Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo.
Dual CD4-based CAR T cells with distinct costimulatory domains mitigate HIV pathogenesis in vivo.
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DOI：
10.1038/s41591-020-1039-5
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发表时间：
2020-11
期刊：
影响因子：
82.9
通讯作者：
Allen, Todd M.
中科院分区：
文献类型：
--
作者：
Maldini, Colby R.;Claiborne, Daniel T.;Okawa, Ken;Chen, Tao;Dopkin, Derrick L.;Shan, Xiaochuan;Power, Karen A.;Trifonova, Radiana T.;Krupp, Katharine;Phelps, Meredith;Vrbanac, Vladimir D.;Tanno, Serah;Bateson, Timothy;Leslie, George J.;Hoxie, James A.;Boutwell, Christian L.;Riley, James L.;Allen, Todd M.
治愈艾滋病毒的有效策略可能需要强大和持续的抗病毒T细胞反应。在这里，我们探索了嵌合抗原受体(CAR)T细胞，表达CD4胞外区以赋予HIV包膜的特异性，以减轻HIV在骨髓、肝脏、胸腺(BLT)人源化小鼠中诱导的致病作用。停止抗逆转录病毒治疗后，表达4-1BB/CD3CD3-ζ内域的CAR T细胞不足以防止病毒反弹和CD4+T细胞丢失。通过对CAR T细胞产品的迭代改进，我们开发出同时表达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，激发了相当于CD28共刺激CAR T细胞的效应功能，并防止了HIV诱导的CD4+T细胞丢失，尽管存在持续的病毒血症。此外，当通过表达C34-CXCR4融合抑制物来保护双CAR T细胞免受艾滋病毒感染时，这些细胞显著减少了急性期病毒血症，并在存在抗逆转录病毒治疗的情况下加速了对艾滋病毒的抑制，降低了组织病毒负担。总而言之，这些研究证明了一种新型双CAR T细胞产品的增强治疗效力，具有有效治疗艾滋病毒感染的潜力。
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.
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HIV-1对人源化BLT小鼠中功能性CD8⁺T细胞反应的快速演变。
影响因子：
17.1
作者：
Dudek TE;No DC;Seung E;Vrbanac VD;Fadda L;Bhoumik P;Boutwell CL;Power KA;Gladden AD;Battis L;Mellors EF;Tivey TR;Gao X;Altfeld M;Luster AD;Tager AM;Allen TM
通讯作者：
Allen TM
影响因子：
6.7
作者：
Buggert M;Tauriainen J;Yamamoto T;Frederiksen J;Ivarsson MA;Michaëlsson J;Lund O;Hejdeman B;Jansson M;Sönnerborg A;Koup RA;Betts MR;Karlsson AC
通讯作者：
Karlsson AC
影响因子：
12.4
作者：
Cheng, Zhi;Wei, Runhong;Wang, Pin
通讯作者：
Wang, Pin
影响因子：
7.4
作者：
Hindson, Benjamin J.;Ness, Kevin D.;Masquelier, Donald A.;Belgrader, Phillip;Heredia, Nicholas J.;Makarewicz, Anthony J.;Bright, Isaac J.;Lucero, Michael Y.;Hiddessen, Amy L.;Legler, Tina C.;Kitano, Tyler K.;Hodel, Michael R.;Petersen, Jonathan F.;Wyatt, Paul W.;Steenblock, Erin R.;Shah, Pallavi H.;Bousse, Luc J.;Troup, Camille B.;Mellen, Jeffrey C.;Wittmann, Dean K.;Erndt, Nicholas G.;Cauley, Thomas H.;Koehler, Ryan T.;So, Austin P.;Dube, Simant;Rose, Klint A.;Montesclaros, Luz;Wang, Shenglong;Stumbo, David P.;Hodges, Shawn P.;Romine, Steven;Milanovich, Fred P.;White, Helen E.;Regan, John F.;Karlin-Neumann, George A.;Hindson, Christopher M.;Saxonov, Serge;Colston, Bill W.
通讯作者：
Colston, Bill W.
影响因子：
17.1
作者：
Anthony-Gonda, Kim;Bardhi, Ariola;Dropulic, Boro
通讯作者：
Dropulic, Boro