Zhou Jiehua, Satheesan Sangeetha, Li Haitang, Weinberg Marc S, Morris Kevin V, Burnett John C, Rossi John J
Department of Molecular and Cellular Biology, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Division of Comparative Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA; Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
Chem Biol. 2015 Mar 19;22(3):379-90. doi: 10.1016/j.chembiol.2015.01.005. Epub 2015 Mar 5.
The C-C chemokine receptor type 5 (CCR5) is a receptor expressed by T cells and macrophages that serves as a coreceptor for macrophage-tropic HIV-1. Loss of CCR5 is associated with resistance to HIV-1. Here, we combine the live-cell-based SELEX with high-throughput sequencing technology to generate CCR5 RNA aptamers capable of specifically targeting HIV-1 susceptible cells (as small interfering RNA [siRNA] delivery agent) and inhibiting HIV-1 infectivity (as antiviral agent) via block of the CCR5 required for HIV-1 to enter cells. One of the best candidates, G-3, efficiently bound and was internalized into human CCR5-expressing cells. The G-3 specifically neutralized R5 virus infection in primary peripheral blood mononuclear cells, and in vivo generated human CD4(+) T cells with a nanomolar inhibitory concentration 50%. G-3 was also capable of transferring functional siRNAs to CCR5-expressing cells. Collectively, the cell-specific, internalizing, CCR5-targeted aptamers and aptamer-siRNA conjugates offer promise for overcoming some of the current challenges of drug resistance in HIV-1 by providing cell-type- or tissue-specific delivery of various therapeutic moieties.
C-C趋化因子受体5型（CCR5）是一种由T细胞和巨噬细胞表达的受体，它作为嗜巨噬细胞性HIV-1的共受体。CCR5的缺失与对HIV-1的抗性相关。在此，我们将基于活细胞的SELEX与高通量测序技术相结合，以生成能够特异性靶向HIV-1易感细胞（作为小干扰RNA [siRNA]递送剂）并通过阻断HIV-1进入细胞所需的CCR5来抑制HIV-1感染性（作为抗病毒剂）的CCR5 RNA适配体。最佳候选物之一G-3能有效结合并内化进入表达人CCR5的细胞。G-3在原代外周血单核细胞中特异性中和R5病毒感染，并在体内产生具有纳摩尔抑制浓度50%的人CD4(+) T细胞。G-3还能够将功能性siRNAs转运至表达CCR5的细胞。总的来说，细胞特异性、内化性、靶向CCR5的适配体以及适配体-siRNA偶联物通过提供各种治疗部分的细胞类型或组织特异性递送，有望克服目前HIV-1耐药性的一些挑战。
