RT Journal Article
SR Electronic
T1 Allogeneic gene-edited HIV-specific CAR-T cells secreting PD-1 blocking scFv enhance anti-HIV activity in vitro
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.14.476413
DO 10.1101/2022.01.14.476413
A1 Hanyu Pan
A1 Jing Wang
A1 Huitong Liang
A1 Zhengtao Jiang
A1 Lin Zhao
A1 Yanan Wang
A1 Xinyi Yang
A1 Zhiming Liang
A1 Xiaoting Shen
A1 Qinru Lin
A1 Yue Liang
A1 Jinglong Yang
A1 Panpan Lu
A1 Yuqi Zhu
A1 Weirong Xiang
A1 Min Li
A1 Pengfei Wang
A1 Huanzhang Zhu
YR 2022
UL http://biorxiv.org/content/early/2022/01/15/2022.01.14.476413.abstract
AB HIV-specific chimeric antigen receptor (CAR) T cells have been developed to target latently infected CD4+ T cells that express virus either spontaneously or after intentional latency reversal. However, the T-cell exhaustion and the patient-specific autologous paradigm of CAR-T hurdled the clinical application. Here, we created HIV-specific CAR-T cells using human peripheral blood mononuclear cells and a 3BNC117-E27 CAR (3BE CAR) construct that enables the expression of PD-1 blocking scFv E27 and the single-chain variable fragment of the HIV-1-specific broadly neutralizing antibody 3BNC117 to target native HIV envelope glycoprotein (Env). In comparison with T cells expressing 3BNC117-CAR alone, 3BE CAR-T cells showed greater anti-HIV potency with stronger proliferation capability, higher killing efficiency (up to ~75%) and enhanced cytokine secretion in the presence of HIV envelope glycoprotein-expressing cells. Furthermore, our approach achieved high levels (over 97%) of the TCR-deficient 3BE CAR-T cells with the functional inactivation of endogenous TCR to avoid graft-versus-host disease without compromising their antiviral activity relative to standard anti-HIV CAR-T cells. These data suggest that we have provided a feasible approach to large-scale generation of “off-the-shelf” anti-HIV CAR-T cells in combination with antibody therapy of PD-1 blockade, which can be a powerful therapeutic candidate for the functional cure of HIV.Competing Interest StatementThe authors have declared no competing interest.