An effective strategy to cure HIV will likely require a potent and sustained antiviral T cell response. Here we explored the utility of chimeric antigen receptor (CAR) T cells, expressing the CD4 ectodomain to confer specificity for the HIV envelope, to mitigate HIV-induced pathogenesis in bone marrow, liver, thymus (BLT) humanized mice. CAR T cells expressing the 4-1BB/CD3-ζ endodomain were insufficient to prevent viral rebound and CD4⁺ T cell loss after the discontinuation of antiretroviral therapy. Through iterative improvements to the CAR T cell product, we developed Dual-CAR T cells that simultaneously expressed both 4-1BB/CD3-ζ and CD28/CD3-ζ endodomains. Dual-CAR T cells exhibited expansion kinetics that exceeded 4-1BB-, CD28- and third-generation costimulated CAR T cells, elicited effector functions equivalent to CD28-costimulated CAR T cells and prevented HIV-induced CD4⁺ T cell loss despite persistent viremia. Moreover, when Dual-CAR T cells were protected from HIV infection through expression of the C34-CXCR4 fusion inhibitor, these cells significantly reduced acute-phase viremia, as well as accelerated HIV suppression in the presence of antiretroviral therapy and reduced tissue viral burden. Collectively, these studies demonstrate the enhanced therapeutic potency of a novel Dual-CAR T cell product with the potential to effectively treat HIV infection.

治愈 HIV 的有效策略可能需要有效且持续的抗病毒 T 细胞反应。在这里，我们探讨了嵌合抗原受体 (CAR) T 细胞的效用，表达 CD4 胞外域以赋予 HIV 包膜特异性，以减轻 HIV 诱导的骨髓、肝脏、胸腺 (BLT) 人源化小鼠的发病机制。表达 4-1BB/CD3-ζ 内域的 CAR T 细胞不足以防止病毒反弹和 CD4 ⁺停止抗逆转录病毒治疗后 T 细胞丢失。通过对 CAR T 细胞产品的迭代改进，我们开发了同时表达 4-1BB/CD3-ζ 和 CD28/CD3-ζ 内域的双 CAR T 细胞。双CAR T细胞表现出超过4-1BB-、CD28-和第三代共刺激CAR T细胞的扩增动力学，引发相当于CD28共刺激CAR T细胞的效应子功能并阻止HIV诱导的CD4 ⁺尽管病毒血症持续存在，T 细胞仍然丢失。此外，当通过 C34-CXCR4 融合抑制剂的表达保护 Dual-CAR T 细胞免受 HIV 感染时，这些细胞显着减少了急性期病毒血症，并在抗逆转录病毒治疗和减少组织病毒负荷的情况下加速了 HIV 抑制。总的来说，这些研究证明了一种新型双 CAR T 细胞产品具有增强的治疗效力，具有有效治疗 HIV 感染的潜力。