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Volume 38 Issue 2
April 2023

    . doi: 10.1016/j.virs.2023.01.003
    Citation: Hanyu Pan, Xinyi Yang, Jing Wang, Huitong Liang, Zhengtao Jiang, Lin Zhao, Yanan Wang, Zhiming Liang, Xiaoting Shen, Qinru Lin, Yue Liang, Jinglong Yang, Panpan Lu, Yuqi Zhu, Min Li, Pengfei Wang, Jianqing Xu, Hongzhou Lu, Huanzhang Zhu. Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance specific cytotoxic activity against HIV Env+ cells in vivo .VIROLOGICA SINICA, 2023, 38(2) : 285-295.  http://dx.doi.org/10.1016/j.virs.2023.01.003
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    分泌PD-1阻断抗体的HIV特异性基因编辑异体CAR-T细胞增强了其体内靶向HIV Env阳性细胞的细胞毒性作用

    • 1. 复旦大学生命科学学院国家遗传工程重点实验室与教育部/卫生部医学分子病毒学重点实验室(中国上海, 邮编:200438);

    • 2. 复旦大学生命科学学院上海市重大传染病和生物安全研究院(中国上海, 邮编:200438);

    • 3. 复旦大学基础医学院与上海市公共卫生临床中心传染病科教育部/卫生部医学分子病毒学重点实验室(中国上海, 邮编:201508);

    • 4. 复旦大学附属上海市公共卫生临床中心科学研究中心(中国上海, 邮编:201508);

    • 5. 复旦大学附属上海市公共卫生临床中心传染病与免疫科(中国上海, 邮编:201508);

    • 6. 深圳市第三人民医院国家感染性疾病临床医学研究中心传染病与护理研究部(中国深圳, 邮编:518112)

    • 通讯作者： 朱焕章, hzzhu@fudan.edu.cn
    • 收稿日期： 2022-08-30
      录用日期： 2023-01-11
    • 表达HIV特异性嵌合抗原受体（CAR）的T细胞已经被开发出来靶向表达HIV Env蛋白的HIV-1感染的CD4阳性T细胞。然而，T细胞耗竭与CAR-T细胞的患者特异性自体模式是其临床应用的重要障碍。本文中，我们使用人外周血单核细胞和3BNC117-E27（3BE）CAR构建了特异性抗HIV的CAR-T细胞，该细胞可以同时表达程序性细胞凋亡蛋白1（PD-1）的阻断抗体E27与靶向HIV Env的HIV-1特异性广泛中和性抗体3BNC117的单链可变片段。与单独表达3BNC117 CAR的T细胞相比，3BE CAR-T细胞对HIV Env阳性细胞具有更强的细胞毒活性，在与HIV Env阳性细胞共孵育时展现了更好的增殖能力、更高的杀伤效率以及更强的细胞因子分泌能力。我们进一步通过基因编辑制造了TCR缺失的3BE CAR-T细胞，并证实这些CAR-T细胞在NSG小鼠体内可以有效杀伤HIV Env阳性细胞，且没有引发严重的移植物抗宿主病（GvHD）。本文的数据表明，我们为“通用型”抗HIV CAR-T细胞制备与PD-1免疫检查点阻断疗法的结合提供了可行的方法，从而为HIV的功能性治愈提供了有力的候选疗法。

    Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance specific cytotoxic activity against HIV Env+ cells in vivo

    • a. State Key Laboratory of Genetic Engineering, And Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, 200438, China;

    • b. Shanghai Institute of Infectious Disease and Biosecurity, School of Life Sciences, Fudan University, Shanghai, 200438, China;

    • c. Department of Infectious Disease, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China;

    • d. Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China;

    • e. Department of Infectious Diseases and Immunology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China;

    • f. Department of Infectious Diseases and Nursing Research Institution, National Clinical Research Center for Infectious Diseases, The Third People's Hospital of Shenzhen, Shenzhen, 518112, China

    • Corresponding author: Huanzhang Zhu, hzzhu@fudan.edu.cn
    • Received Date: 30 August 2022
      Accepted Date: 11 January 2023
    • HIV-specific chimeric antigen receptor (CAR) T-cells have been developed to target HIV-1 infected CD4+ T-cells that express HIV Env proteins. However, T cell exhaustion and the patient-specific autologous paradigm of CAR-T cell hurdled clinical applications. Here, we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells and a 3BNC117-E27 (3BE) CAR construct that enabled the expression of programmed cell death protein (PD-1) -blocking scFv E27 and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV Env. Compared with T cells expressing 3BNC117-CAR alone, 3BE CAR-T cells showed greater cytotoxic activity against HIV Env+ cells with stronger proliferation capability, higher killing efficiency, and enhanced cytokine secretion in the presence of HIV Env-expressing cells. Furthermore, we manufactured TCR-deficient 3BE CAR-T cells through gene editing and demonstrated that these CAR-T cells could effectively kill HIV Env + cells in vivo without the occurrence of severe graft-versus-host disease (GvHD) in NSG mice. These data suggest that we have provided a feasible approach to the generation of “off-the-shelf” anti-HIV CAR-T cells in combination with PD-1 checkpoint blockade immunotherapy, which can be a powerful therapeutic candidate for the functional cure of HIV.
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      Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance specific cytotoxic activity against HIV Env+ cells in vivo

        Corresponding author: Huanzhang Zhu, hzzhu@fudan.edu.cn
      • a. State Key Laboratory of Genetic Engineering, And Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Life Sciences, Fudan University, Shanghai, 200438, China;
      • b. Shanghai Institute of Infectious Disease and Biosecurity, School of Life Sciences, Fudan University, Shanghai, 200438, China;
      • c. Department of Infectious Disease, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China;
      • d. Scientific Research Center, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China;
      • e. Department of Infectious Diseases and Immunology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China;
      • f. Department of Infectious Diseases and Nursing Research Institution, National Clinical Research Center for Infectious Diseases, The Third People's Hospital of Shenzhen, Shenzhen, 518112, China
      • Received Date: 30 August 2022
      • Accepted Date: 11 January 2023

      Abstract: HIV-specific chimeric antigen receptor (CAR) T-cells have been developed to target HIV-1 infected CD4+ T-cells that express HIV Env proteins. However, T cell exhaustion and the patient-specific autologous paradigm of CAR-T cell hurdled clinical applications. Here, we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells and a 3BNC117-E27 (3BE) CAR construct that enabled the expression of programmed cell death protein (PD-1) -blocking scFv E27 and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV Env. Compared with T cells expressing 3BNC117-CAR alone, 3BE CAR-T cells showed greater cytotoxic activity against HIV Env+ cells with stronger proliferation capability, higher killing efficiency, and enhanced cytokine secretion in the presence of HIV Env-expressing cells. Furthermore, we manufactured TCR-deficient 3BE CAR-T cells through gene editing and demonstrated that these CAR-T cells could effectively kill HIV Env + cells in vivo without the occurrence of severe graft-versus-host disease (GvHD) in NSG mice. These data suggest that we have provided a feasible approach to the generation of “off-the-shelf” anti-HIV CAR-T cells in combination with PD-1 checkpoint blockade immunotherapy, which can be a powerful therapeutic candidate for the functional cure of HIV.

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