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: 10380777
• 负责人: Catherine A Blish
• 金额: $ 77.21万
• 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/10380777
• 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; Life; 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; base; bryostatin; chemical synthesis; chimeric antigen receptor; clinical application; conditioning; cost; cytotoxic; 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.

抽象的 艾滋病毒仍然是全球卫生问题，已经夺走了数百万人的生命。虽然抗返回病毒疗法 （ART）减慢疾病的进展，由于某些复制能力的病毒，ART无法治愈 在治疗过程中持续存在。因此，如果停止了艺术 传播，导致对艾滋病的新进展。此外，终身使用艺术与问题有关 与成本，医疗合规性和不良药物事件有关。清除潜在的水库的一种策略 感染的细胞是使用踢和杀死方法，其中潜在细胞被“踢”或从延迟中激活，并且 然后同时清除或“杀死”。潜伏期逆转代理（LRA）可以“踢”或引起HIV表达 潜在细胞，但到目前为止，仅一部分活化的潜在细胞死亡。天然杀手（NK）细胞具有巨大的希望 杀死感染的艾滋病毒细胞的杀死药物因先天性抗病毒识别而从潜伏期中重新出现时， 细胞毒性功能。该研究项目的目的是开发新方法来增强内在的杀戮 NK细胞的活动并开发基于NK细胞的踢脚并杀死策略，以减少终身艺术的需求 减少或消除潜在病毒储存库。我们打算通过使用尖端来解决这一建议 技术来设计NK细胞增强生存和抗病毒功能，复杂的人源性小鼠 艾滋病毒潜伏期的模型以及衡量和研究我们疗法对艾滋病毒影响的创新工具 水库。我们将测试我们的总体假设，即踢和杀死方法将减少或消除潜伏 在以下目的中，储层：1）工程师NK细胞，以增强其消除HIV感染的细胞 创新的非病毒mRNA转化技术，以及2）研究新延迟逆转剂的效果 （LRA）与艾滋病毒潜伏期的人源化小鼠模型中的HIV储层上的修饰的NK细胞结合使用。 该提案利用Jerome Zack博士（UCLA Lead Pi）广泛的艾滋病毒潜伏期和动物背景 建模，Catherine Blish博士（Dual-Pi，Stanford）在NK细胞免疫生物学和细胞操纵方面的专业知识， 并包括与化学合成专家保罗·温德（Paul Wender）（斯坦福大学）的独特合作， 开发了一个具有前所未有的延迟逆转的全球独特的延迟重新激活剂（LRAS）库 能力和扩展的耐受性，将在与NK细胞的协同组合中进行单独测试。 我们一起希望充分利用NK细胞疗法的潜力，并发展LRA和NK细胞 联合疗法的方法可为患者提供持续的病毒性缓解或完全病毒 根除。