| Autor: |
Zhengtao Jiang, Huitong Liang, Hanyu Pan, Yue Liang, Hua Wang, Xinyi Yang, Panpan Lu, Xiao Zhang, Jinlong Yang, Dengji Zhang, Xiaoting Shen, Jing Wang, Zhiming Liang, Qinru Lin, Yanan Wang, Lin Zhao, Yangcheng Zhong, Hongzhou Lu, Huanzhang Zhu |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
Frontiers in Microbiology, Vol 12 (2021) |
| Druh dokumentu: |
article |
| ISSN: |
1664-302X |
| DOI: |
10.3389/fmicb.2021.684016 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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