HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies
HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies
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DOI：
10.1128/jvi.00805-16
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发表时间：
2016-08-01
影响因子：
5.4
通讯作者：
Yang, Otto O.
中科院分区：
文献类型：
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作者：
Ali, Ayub;Kitchen, Scott G.;Yang, Otto O.
尽管基于单链抗体的嵌合抗原受体（CAR）用于癌症的基因免疫治疗由于最近的有希望的结果而越来越多，但最早的CAR治疗试验是在20世纪90年代末对HIV-1感染进行的。该方法利用基于人类CD4的CAR作为结合域，但由于缺乏疗效而被放弃。越来越多的HIV-1广泛中和抗体（bnabs）为产生可能更活跃的新型car提供了机会，并重新审视了HIV-1免疫治疗的这种模式。我们使用了来自7个明确定义的结合位点不同的BNAbs序列，并生成了基于单链抗体的car。这些CARs包括10E8、3BNC117、PG9、PGT126、PGT128、VRC01和X5。每一种新型CAR在转导细胞表面都表现出构象相关的表达，介导了针对hiv -1感染细胞的特异性增殖和杀伤，并向转导的CD8(+) T淋巴细胞提供了有效的抗病毒活性（以log（10）单位减少病毒复制）。这些CARs的抗病毒活性是可复制的，但因病毒株而异。这些发现表明，BNAbs是开发用于HIV-1免疫治疗的新型car的绝佳候选者。虽然使用单链抗体作为结合域的嵌合抗原受体（CARs）在癌症的基因免疫治疗中越来越受欢迎，但最早的car的人体试验是针对HIV-1感染进行的。然而，这些试验失败了，这种方法被放弃用于HIV-1。唯一测试过的对抗HIV-1的CAR是基于使用CD4作为结合域。越来越多的HIV-1广泛中和抗体（9BNAbs）提供了重新审视基于单链抗体的新型car的HIV-1基因免疫治疗的机会。在这里，我们构建并测试了基于不同BNAb类型的七种新型car，并表明所有这些car都具有抗HIV-1的功能。
Although the use of chimeric antigen receptors 9CARs) based on single-chain antibodies for gene immunotherapy of cancers is increasing due to promising recent results, the earliest CAR therapeutic trials were done for HIV-1 infection in the late 1990s. This approach utilized a CAR based on human CD4 as a binding domain and was abandoned for a lack of efficacy. The growing number of HIV-1 broadly neutralizing antibodies 9BNAbs) offers the opportunity to generate novel CARs that may be more active and revisit this modality for HIV-1 immunotherapy. We used sequences from seven well-defined BNAbs varying in binding sites and generated single-chain-antibody-based CARs. These CARs included 10E8, 3BNC117, PG9, PGT126, PGT128, VRC01, and X5. Each novel CAR exhibited conformationally relevant expression on the surface of transduced cells, mediated specific proliferation and killing in response to HIV-1-infected cells, and conferred potent antiviral activity 9reduction of viral replication in log(10) units) to transduced CD8(+) T lymphocytes. The antiviral activity of these CARs was reproducible but varied according to the strain of virus. These findings indicated that BNAbs are excellent candidates for developing novel CARs to consider for the immunotherapeutic treatment of HIV-1.IMPORTANCEWhile chimeric antigen receptors 9CARs) using single-chain antibodies as binding domains are growing in popularity for gene immunotherapy of cancers, the earliest human trials of CARs were done for HIV-1 infection. However, those trials failed, and the approach was abandoned for HIV-1. The only tested CAR against HIV-1 was based on the use of CD4 as the binding domain. The growing availability of HIV-1 broadly neutralizing antibodies 9BNAbs) affords the opportunity to revisit gene immunotherapy for HIV-1 using novel CARs based on single-chain antibodies. Here we construct and test a panel of seven novel CARs based on diverse BNAb types and show that all these CARs are functional against HIV-1.