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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-\u03b1CD3) 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-\u03b1CD3 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\n              <jats:sup>+<\/jats:sup>\n              T cells exhibited long-lasting suppression of infected cells and stronger killing effect on latency-reactivated cells\n              <jats:italic>in vitro<\/jats:italic>\n              . 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.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                Adoptive 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\n                <jats:sup>+<\/jats:sup>\n                T cells equipped with the bifunctional synNotch circuit CD4-17b-VN can effectively suppress long-term viral replication and reduce latency-reactivated cells\n                <jats:italic>in vitro<\/jats:italic>\n                , without the undesired risk of being infected by the virus, suggesting their potential candidacy for AIDS therapy with prospects for future clinical applications.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/mbio.03839-24","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T14:11:42Z","timestamp":1740492702000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":13,"title":["Engineering of CD8\n            <sup>+<\/sup>\n            T cells with an HIV-specific synthetic notch receptor to secrete broadly therapeutic antibodies for combining antiviral humoral and cellular immune responses"],"prefix":"10.1128","volume":"16","author":[{"given":"Lina","family":"Meng","sequence":"first","affiliation":[{"name":"National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haichi","family":"Zhao","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shangkun","family":"Chang","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiting","family":"Li","sequence":"additional","affiliation":[{"name":"National Engineering Laboratory for AIDS Vaccine, School 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