Dual CMV and HIV CARs for Cure of HIV

CMV 和 HIV 双重 CAR 用于治愈 HIV

• 批准号: 10001141
• 负责人: OTTO O YANG
• 金额: $ 19.5万
• 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: 2020-03-05 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001141
• 关键词: Abnormal Cell; Acute; Address; Aftercare; Animals; Antigens; Antiviral Agents; Area; Automobile Driving; Back; Binding; CD8-Positive T-Lymphocytes; Cell surface; Cells; Chronic; Chronic Phase; Clonal Expansion; Containment; Cytomegalovirus; Cytoplasmic Protein; Cytotoxic T-Lymphocytes; Data; Defect; Detection; Drops; Effector Cell; Engineering; Evolution; Failure; Functional disorder; Future; Generations; Genome Scan; Goals; HIV; HIV Infections; HIV vaccine; HIV-1; Histocompatibility Antigens Class I; Human; Immune; Immunity; In Vitro; Infection; Infection Control; Interruption; Laboratories; Lentivirus Vector; Macaca; Maintenance; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Memory; Mutation; Natural regeneration; Pathogenesis; Pathogenicity; Pathway interactions; Peptides; Persons; Play; Population; Process; Proteins; Public Health; Receptor Signaling; Rest; Role; SIV; Sampling; Scanning; Stimulus; T-Cell Receptor; Testing; Text; Therapeutic; Transportation; Viral; Viremia; Virus; Virus Replication; acute infection; adaptive immunity; antiretroviral therapy; arm; cancer therapy; chimeric antigen receptor; chimeric antigen receptor T cells; chronic infection; cytotoxic CD8 T cells; exhaustion; gene therapy; improved; in vivo; multicatalytic endopeptidase complex; pathogen; prevent; response; vector

PROJECT SUMMARY/ABSTRACT CD8+ cytotoxic T lymphocytes (CTLs) play a key role protective role in the immunopathogenesis of HIV-1 infection, but eventually fail in most persons due to lagging behind the virus. Numerous data indicate that HIV- 1-specific CTLs mediate the suppression of HIV-1 that mediates the “asymptomatic phase” of chronic infection. The CTL response arises by clonal expansion from the naïve cell population, and once the antigen is cleared to low or absent levels, most of these cells die, leaving resting central memory cells with low effector function, but which are primed for more rapid expansion upon re-challenge to effector cells. This process results in the lag of CTLs behind HIV-1, and viral sequence evolution outpaces CTLs to allow mutational escape during established infection that is likely a major mechanism of viral persistence leading to CTL exhaustion and eventual failure. Although treatment with antiretroviral therapy (ART) stops most ongoing viral replication and could potentially allow immune regeneration that could control infection after treatment interruption, CTL responses to decay to resting memory levels, and treatment interruption usually leads to a rapid rise in viremia similar to acute infection. We hypothesize that continuously driving persistence of effector CTLs against HIV-1 could interrupt this pathogenic cycle. Rather than allowing CTLs to lag behind HIV-1, we propose a strategy to maintain levels of HIV-1-specific effector CTLs independently of HIV-1 replication. This could prevent (in the case of an uninfected person) or break (in the case of an infected person on ART) the pathogenic cycle leading to CTL dysfunction. To achieve this goal, we will take advantage of the in vivo chronic antigenic stimulus of human cytomegalovirus (CMV) to drive CTLs that recognize both CMV and HIV-1. Specifically, we aim: 1. To engineer lentiviral vectors that generate CAR T cells targeting CMV and HIV-1 simultaneously; 2. To confirm the function of these vectors in vitro as a prerequisite for future animal studies.

项目摘要/摘要 CD8+细胞毒性T淋巴细胞（CTL）在HIV-1的免疫发病中起关键作用。 感染，但由于落后于病毒，大多数人有时会失败。大量数据表明HIV- 1特异性CTL介导了介导慢性感染的“无症状相”的HIV-1抑制。 CTL响应是由幼稚细胞种群的克隆膨胀而产生的，一旦清除了抗原 到低或不存在的水平，这些细胞中的大多数都会死亡，使静止的中央记忆细胞具有低效应函数， 但是，在重新挑战效应细胞后，它们会以更快的速度扩展。这个过程导致 HIV-1后CTL的滞后和病毒序列演化超过CTL，以使突变逃逸在期间 已建立的感染可能是病毒持久性的主要机制，导致CTL疲惫和 最终失败。尽管使用抗逆转录病毒疗法（ART）治疗可阻止大多数持续的病毒复制和 可能允许免疫再生可以控制治疗后感染，CTL 对衰减对静止记忆水平的反应和治疗中断通常会导致病毒血症迅速增加 类似于急性感染。 我们假设持续推动效应子CTL对HIV-1的持续性可能会中断这一点 致病周期。我们不允许CTL落后于HIV-1，而是提出了一种策略来维持的水平 HIV-1特异性效应子CTL独立于HIV-1复制。这可以防止（在 未感染的人）或破裂（对于被感染的艺术感染者）导致CTL的致病周期 功能障碍。为了实现这一目标，我们将利用人体内的慢性抗原刺激 巨细胞病毒（CMV）驱动识别CMV和HIV-1的CTL。特别是，我们的目标是： 1。用于慢病毒载体，以生成靶向CMV和HIV-1的CAR T细胞； 2。为了确认这些载体在体外的功能，作为未来动物研究的先决条件。