Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model
Multispecific anti-HIV duoCAR-T cells display broad in vitro antiviral activity and potent in vivo elimination of HIV-infected cells in a humanized mouse model
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DOI：
10.1126/scitranslmed.aav5685
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发表时间：
2019-08-07
影响因子：
17.1
通讯作者：
Dropulic, Boro
中科院分区：
文献类型：
--
作者：
Anthony-Gonda, Kim;Bardhi, Ariola;Dropulic, Boro
使用嵌合抗原受体修饰的T细胞（CAR-T）的连续免疫疗法对某些B细胞恶性肿瘤的治疗做出了实质性贡献。这种治疗方式可能会减少艾滋病毒/艾滋病长期抗逆转录病毒药物治疗的需要。在这里，我们报告了基于HIV-1的慢病毒载体的开发，该载体编码称为duoCAR的结构。我们表明，用编码多特异性抗HIV duoCAR的慢病毒载体转导，使原代T细胞能够在体外有效降低高达99%的细胞HIV感染，在体内降低> 97%。T细胞是HIV感染的靶细胞，但转导的T细胞受到保护，不受遗传多样性HIV-1毒株的影响。CAR-T细胞还有效地消除了感染广泛中和抗体耐药HIV毒株的PBMC，包括VRC 01/3BNC 117耐药HIV-1。此外，使用脾内HIV感染的人源化NSG小鼠模型，多特异性抗HIV duoCAR-T细胞证明了体内HIV感染的长期控制，并防止了HIV感染期间CD 4（+）T细胞的损失。这些数据表明，多特异性抗HIV duoCAR-T细胞可能是治疗HIV-1感染患者的有效方法。
Adoptive immunotherapy using chimeric antigen receptor-modified T cells (CAR-T) has made substantial contributions to the treatment of certain B cell malignancies. Such treatment modalities could potentially obviate the need for long-term antiretroviral drug therapy in HIV/AIDS. Here, we report the development of HIV-1-based lentiviral vectors that encode architecture, termed duoCAR. We show that transduction with lentiviral vectors encoding multispecific anti-HIV duoCARs confer primary T cells with the capacity to potently reduce cellular HIV infection by up to 99% in vitro and > 97% in vivo. T cells are the targets of HIV infection, but the transduced T cells are protected from genetically diverse HIV-1 strains. The CAR-T cells also potently eliminated PBMCs infected with broadly neutralizing antibody-resistant HIV strains, including VRC01/3BNC117-resistant HIV-1. Furthermore, multispecific anti-HIV duoCAR-T cells demonstrated long-term control of HIV infection in vivo and prevented the loss of CD4(+) T cells during HIV infection using a humanized NSG mouse model of intrasplenic HIV infection. These data suggest that multispecific anti-HIV duoCAR-T cells could be an effective approach for the treatment of patients with HIV-1 infection.