Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Sanofi, 640 Memorial Dr., Cambridge, MA, 02139, USA.
Nat Commun. 2023 Jun 22;14(1):3719. doi: 10.1038/s41467-023-39265-z.
Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4 and CD8 T cells. Co-culturing CD4 with autologous CD8 T cells from ART-suppressed HIV donors with N6/αCD3-αCD28, results in activation of latently-infected cells and their elimination by activated CD8 T cells. This trispecific antibody mediates CD4 and CD8 T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection.
同时能激活潜伏 HIV、增加免疫激活并增强杀伤潜伏感染细胞的药物代表了 HIV 治愈的有前途的方法。在这里，我们开发并评估了一种三特异性抗体（Ab）N6/αCD3-αCD28，它靶向三种独立的蛋白：（1）通过广泛反应性的 CD4 结合位点 Ab N6 靶向 HIV 包膜；（2）T 细胞抗原 CD3；（3）共刺激分子 CD28。我们发现，三特异性抗体显著增加了 CD4 和 CD8 T 细胞中抗原特异性 T 细胞的激活和细胞因子释放。将 N6/αCD3-αCD28 与接受 ART 抑制的 HIV 供体的自体 CD4+T 细胞共培养，导致潜伏感染细胞的激活，并被激活的 CD8+T 细胞消除。这种三特异性抗体在非人类灵长类动物中介导 CD4 和 CD8 T 细胞的激活，并且在体内具有良好的耐受性。因此，这种 HIV 定向抗体值得进一步开发，作为根除潜伏 HIV 感染的潜在干预措施。
