Impact of engineered immune cells on viral rebound

工程免疫细胞对病毒反弹的影响

• 批准号: 10226141
• 负责人: Jerome A. Zack
• 金额: $ 33.68万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-10 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226141
• 关键词: Affect; Autologous; Bar Codes; Cells; Cellular Immunity; Coupled; Disease; Disease Progression; Disease remission; Engineering; Genetic; Genetic Engineering; Genetic Enhancement; Goals; HIV; Immune response; In Vitro; Individual; Infection; Innate Immune Response; Life; Modeling; Modification; Natural Killer Cells; Patients; Pharmaceutical Preparations; Proviruses; Reporter; Stimulus; System; T-Lymphocyte; Therapeutic; Viremia; Virus; Virus Replication; Withholding Treatment; antiretroviral therapy; chimeric antigen receptor; design; humanized mouse; immunoengineering; in vivo; mouse model; novel; prevent; programs; viral rebound

Antiretroviral therapy is effective in preventing HIV replication, however it does not eliminate all HIV proviruses, resulting in the presence of long-lasting reservoirs that re-kindle infection following cessation of treatment. Thus HIV infected individuals are required to remain on therapy for life, to prevent viral rebound. If we can control or prevent viral rebound, we may be able to provide patients a drug-free remission period, or a functional cure to HIV disease. Project 2 is designed to determine whether enhanced or genetically engineered immune cells can help to delay or minimize viral rebound. We will utilize cutting edge humanized mouse models, a novel barcoded virus reporter system, and several anti-HIV chimeric antigen receptors (CARs) to accomplish 3 aims: 1) Evaluate the effects of engineered anti-HIV T cells on HIV rebound following cessation of ART; 2) Evaluate the effects of natural killer cells on HIV rebound following cessation of ART; 3) Determine if reduction of the latent reservoir influences viral rebound after cessation of ART. Together these aims should allow us to better understand factors controlling viral rebound and determine whether genetic enhancement of cellular immunity or manipulation of innate immune responses can affect viral rebound. If so, this may point the way towards a new adjunctive therapeutic approach for HIV disease.

抗逆转录病毒疗法在预防艾滋病毒复制方面是有效的，但它不能消除所有的艾滋病毒前病毒， 导致存在持久的储库，其在停止治疗后重新引发感染。 因此，HIV感染者需要终身保持治疗，以防止病毒反弹。如果我们能 控制或预防病毒反弹，我们可能能够为患者提供一个无药物缓解期，或 功能性治愈艾滋病。项目2旨在确定是否增强或基因 工程免疫细胞可以帮助延迟或最小化病毒反弹。我们将利用最先进的人性化 小鼠模型、新型条形码病毒报告系统和几种抗HIV嵌合抗原受体 （汽车）以实现3个目标：1）评估工程化抗HIV T细胞对HIV反弹的影响， 停止抗逆转录病毒疗法; 2）评价自然杀伤细胞对停止抗逆转录病毒疗法后艾滋病毒反弹的影响; 3） 确定是否减少潜在水库影响病毒反弹后停止抗逆转录病毒治疗。 目的应该让我们更好地了解控制病毒反弹的因素，并确定是否遗传 细胞免疫的增强或先天免疫应答的操纵可影响病毒反弹。如果是这样的话， 这可能为HIV疾病的新的连续治疗方法指明了方向。