HIV-1-Specific CAR-T Cells With Cell-Intrinsic PD-1 Checkpoint Blockade Enhance Anti-HIV Efficacy in vivo

• Published in: Frontiers in microbiology 2021-07, Vol.12, p.684016-684016
• Main Authors: Jiang, Zhengtao, Liang, Huitong, Pan, Hanyu, Liang, Yue, Wang, Hua, Yang, Xinyi, Lu, Panpan, Zhang, Xiao, Yang, Jinlong, Zhang, Dengji, Shen, Xiaoting, Wang, Jing, Liang, Zhiming, Lin, Qinru, Wang, Yanan, Zhao, Lin, Zhong, Yangcheng, Lu, Hongzhou, Zhu, Huanzhang
• Format: Article
• Language: English
• Subjects: CAR-T; cellular immunotherapy; HIV-1 functional cure; immune checkpoint; Microbiology; PD-1/PD-L1
• ISSN: 1664-302X; 1664-302X
• DOI: 10.3389/fmicb.2021.684016

Adoptive cellular immunotherapy therapy using broadly neutralizing antibody-based chimeric antigen receptor-T cells (bNAb-based CAR-T) has shown great potency and safety for the functional cure of HIV. The efficacy of bNAb-based CAR-T cells could be compromised by adaptive resistance during HIV chronic infection according to the phenomenon that cellular exhaustion was observed in endogenous cytotoxic T-lymphocytes (CTLs) along with upregulated expression of PD−1. Here, we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells (PBMCs) and a 3BNC117-DNR CAR (3BD CAR) construct that enables the expression of PD-1 dominant negative receptor (DNR) and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV envelope glycoprotein (Env). Compared with HIV CAR expression alone, 3BD CAR-T cells displayed potent lytic and functional responses to Env-expressing cell lines and HIV-infected CD4 + T cells. Moreover, 3BD CAR-T cells can kill HIV-latently-infected cell lines, which are reactivated by the secretory cytokines of effector cells followed by contact with initial HIV-expressing fraction. Furthermore, bioluminescence imaging indicated that 3BD CAR-T cells displayed superior anti-HIV function in an HIV NCG mouse model of transplanting Env + /PD-L1 + cells (LEL6). These studies suggested that our proposed combinational strategy of HIV CAR-T therapy with PD-1 blockade therapy is feasible and potent, making it a promising therapeutic candidate for HIV functional cure.