The Effect of Natural Killer Cell-Based Therapy on the HIV Reservoir

基于自然杀伤细胞的疗法对 HIV 病毒库的影响

• 批准号: 10222536
• 负责人: Jocelyn T Kim
• 金额: $ 20.44万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-23 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10222536
• 关键词: Advisory Committees; Affect; Allogenic; Anti-Retroviral Agents; Antigens; Applications Grants; Autologous; Award; Baltimore; Bar Codes; Biological; Biology; Blood Cells; Blood donor; California; Cell Therapy; Cells; Cellular Immunity; Chronic; Clinical; Collaborations; Communicable Diseases; Complex; Data; Disease Progression; Doctor of Philosophy; Engineering; Funding; Gays; Generations; Genetic; Genetic Enhancement; HIV; HIV Infections; HIV-1; Hematopoietic stem cells; Immune system; In Vitro; Innate Immune Response; Institutes; Intention; Interruption; Knowledge; Measures; Mentors; Mentorship; Methods; Modeling; Molecular Cloning; Morbidity - disease rate; Natural Killer Cells; Pathogenesis; Pathogenicity; Peripheral; Pharmaceutical Preparations; Physicians; Production; Professional Competence; Protein Kinase C; Public Health; Reporter; Research; Research Personnel; Scientist; Source; T cell differentiation; T-Lymphocyte; Technology; Testing; Therapeutic; Training; Training Programs; Viral; Viral reservoir; Virus; Virus Diseases; Virus Replication; Writing; adaptive immune response; antiretroviral therapy; base; career development; chimeric antigen receptor; chimeric antigen receptor T cells; clinical application; combinatorial; comparative efficacy; efficacy testing; graft vs host disease; humanized mouse; in vitro Assay; in vivo; innovation; medical specialties; mortality; mouse model; neutralizing antibody; novel; novel therapeutics; peripheral blood; professor; programs; public health relevance; skills; stem cell differentiation; synthetic protein; tool; viral rebound

PROJECT SUMMARY/ABSTRACT This grant proposal describes a five-year mentored training program for the career development of Dr. Jocelyn Kim, a physician-scientist, who will develop cutting-edge methods to quantify the HIV reservoir and investigate novel therapies to cure HIV infection. She has recently discovered that natural killer (NK) cells delays viral rebound in a sophisticated humanized mouse model of HIV latency. She has also found that anti-HIV chimeric antigen receptor (CAR)-on NK cells efficiently kill HIV-infected cells in vitro. In addition, a novel synthetic latency reactivating agent (LRA) activates latent HIV in the presence of ART in vivo. Importantly, she has innovated a genetically barcoded reporter HIV-1 and demonstrated that this diverse virus swarm is replication-competent and pathogenic in vivo and forms a latent reservoir, which rebounds after cessation of antiretroviral therapy (ART). She will use this novel barcoded-virus tool to accurately quantify the number of latently infected clones in vivo. These preliminary data are the basis of the current proposal, which involves the completion of the following aims. First, she will investigate whether NK cells from peripheral blood or hematopoietic stem cell progenitors (HSCPs) are more effective in delaying HIV rebound in vivo using new methods of stem cell differentiation and analysis. Second, she will test of efficacy of CAR-NK cells versus CAR-T cells on viral rebound in vivo. Lastly, she will use state-of-the-art approach in genetic barcoded virus to determine whether combinatorial therapies (LRA and NK cell-based therapies) affect the HIV reservoir in vivo. With K08 funding, she we will complete these studies with the intention of deepening our understanding of HIV pathogenesis and curative strategies. Dr. Kim is currently an assistant clinical professor in the UCLA Division of Infectious Diseases and recent graduate of the UCLA Specialty Training and Advanced Research (STAR) program, from which she received a PhD in Biology and Biological Engineering from California Institute of Technology under her PhD advisor Dr. David Baltimore. During the proposed award period, she will continue under the primary mentorship of Dr. Jerome Zack at UCLA with additional mentorship through an advisory committee comprised of Drs. Gay Crooks (UCLA), Alex Hoffman (UCLA) and Judith Currier (UCLA). With their guidance, she will attain the necessary research and career skills to apply successfully for independent funding and transition to independence. As such, through her collaborations as well as didactic training, she will expand her NK cell project and use complex computational skills for high-throughout barcode sequencing analysis to understand the HIV reservoir. She will also acquire new skills in stem cell differentiation and analysis, molecular cloning, and writing and grantsmanship. K08 funding will allow her to develop all of the skills and tools needed to become a successful independent investigator.

项目总结/摘要 这项拨款提案描述了一个为期五年的指导培训计划，为乔斯林博士的职业发展 他将开发尖端的方法来量化艾滋病病毒库， 治疗HIV感染的新疗法。她最近发现，自然杀伤（NK）细胞可以延缓病毒的传播。 一个复杂的HIV潜伏期人源化小鼠模型的反弹。她还发现，抗艾滋病毒嵌合体 NK细胞上的抗原受体（CAR）在体外有效地杀死HIV感染的细胞。此外，一种新的合成延迟 再活化剂（LRA）在ART存在下在体内活化潜伏的HIV。重要的是，她创新了一种 基因条形码报告HIV-1，并证明这种不同的病毒群是复制能力， 在体内是致病的，并形成一个潜在的水库，它在停止抗逆转录病毒治疗后反弹 （ART）。她将使用这种新的条形码病毒工具来精确地量化潜伏感染克隆的数量 in vivo.这些初步数据是目前提案的基础，该提案涉及完成 的目标。首先，她将研究NK细胞是否来自外周血或造血干细胞， 使用干细胞移植的新方法， 分化与分析。其次，她将测试CAR-NK细胞与CAR-T细胞对病毒反弹的功效。 in vivo.最后，她将使用最先进的方法在遗传条形码病毒，以确定是否 组合疗法（基于LRA和NK细胞的疗法）影响体内HIV储库。在K 08的资助下， 她说，我们将完成这些研究，以加深我们对艾滋病毒发病机制的理解， 治疗策略金博士目前是加州大学洛杉矶分校传染病系的临床助理教授 最近毕业于加州大学洛杉矶分校专业培训和高级研究（星星）计划，从她 获得加州理工学院生物学和生物工程博士学位 巴尔的摩的顾问大卫医生。在建议的奖励期间，她将继续接受初级指导 杰罗姆扎克博士在加州大学洛杉矶分校与额外的指导，通过一个咨询委员会组成的博士盖伊 克鲁克斯（加州大学洛杉矶分校），亚历克斯霍夫曼（加州大学洛杉矶分校）和朱迪思柯里尔（加州大学洛杉矶分校）。在他们的引导下， 必要的研究和职业技能，成功申请独立资助和过渡到 独立因此，通过她的合作以及教学培训，她将扩大她的NK细胞 项目和使用复杂的计算技能进行高通量条形码测序分析，以了解 艾滋病病毒的储存库她还将获得干细胞分化和分析，分子克隆， 写作和语法。K 08的资金将使她能够发展成为一名 成功的独立调查员