美国拉根MGH研究所Todd M. Allen和宾夕法尼亚大学佩雷尔曼医学院James L. Riley研究组合作取得最新进展。他们发现具有不同共刺激结构域并基于CD4的双嵌合抗原受体（CAR）T细胞可减轻体内HIV的发病机理。相关论文发表在2020年8月31日的《自然-医学》杂志上。

他们探索了CAR T细胞的功能，该CD细胞表达CD4胞外域，赋予HIV包膜特异性，以减轻HIV诱导的骨髓、肝、胸腺（BLT）人源化小鼠的发病机理。在停止抗逆转录病毒治疗后，表达4-1BB /CD3-ζ内结构域的CAR T细胞不足以阻止病毒反弹和CD4 + T细胞丢失。通过迭代改进CAR T细胞产物，他们开发了同时表达4-1BB /CD3-ζ和CD28 /CD3-ζ内部结构域的Dual-CAR T细胞。双CAR T细胞表现出超过4-1BB、CD28和第三代共同刺激的CAR T细胞的扩展动力学，诱发的效应子功能与CD28共同刺激的CAR T细胞等效，并且即使持续病毒血症也可以防止HIV诱导的CD4 + T细胞丢失。

此外，当通过表达C34-CXCR4融合抑制剂保护Dual-CAR T细胞免受HIV感染时，这些细胞显著降低了急性阶段病毒血症，并在存在抗逆转录病毒疗法的情况下加速了HIV抑制，并减轻了组织病毒负荷。总而言之，这些研究证明了新型Dual-CAR T细胞产物具有增强的治疗功效，具有有效治疗HIV感染的潜力。

据了解，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。

附：英文原文

Title: Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo

Author: Colby R. Maldini, Daniel T. Claiborne, Ken Okawa, Tao Chen, Derrick L. Dopkin, Xiaochuan Shan, Karen A. Power, Radiana T. Trifonova, Katharine Krupp, Meredith Phelps, Vladimir D. Vrbanac, Serah Tanno, Timothy Bateson, George J. Leslie, James A. Hoxie, Christian L. Boutwell, James L. Riley, Todd M. Allen

Issue&Volume: 2020-08-31

Abstract: 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.

DOI: 10.1038/s41591-020-1039-5

Source: https://www.nature.com/articles/s41591-020-1039-5