Dual CMV and HIV CARs for Cure of HIV

CMV 和 HIV 双重 CAR 用于治愈 HIV

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要 CD8+ 细胞毒性 T 淋巴细胞 (CTL) 在 HIV-1 免疫发病机制中发挥关键保护作用感染，但由于落后于病毒，大多数人最终都失败了。 1 特异性 CTL 介导对 HIV-1 的抑制，从而介导慢性感染的“无症状期”。 CTL 反应是由初始细胞群的克隆扩增产生的，一旦抗原被清除当水平较低或不存在时，大多数细胞都会死亡，留下休眠的中央记忆细胞，其效应功能较低，但在再次攻击效应细胞时，它们已准备好进行更快速的扩增。 CTL 落后于 HIV-1，并且病毒序列进化超过 CTL，从而允许突变逃逸已建立的感染可能是导致 CTL 耗竭的病毒持续存在的主要机制尽管抗逆转录病毒疗法（ART）停止了大多数正在进行的病毒复制，但最终还是失败了。可能允许潜在的免疫再生，从而可以在治疗中断后控制感染，CTL 对静息记忆水平衰退的反应，治疗中断通常会导致病毒血症迅速上升与急性感染类似。我们追求持续驱动针对 HIV-1 的效应 CTL 的持久性可能会中断这一过程我们提出了一种维持 CTL 水平的策略，而不是让 CTL 落后于 HIV-1。 HIV-1 特异性效应 CTL 独立于 HIV-1 复制，这可以防止（在 HIV-1 复制的情况下）。未感染者）或打破（在接受抗逆转录病毒治疗的感染者的情况下）导致 CTL 的致病循环为了实现这一目标，我们将利用人类体内的慢性抗原刺激。具体来说，我们的目标是： 1. 设计慢病毒载体，产生同时靶向CMV和HIV-1的CAR T细胞； 2. 体外确认这些载体的功能，作为未来动物研究的先决条件。