Broadly neutralizing antibody–derived CAR T cells reduce viral reservoir in individuals infected with HIV-1
Bingfeng Liu, … , Linghua Li, Hui Zhang
Bingfeng Liu, … , Linghua Li, Hui Zhang
Published August 10, 2021
Citation Information: J Clin Invest. 2021;131(19):e150211. https://doi.org/10.1172/JCI150211.
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Clinical Research and Public Health AIDS/HIV

Broadly neutralizing antibody–derived CAR T cells reduce viral reservoir in individuals infected with HIV-1

Abstract

BACKGROUND Chimeric antigen receptor (CAR) T cells have emerged as an approach to treat malignant tumors. This strategy has also been proposed for the treatment of HIV-1 infection. We have developed a broadly neutralizing antibody–derived (bNAb-derived) CAR T cell therapy that can exert specific cytotoxic activity against HIV-1–infected cells.METHODS We conducted an open-label trial of the safety, side-effect profile, pharmacokinetic properties, and antiviral activity of bNAb-derived CAR T cell therapy in individuals infected with HIV-1 who were undergoing analytical interruption of antiretroviral therapy (ART).RESULTS A total of 14 participants completed only a single administration of bNAb-derived CAR T cells. CAR T cell therapy administration was safe and well tolerated. Six participants discontinued ART, and viremia rebound occurred in all of them, with a 5.3-week median time. Notably, the cell-associated viral RNA and intact proviruses decreased significantly after CAR T cell treatment. Analyses of HIV-1 variants before or after CAR T cell administration suggested that CAR T cells exerted pressure on rebound viruses, resulting in a selection of viruses with less diversity and mutations against CAR T cell–mediated cytotoxicity.CONCLUSION No safety concerns were identified with adoptive transfer of bNAb-derived CAR T cells. They reduced viral reservoir. All the rebounds were due to preexisting or emergence of viral escape mutations.TRIAL REGISTRATION ClinicalTrials.gov (NCT03240328).FUNDING Ministry of Science and Technology of China, National Natural Science Foundation of China, and Department of Science and Technology of Guangdong Province.

Authors

Bingfeng Liu, Wanying Zhang, Baijin Xia, Shuliang Jing, Yingying Du, Fan Zou, Rong Li, Lijuan Lu, Shaozhen Chen, Yonghong Li, Qifei Hu, Yingtong Lin, Yiwen Zhang, Zhangping He, Xu Zhang, Xiejie Chen, Tao Peng, Xiaoping Tang, Weiping Cai, Ting Pan, Linghua Li, Hui Zhang

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Figure 6

Rebound virus clonality and resistance to bNAb-derived CAR T cell–mediated cytotoxicity.

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Rebound virus clonality and resistance to bNAb-derived CAR T cell–mediat...
(A) Clonal Env mutations on inner domain, V2 loop, loop D, CD4-binding site, and V5 loop after viral rebound in patients 002 and 006. All sequences were compared with the consensus of the rebound viruses. The residue numbers are based on HIV-1 HXB2 sequence. The top line shows amino acid differences in the pre–CAR T cell sequences from the rebound consensus. (B) PBMCs were isolated from healthy donors and divided into 2 populations. The CD8+ T lymphocytes were used to generate CAR T cells while the autologous CD4+ T cells were infected with outgrown HIV-1 from pre–CAR T cell latent reservoir (LR) or rebound reservoir (RD) (1 ng/mL p24). Six days after HIV-1 infection, antiretroviral compounds (azidothymidine and lopinavir) were added to the CD4+ T cell culture to inhibit virus production. Then the anti–HIV-1 drugs were withdrawn and CAR or control CD8+ T cells were mixed at a 1:1 ratio. Every 2 days the cultures were tested for the presence of p24 in the supernatant, using ELISA. Gray shade represents the addition of antiviral drugs. (C) HIV-1 Env derived from pre–CAR T cell latent reservoir or rebound reservoir was ectopically expressed on the HEK293T cell line. These target cell lines were compared for changes in sensitivity to CAR T cell–mediated specific cytotoxicity. Env derived from HIV-1NL4-3 served as the positive control. Direct killing of target cell lines was tested after 24-hour coculture by detecting LDH release. A 2‑sided P value for the estimated difference in pre–CAR T cell and rebound resistance was calculated. Data represent the mean of triplicate values, and error bars represent SEM. P values were calculated using the 2-tailed unpaired Student’s t test with equal variances.