Yu Xinwei, Xu Fangda, Ramirez Nora-Guadalupe P, Kijewski Suzanne D G, Akiyama Hisashi, Gummuluru Suryaram, Reinhard Björn M
†Department of Chemistry and The Photonics Center, Boston University, Boston, Massachusetts 02215, United States.
‡Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118, United States.
ACS Nano. 2015;9(4):4182-92. doi: 10.1021/acsnano.5b00415. Epub 2015 Apr 14.
Next-generation nanoparticle-based drug delivery systems require the ability to target specific organelles or subcellular regions in selected target cells. Human immunodeficiency virus type I (HIV-1) particles are evolutionarily optimized nanocarriers that have evolved to avoid intracellular degradation and achieve enrichment at the synapse between mature dendritic cells (mDCs) and T cells by subverting cellular trafficking mechanisms. This study demonstrates that integration of the glycosphingolipid, GM3, in a membrane around a solid nanoparticle (NP) core is sufficient to recapitulate key aspects of the virus particle trafficking in mDCs. GM3-presenting artificial virus NPs (GM3-AVNs) accumulate in CD169(+) and CD81(+) nonlysosomal compartments in an actin-dependent process that mimics the sequestration of HIV-1. Live-cell optical tracking studies reveal a preferential recruitment and arrest of surface scanning CD4(+) T cells in direct vicinity to the AVN-enriched compartments. The formed mDC-T cell conjugates exhibit strong morphological similarities between the GM3-AVN-containing mDC-T cell synapse and the HIV-1 virological synapse, indicating that GM3-CD169 interactions alone are sufficient for establishing the mDC-T cell virological synapse. These results emphasize the potential of the GM3-AVN approach for providing therapeutic access to a key step of the host immune response--formation of the synaptic junction between an antigen-presenting cell (mDC) and T cells--for modulating and controlling immune responses.
下一代基于纳米颗粒的药物递送系统需要具备靶向选定靶细胞中特定细胞器或亚细胞区域的能力。I型人类免疫缺陷病毒（HIV-1）颗粒是经过进化优化的纳米载体，通过颠覆细胞运输机制，已进化到可避免细胞内降解并在成熟树突状细胞（mDC）与T细胞之间的突触处实现富集。本研究表明，在固体纳米颗粒（NP）核心周围的膜中整合糖鞘脂GM3足以重现mDC中病毒颗粒运输的关键方面。呈现GM3的人工病毒NP（GM3-AVN）以肌动蛋白依赖性过程积聚在CD169(+)和CD81(+)非溶酶体区室中，该过程模拟了HIV-1的隔离。活细胞光学追踪研究揭示，表面扫描的CD4(+) T细胞优先募集并停滞在富含AVN的区室附近。形成的mDC-T细胞共轭物在含GM3-AVN的mDC-T细胞突触与HIV-1病毒突触之间表现出强烈的形态相似性，表明仅GM3-CD169相互作用就足以建立mDC-T细胞病毒突触。这些结果强调了GM3-AVN方法在为宿主免疫反应的关键步骤——抗原呈递细胞（mDC）与T细胞之间突触连接的形成——提供治疗途径以调节和控制免疫反应方面的潜力。
