reservoirs treated with latency antagonists. However, CTLs are limited in the extent to which they can effectively clear infection. Our long-term goal is to understand how to enable the immune response to more effectively recognize and eradicate latently infected cells that have been treated with latency antagonists. The overall objective of this application, which is the next step toward attainment of our long-term goal, is to identify compounds that maximize viral antigen presentation in HIV-infected cells. We hypothesize that while CTLs have activity against latently infected cells that have been induced to express HIV-1 genes, HIV-1 Nef, which down modulates MHC-I, limits the extent to which induced cells can be killed. Preliminary studies indicate that Nef inhibitors found in natural product extracts can reverse the effects of Nef and sensitize infected cells to CTL killing. These studies have led to the hypothesis that combination therapy with latency antagonists plus Nef inhibitors could act synergistically to clear reservoirs. The R21 phase of this proposal aims to complete the identification of inhibitory factors in high priority natural product extracts that contain anti-Nef activity. Upon successful completion of the R21 phase, The R33 phase will involve (1) determining the mechanism by which each factor inhibits Nef-mediated MHC-1 down modulation and (2) conducting lead compound optimization to improve the pharmaceutical properties and identify a leading drug candidate for development.

 描述：HIV-1 由于潜伏感染细胞的长期储存而导致持续感染，这对实现治愈构成了障碍。人们正在积极努力，通过使用拮抗潜伏并激活病毒基因表达的药物来消除潜伏感染的细胞。迄今为止，已鉴定的拮抗剂往往会重新激活病毒基因表达，但无法有效杀死受感染的细胞并清除病毒库。因此，我可能有必要开发免疫治疗方法以最终清除病毒并治愈疾病。细胞毒性 T 淋巴细胞可以识别主动感染的细胞，可能有助于清除用潜伏拮抗剂治疗的储存库。然而，CTL 有效清除感染的程度有限。我们的长期目标是了解如何使免疫反应更有效地识别和根除经过潜伏拮抗剂处理的潜伏感染细胞。该应用的总体目标是实现我们长期目标的下一步，是鉴定能够最大限度地在 HIV 感染细胞中呈递病毒抗原的化合物。我们假设，虽然 CTL 对被诱导表达 HIV-1 基因的潜伏感染细胞具有活性，但下调 MHC-I 的 HIV-1 Nef 限制了诱导细胞被杀死的程度。初步研究表明，天然产物提取物中发现的 Nef 抑制剂可以逆转 Nef 的作用，并使受感染的细胞对 CTL 杀伤敏感。这些研究提出了这样的假设：潜伏期拮抗剂加 Nef 抑制剂的联合治疗可以协同作用，以清除 水库。该提案的 R21 阶段旨在完成含有抗 Nef 活性的高优先级天然产物提取物中抑制因子的鉴定。成功完成 R21 阶段后，R33 阶段将涉及 (1) 确定每个因素抑制 Nef 介导的 MHC-1 下调的机制，以及 (2) 进行先导化合物优化，以改善药物特性并确定用于开发的主要候选药物。