Supraphysiologic control over HIV-1 replication mediated by CD8 T cells expressing a re-engineered CD4-based chimeric antigen receptor.
Supraphysiologic control over HIV-1 replication mediated by CD8 T cells expressing a re-engineered CD4-based chimeric antigen receptor.
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DOI：
10.1371/journal.ppat.1006613
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发表时间：
2017-10
期刊：
影响因子：
6.7
通讯作者：
Riley JL
中科院分区：
文献类型：
--
作者：
Leibman RS;Richardson MW;Ellebrecht CT;Maldini CR;Glover JA;Secreto AJ;Kulikovskaya I;Lacey SF;Akkina SR;Yi Y;Shaheen F;Wang J;Dufendach KA;Holmes MC;Collman RG;Payne AS;Riley JL
HIV 善于避免自然产生的 T 细胞反应；因此，需要开发具有更大效力的 HIV 特异性 T 细胞，用于 HIV 治疗策略。从之前在临床试验中使用的无毒性的基于 CD4 的嵌合抗原受体 (CAR) 开始，我们优化了载体主链、启动子、HIV 靶向部分以及跨膜和信号传导域，以确定哪些组件增强了 T 细胞控制 HIV 复制的能力。这种重新设计的 CAR 在体外控制 HIV 复制方面比原始 CD4 CAR 或基于 TCR 的方法有效至少 50 倍，并且比基于广泛中和抗体的 CAR 明显更好。 HIV 感染的人源化小鼠模型表明，与表达原始临床试验 CAR 的 T 细胞相比，表达优化 CAR 的 T 细胞在响应抗原而扩增、保护 CD4 T 细胞免受感染以及减少病毒载量方面表现出色。此外，在 HIV 治疗的人源化小鼠模型中，含有 4-1BB 共刺激结构域的 CD4 CAR T 细胞在 ART 去除后比含有 CD28 共刺激结构域的类似 CAR T 细胞更好地控制了 HIV 传播。总之，这些数据表明，使用改进的 CAR 设计可以产生有效的 HIV 特异性 T 细胞，并且 CAR T 细胞可能是 HIV 治疗策略的重要组成部分。传统的 T 细胞很少能对 HIV 复制提供持久的控制。嵌合抗原受体 (CAR) 改变 T 细胞识别受感染 T 细胞的方式，绕过许多 HIV 的免疫逃逸机制。因此，我们假设，经过改造后表达这些受体的 T 细胞将更有效（超生理），并且能够以比传统 T 细胞低得多的效应子与靶标比率来控制 HIV 感染。从进入临床试验但未能可靠降低患者 HIV 检测结果的 CAR 开始，我们系统地优化了表达、结构和激活组件，以增强其功能。表达这种重新设计的 CAR 的 CD8 T 细胞在体外非常有效地抑制 HIV，其预防病毒传播的能力比原始 CAR 构建体或 HIV 特异性 TCR 方法高出 50 倍以上。重要的是，在 HIV 感染的人源化小鼠模型中，这些优化的 CAR T 细胞可以保护 CD4 T 细胞免受 HIV 介导的耗竭，并可以显着延迟 ART 停止后的病毒反弹。这些数据令人乐观地认为，重新设计的 HIV 特异性 CAR 可能能够对患者体内的 HIV 复制提供持久的控制。
HIV is adept at avoiding naturally generated T cell responses; therefore, there is a need to develop HIV-specific T cells with greater potency for use in HIV cure strategies. Starting with a CD4-based chimeric antigen receptor (CAR) that was previously used without toxicity in clinical trials, we optimized the vector backbone, promoter, HIV targeting moiety, and transmembrane and signaling domains to determine which components augmented the ability of T cells to control HIV replication. This re-engineered CAR was at least 50-fold more potent in vitro at controlling HIV replication than the original CD4 CAR, or a TCR-based approach, and substantially better than broadly neutralizing antibody-based CARs. A humanized mouse model of HIV infection demonstrated that T cells expressing optimized CARs were superior at expanding in response to antigen, protecting CD4 T cells from infection, and reducing viral loads compared to T cells expressing the original, clinical trial CAR. Moreover, in a humanized mouse model of HIV treatment, CD4 CAR T cells containing the 4-1BB costimulatory domain controlled HIV spread after ART removal better than analogous CAR T cells containing the CD28 costimulatory domain. Together, these data indicate that potent HIV-specific T cells can be generated using improved CAR design and that CAR T cells could be important components of an HIV cure strategy. Conventional T cells rarely provide durable control over HIV replication. Chimeric antigen receptors (CARs) alter how T cells recognize infected T cells, bypassing many of HIV’s immune escape mechanisms. Therefore, we hypothesized that T cells engineered to express these receptors would be more potent (supraphysiologic) and would be able to control HIV infection at much lower effector to target ratios than conventional T cells. Starting with a CAR that entered clinical trials but did not reliably reduce measures of HIV in patients, we systematically optimized the expression, structure, and activation components to increase its functionality. CD8 T cells expressing this re-engineered CAR were extremely potent at suppressing HIV in vitro, exhibiting greater than 50-fold more potency in the ability to prevent viral spread than the original CAR construct or an HIV-specific TCR approach. Importantly, in a humanized mouse model of HIV infection, these optimized CAR T cells could protect CD4 T cells from HIV-mediated depletion and could significantly delay viral rebound after the cessation of ART. These data provide optimism that a re-engineered HIV-specific CAR may be able to provide durable control of HIV replication in patients.
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影响因子：
10.1
作者：
Hudecek M;Sommermeyer D;Kosasih PL;Silva-Benedict A;Liu L;Rader C;Jensen MC;Riddell SR
通讯作者：
Riddell SR
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DOI：
10.1038/nri3405
发表时间：
2013-04
期刊：
Nature reviews. Immunology
影响因子：
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影响因子：
9.4
作者：
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通讯作者：
Mellors, John W.
影响因子：
10.1
作者：
Frigault MJ;Lee J;Basil MC;Carpenito C;Motohashi S;Scholler J;Kawalekar OU;Guedan S;McGettigan SE;Posey AD Jr;Ang S;Cooper LJ;Platt JM;Johnson FB;Paulos CM;Zhao Y;Kalos M;Milone MC;June CH
通讯作者：
June CH
带有嵌合抗原受体的T细胞具有有效的抗肿瘤作用，可以在晚期白血病患者中建立记忆。
影响因子：
17.1
作者：
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通讯作者：
June CH