期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 125, 期 11, 页码 4077-4090出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI82314
关键词
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资金
- NIH [U19 AI096113]
- Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery [UM1 AI10064]
- UNC Center for AIDS Research [P30 AI50410]
- Duke Center for AIDS Research [P30 AI64518]
- Zeegen Pediatric Foundation Scholarship
- Consortium for AIDS Vaccine Discovery [1032144]
- [T32-AI007001]
Enhancement of HIV-specific immunity is likely required to eliminate latent HIV infection. Here, we have developed an immunotherapeutic modality aimed to improve T cell-mediated clearance of HIV-1-infected cells. Specifically, we employed Dual-Affinity Re-Targeting (DART) proteins, which are bispecific, antibody-based molecules that can bind 2 distinct cell-surface molecules simultaneously. We designed DARTs with a monovalent HIV-1 envelope-binding (Env-binding) arm that was derived from broadly binding, antibody-dependent cellular cytotoxicity-mediating antibodies known to bind to HIV-infected target cells coupled to a monovalent CD3 binding arm designed to engage cytolytic effector T cells (referred to as HIVxCD3 DARTs). Thus, these DARTs redirected polyclonal T cells to specifically engage with and kill Env-expressing cells, including CD4(+)T cells infected with different HIV-1 subtypes, thereby obviating the requirement for HIV-specific immunity. Using lymphocytes from patients on suppressive antiretroviral therapy (ART), we demonstrated that DARTs mediate CD8(+)T cell clearance of CD4(+)T cells that are superinfected with the HIV-1 strain JR-CSF or infected with autologous reservoir viruses isolated from HIV-infected-patient resting CD4(+) T cells. Moreover, DARTs mediated CD8(+) T cell clearance of HIV from resting CD4(+)T cell cultures following induction of latent virus expression. Combined with HIV latency reversing agents, HIVxCD3 DARTs have the potential to be effective immunotherapeutic agents to clear latent HIV-1 reservoirs in HIV-infected individuals.
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