Engineering of CD8+ T cells with an HIV-specific synthetic notch receptor to secrete broadly therapeutic antibodies for combining antiviral humoral and cellular immune responses
ABSTRACT The application of immunotherapeutic strategies, such as chimeric antigen receptor-T cells and broadly neutralizing antibodies (bNAbs), for the treatment of human immunodeficiency virus (HIV) infection is hindered by the latent reservoirs and viral escape. Achieving long-term control of vir...
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American Society for Microbiology
2025-04-01
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.03839-24 |
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| author | Lina Meng Haichi Zhao Shangkun Chang Weiting Li Yinghui Tian Ruihong Wang Libian Wang Tiejun Gu Jiaxin Wu Bin Yu Chu Wang Xianghui Yu |
| author_facet | Lina Meng Haichi Zhao Shangkun Chang Weiting Li Yinghui Tian Ruihong Wang Libian Wang Tiejun Gu Jiaxin Wu Bin Yu Chu Wang Xianghui Yu |
| author_sort | Lina Meng |
| collection | DOAJ |
| description | ABSTRACT The application of immunotherapeutic strategies, such as chimeric antigen receptor-T cells and broadly neutralizing antibodies (bNAbs), for the treatment of human immunodeficiency virus (HIV) infection is hindered by the latent reservoirs and viral escape. Achieving long-term control of viral load in the absence of antiretroviral therapy requires a combination approach utilizing these immunotherapeutic strategies. For this purpose, we developed novel anti-HIV-1 synthetic Notch (synNotch) receptor-T cells, termed CD4-17b-VN, which express both a bNAb (VRC01) and a bispecific T cell-engaging protein (N6-αCD3) with antigenic control. The synNotch receptor-expressing cells can sense the viral antigen presented on both HIV-1 particles and the surface of target cells. A human T cell line equipped with the CD4-17b-VN circuit could effectively control VRC01 and N6-αCD3 secretion upon sensitization, suppress the infection of diverse subtypes of HIV-1 strains, and mediate specific bypass cytotoxic activity against infected and latency-reactivated cells. Additionally, CD4-17b-VN CD8+ T cells exhibited long-lasting suppression of infected cells and stronger killing effect on latency-reactivated cells in vitro. Importantly, we demonstrated that the synNotch receptor did not increase susceptibility to HIV-1 infection in the engineered cells. Our study validates the concept of a synNotch platform-based T cell therapeutic approach that can deliver broadly therapeutic antibodies in an HIV-1 antigen-controlled manner, which may have important implications for the functional cure of AIDS.IMPORTANCEAdoptive transfer of effector T cells modified with a chimeric antigen receptor has been proposed as an applicable approach to treat human immunodeficiency virus (HIV) infection. The synNotch receptor (SNR) system serves as a versatile tool, enabling customized programming of input and output functions in mammalian cells. Herein, we report a novel synNotch platform-based approach for T cell engineering targeting both cell-free particles and infected cells by coupling antibody neutralization with cytotoxicity. Our findings demonstrate that the engineered CD4-17b SNR enables controllable production of functional anti-HIV-1 broadly neutralizing antibody and bispecific T cell-engaging protein upon recognition of the viral particle and cell surface antigens by the bifunctional synNotch-T cells. Human primary CD8+ T cells equipped with the bifunctional synNotch circuit CD4-17b-VN can effectively suppress long-term viral replication and reduce latency-reactivated cells in vitro, without the undesired risk of being infected by the virus, suggesting their potential candidacy for AIDS therapy with prospects for future clinical applications. |
| format | Article |
| id | doaj-art-267cc67ee666467b801f2a3f9941edd5 |
| institution | DOAJ |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | American Society for Microbiology |
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| series | mBio |
| spelling | doaj-art-267cc67ee666467b801f2a3f9941edd52025-08-20T03:08:35ZengAmerican Society for MicrobiologymBio2150-75112025-04-0116410.1128/mbio.03839-24Engineering of CD8+ T cells with an HIV-specific synthetic notch receptor to secrete broadly therapeutic antibodies for combining antiviral humoral and cellular immune responsesLina Meng0Haichi Zhao1Shangkun Chang2Weiting Li3Yinghui Tian4Ruihong Wang5Libian Wang6Tiejun Gu7Jiaxin Wu8Bin Yu9Chu Wang10Xianghui Yu11National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, ChinaNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, ChinaNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, ChinaNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, ChinaNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, ChinaNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, ChinaNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, ChinaNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, ChinaNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, ChinaNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, ChinaNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, ChinaNational Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, ChinaABSTRACT The application of immunotherapeutic strategies, such as chimeric antigen receptor-T cells and broadly neutralizing antibodies (bNAbs), for the treatment of human immunodeficiency virus (HIV) infection is hindered by the latent reservoirs and viral escape. Achieving long-term control of viral load in the absence of antiretroviral therapy requires a combination approach utilizing these immunotherapeutic strategies. For this purpose, we developed novel anti-HIV-1 synthetic Notch (synNotch) receptor-T cells, termed CD4-17b-VN, which express both a bNAb (VRC01) and a bispecific T cell-engaging protein (N6-αCD3) with antigenic control. The synNotch receptor-expressing cells can sense the viral antigen presented on both HIV-1 particles and the surface of target cells. A human T cell line equipped with the CD4-17b-VN circuit could effectively control VRC01 and N6-αCD3 secretion upon sensitization, suppress the infection of diverse subtypes of HIV-1 strains, and mediate specific bypass cytotoxic activity against infected and latency-reactivated cells. Additionally, CD4-17b-VN CD8+ T cells exhibited long-lasting suppression of infected cells and stronger killing effect on latency-reactivated cells in vitro. Importantly, we demonstrated that the synNotch receptor did not increase susceptibility to HIV-1 infection in the engineered cells. Our study validates the concept of a synNotch platform-based T cell therapeutic approach that can deliver broadly therapeutic antibodies in an HIV-1 antigen-controlled manner, which may have important implications for the functional cure of AIDS.IMPORTANCEAdoptive transfer of effector T cells modified with a chimeric antigen receptor has been proposed as an applicable approach to treat human immunodeficiency virus (HIV) infection. The synNotch receptor (SNR) system serves as a versatile tool, enabling customized programming of input and output functions in mammalian cells. Herein, we report a novel synNotch platform-based approach for T cell engineering targeting both cell-free particles and infected cells by coupling antibody neutralization with cytotoxicity. Our findings demonstrate that the engineered CD4-17b SNR enables controllable production of functional anti-HIV-1 broadly neutralizing antibody and bispecific T cell-engaging protein upon recognition of the viral particle and cell surface antigens by the bifunctional synNotch-T cells. Human primary CD8+ T cells equipped with the bifunctional synNotch circuit CD4-17b-VN can effectively suppress long-term viral replication and reduce latency-reactivated cells in vitro, without the undesired risk of being infected by the virus, suggesting their potential candidacy for AIDS therapy with prospects for future clinical applications.https://journals.asm.org/doi/10.1128/mbio.03839-24HIV-1synNotchbroadly neutralizing antibodyT cell re-targeting antibodyCD8+ T cellcell engineering |
| spellingShingle | Lina Meng Haichi Zhao Shangkun Chang Weiting Li Yinghui Tian Ruihong Wang Libian Wang Tiejun Gu Jiaxin Wu Bin Yu Chu Wang Xianghui Yu Engineering of CD8+ T cells with an HIV-specific synthetic notch receptor to secrete broadly therapeutic antibodies for combining antiviral humoral and cellular immune responses mBio HIV-1 synNotch broadly neutralizing antibody T cell re-targeting antibody CD8+ T cell cell engineering |
| title | Engineering of CD8+ T cells with an HIV-specific synthetic notch receptor to secrete broadly therapeutic antibodies for combining antiviral humoral and cellular immune responses |
| title_full | Engineering of CD8+ T cells with an HIV-specific synthetic notch receptor to secrete broadly therapeutic antibodies for combining antiviral humoral and cellular immune responses |
| title_fullStr | Engineering of CD8+ T cells with an HIV-specific synthetic notch receptor to secrete broadly therapeutic antibodies for combining antiviral humoral and cellular immune responses |
| title_full_unstemmed | Engineering of CD8+ T cells with an HIV-specific synthetic notch receptor to secrete broadly therapeutic antibodies for combining antiviral humoral and cellular immune responses |
| title_short | Engineering of CD8+ T cells with an HIV-specific synthetic notch receptor to secrete broadly therapeutic antibodies for combining antiviral humoral and cellular immune responses |
| title_sort | engineering of cd8 t cells with an hiv specific synthetic notch receptor to secrete broadly therapeutic antibodies for combining antiviral humoral and cellular immune responses |
| topic | HIV-1 synNotch broadly neutralizing antibody T cell re-targeting antibody CD8+ T cell cell engineering |
| url | https://journals.asm.org/doi/10.1128/mbio.03839-24 |
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