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淋巴细胞在HIV-1免疫发病机制中的保护作用 感染，但最终在大多数人中由于落后于病毒而失败。大量数据表明，艾滋病毒-- 1-特异性CTL介导HIV-1的抑制，而HIV-1介导慢性感染的“无症状阶段”。 CTL反应是由原始细胞群体的克隆性扩增引起的，一旦抗原被清除 到低水平或缺乏水平时，这些细胞中的大多数都会死亡，留下处于休眠状态的中央记忆细胞具有较低的效应功能， 但在再次攻击效应细胞时，它们已准备好更快地扩张。此过程会导致 CTL落后于HIV-1，病毒序列进化快于CTL，允许突变逃逸 已建立的感染可能是导致CTL耗尽和病毒持续的主要机制 最终的失败。尽管抗逆转录病毒疗法(ART)的治疗阻止了大多数正在进行的病毒复制和 可能允许免疫再生，从而在治疗中断后控制感染，CTL 对静息记忆水平的衰退和治疗中断的反应通常会导致病毒血症的迅速上升 类似于急性感染。 我们假设，持续驱动针对HIV-1的效应器CTL的持久性可能会中断这一过程 致病循环。与其让CTL落后于HIV-1，我们提出了一项战略，以保持 独立于HIV-1复制的HIV-1特异性效应CTL。这可能会阻止(在 非感染者)或(在ART感染者的情况下)中断导致CTL的致病循环 功能障碍。为了实现这一目标，我们将利用人类体内的慢性抗原刺激 巨细胞病毒(CMV)驱动同时识别CMV和HIV-1的CTL。具体来说，我们的目标是： 1.设计慢病毒载体，同时产生针对CMV和HIV-1的CAR T细胞； 2.确定这些载体在体外的功能，为进一步的动物研究奠定基础。