科学家们认为，这一研究成果证实了，使用RNAi技术阻断CCR5受体的治疗方式可能成为治疗HIV的好办法。
Blood, 25 February 2010, Vol. 115, No. 8, pp. 1534-1544.
A highly efficient short hairpin RNA potently down-regulates CCR5 expression in systemic lymphoid organs in the hu-BLT mouse model
Saki Shimizu1,2, Patrick Hong2,3, Balamurugan Arumugam2,3, Lauren Pokomo1,2, Joshua Boyer1,2, Naoya Koizumi1,2, Panyamol Kittipongdaja1,2, Angela Chen4, Greg Bristol1,2, Zoran Galic1,2, Jerome A. Zack13, Otto Yang2,3, Irvin S. Y. Chen13, Benhur Lee2,3, and Dong Sung An1,2
1 Department of Medicine, Division of Hematology-Oncology, 2 UCLA AIDS Institute, and Departments of 3 Microbiology, Immunology and Molecular Genetics and 4 Obstetrics & Gynecology, David Geffen School of Medicine, University of California, Los Angeles
Inhibiting the expression of the HIV-1 coreceptor CCR5 holds great promise for controlling HIV-1 infection in patients. Here we report stable knockdown of human CCR5 by a short hairpin RNA (shRNA) in a humanized bone marrow/liver/thymus (BLT) mouse model. We delivered a potent shRNA against CCR5 into human fetal liver-derived CD34+ hematopoietic progenitor/stem cells (HPSCs) by lentiviral vector transduction. We transplanted vector-transduced HPSCs solidified with Matrigel and a thymus segment under the mouse kidney capsule. Vector-transduced autologous CD34+ cells were subsequently injected in the irradiated mouse, intended to create systemic reconstitution. CCR5 expression was down-regulated in human T cells and monocytes/macrophages in systemic lymphoid tissues, including gut-associated lymphoid tissue, the major site of HIV-1 replication. The shRNA-mediated CCR5 knockdown had no apparent adverse effects on T-cell development as assessed by polyclonal T-cell receptor Vβ family development and naive/memory T-cell differentiation. CCR5 knockdown in the secondary transplanted mice suggested the potential of long-term hematopoietic reconstitution by the shRNA-transduced HPSCs. CCR5 tropic HIV-1 infection was effectively inhibited in mouse-derived human splenocytes ex vivo. These results demonstrate that lentiviral vector delivery of shRNA into human HPSCs could stably down-regulate CCR5 in systemic lymphoid organs in vivo.