Natural killer cell engineering to target the HIV reservoir

自然杀伤细胞工程瞄准艾滋病毒储存库

• 批准号: 10593137
• 负责人: Catherine A Blish
• 金额: $ 76.01万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593137
• 关键词: Ablation; Acquired Immunodeficiency Syndrome; Adverse drug event; Allogenic; Animal Model; Anti-Retroviral Agents; Bar Codes; Cell Therapy; Cells; Cellular Immunity; Cellular immunotherapy; Charge; Chronic; Clinical; Collaborations; DNA; Disease Progression; Disease remission; Engineering; Engraftment; Goals; HIV; HIV Infections; HIV-1; Hematopoietic Stem Cell Transplantation; Human; Immune; Immune system; Immunity; Immunobiology; In Vitro; Individual; Infection; Interruption; Knowledge; Lead; Libraries; Measures; Medical; Messenger RNA; Methods; Modeling; NK cell therapy; Natural Killer Cell toxicity; Natural Killer Cells; Patients; Peripheral; Pharmaceutical Preparations; Production; Protein Kinase C; Proviruses; Recrudescences; Regimen; Reporter; Research Project Grants; Rest; T-Lymphocyte; Technology; Testing; Therapeutic; Transfection; Viral; Viral Physiology; Viral reservoir; Viremia; Virus; Virus Activation; Virus Latency; Virus Replication; analog; antiretroviral therapy; bryostatin; chemical synthesis; chimeric antigen receptor; clinical application; conditioning; cost; cytotoxic; efficacy evaluation; engineered NK cell; global health; humanized mouse; improved; in vivo; in vivo evaluation; innovation; mouse model; novel; pressure; public health relevance; receptor; research clinical testing; response; tool; viral rebound

ABSTRACT HIV continues to be a global health concern that has claimed the lives of millions. Although anti-retroviral therapy (ART) slows disease progression, ART is not curative due to certain reservoirs of replication-competent virus that persist during therapy. Therefore, if ART is stopped, then virus can emerge from these reservoirs and rapidly spread, causing renewed progression towards AIDS. In addition, life-long use of ART is associated with issues related to cost, medical compliance, and adverse drug events. One strategy for clearing the reservoir of latently infected cells is to use a kick and kill approach, in which latent cells are “kicked” or activated from latency, and then concurrently cleared or “killed”. Latency reversal agents (LRA) can “kick” or induce HIV expression from latent cells, but thus far only a subset of activated latent cells die. Natural killer (NK) cells hold great promise as killing agents for HIV-infected cells as they re-emerge from latency due to their innate anti-viral recognition and cytotoxic function. The goal of this research project is to develop new methods to enhance the intrinsic killing activity of NK cells and to develop NK cell-based kick and kill strategies to reduce the need for life-long ART by decreasing or eliminating latent viral reservoirs. We intend to approach this proposal by using cutting-edge technology to engineer the enhanced survival and anti-viral function of NK cells, sophisticated humanized mouse models of HIV latency, and innovative tools to measure and study the effect of our treatments on the HIV reservoir. We will test our overall hypothesis that a kick and kill approach will decrease or eliminate the latent reservoir in the following aims: 1) engineer NK cells to enhance their elimination of HIV-infected cells using an innovative non-viral mRNA transfection technology, and 2) investigate the effect of novel latency reversal agents (LRAs) in combination with modified NK cells on HIV reservoirs in a humanized mouse model of HIV latency. This proposal utilizes Dr. Jerome Zack's (lead PI, UCLA) extensive background in HIV latency and animal modeling, Dr. Catherine Blish's (dual-PI, Stanford) expertise in NK cell immunobiology and cellular manipulation, and includes a unique collaboration with Dr. Paul Wender (Stanford), an expert in chemical synthesis, who has developed a globally unique library of latency reactivating agents (LRAs) with unprecedented latency reversal capabilities and expanded tolerability that will be tested individually and in synergistic combinations with NK cells. Together we hope to fully harness the potential of NK cellular therapies, and develop LRA and NK cell combination therapeutic approaches to provide patients with sustained virologic remissions or complete viral eradication.

摘要 艾滋病毒仍然是一个全球健康问题，已夺去数百万人的生命。虽然抗逆转录病毒疗法 (ART)减缓疾病进展，但由于某些具有复制能力的病毒储库，ART不能治愈 在治疗期间持续存在因此，如果停止ART，那么病毒可以从这些储库中迅速出现， 传播，导致艾滋病的新进展。此外，终身使用抗逆转录病毒疗法与以下问题有关： 与成本、医疗依从性和药物不良事件相关。一种清除潜在水库的策略 被感染的细胞是使用踢和杀死的方法，其中潜伏细胞被“踢”或从潜伏期激活， 然后同时清除或“杀死”。潜伏期逆转剂（LRA）可以“踢”或诱导HIV表达， 在一些实施例中，活化的潜伏细胞死亡，但到目前为止，只有活化的潜伏细胞的子集死亡。自然杀伤（NK）细胞有很大的希望， 当HIV感染细胞由于其先天抗病毒识别而从潜伏期重新出现时， 细胞毒功能本研究项目的目标是开发新的方法来增强内在杀伤力 NK细胞的活性，并开发基于NK细胞的踢杀策略，以减少对终身ART的需求， 减少或消除潜伏的病毒库。我们打算利用最先进的技术来处理这项建议。 技术工程增强生存和抗病毒功能的NK细胞，先进的人源化小鼠 艾滋病毒潜伏期的模型，以及测量和研究我们的治疗对艾滋病毒的影响的创新工具。 水库我们将测试我们的总体假设，即踢和杀的方法将减少或消除潜在的 1）使用免疫调节剂，工程化NK细胞以增强它们对HIV感染细胞的消除， 创新的非病毒mRNA转染技术，以及2）研究新型潜伏期逆转剂的作用 在HIV潜伏期的人源化小鼠模型中，将LRA与修饰的NK细胞组合在HIV储库上。 该提案利用了杰罗姆扎克博士（首席PI，加州大学洛杉矶分校）在艾滋病毒潜伏期和动物方面的广泛背景， Catherine Blish博士（双PI，斯坦福大学）在NK细胞免疫生物学和细胞操作方面的专业知识， 包括与化学合成专家Paul Wender博士（斯坦福大学）的独特合作， 开发了全球唯一的潜伏期再激活剂（LRA）库，具有前所未有的潜伏期逆转 将单独测试和与NK细胞协同组合测试的能力和扩大的耐受性。 我们希望共同充分利用NK细胞疗法的潜力，开发LRA和NK细胞疗法。 为患者提供持续病毒学缓解或完全病毒学缓解的联合治疗方法 根除