HIV-1 reprograms the migration of macrophages.
HIV-1 reprograms the migration of macrophages.
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DOI：
10.1182/blood-2014-08-596775
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发表时间：
2015-03
期刊：
影响因子：
20.3
通讯作者：
C. Vérollet;Shanti Souriant;Emilie M. Bonnaud;P. Jolicoeur;B. Raynaud-Messina;Cassandre Kinnaer;I. Fourquaux;Andrea Imle;S. Bénichou;O. Fackler;Renaud Poincloux;I. Maridonneau-Parini
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文献类型：
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作者：
C. Vérollet;Shanti Souriant;Emilie M. Bonnaud;P. Jolicoeur;B. Raynaud-Messina;Cassandre Kinnaer;I. Fourquaux;Andrea Imle;S. Bénichou;O. Fackler;Renaud Poincloux;I. Maridonneau-Parini
巨噬细胞是活动的白细胞，被HIV-1靶向，被认为在病毒的宿主传播中起关键作用。然而，感染是否会影响他们的移徙能力仍不清楚。我们发现，HIV-1感染的人单核细胞衍生的巨噬细胞的2维迁移和3维（3D）阿米巴样迁移模式被抑制，而3D间充质迁移增强。病毒蛋白Nef是所有HIV-1介导的迁移效应所必需和充分的。在Nef转基因小鼠中，巨噬细胞的组织浸润在肿瘤模型和稳态下的几种组织中增加，表明体内间充质迁移的主导作用。间充质运动涉及基质蛋白水解和podosomes，单核细胞衍生细胞的细胞结构组成。聚焦于HIV-1 Nef控制间充质迁移的机制，我们发现，通过吞噬细胞特异性激酶Hck和Wiskott-Aldrich综合征蛋白（WASP），2个主要的调节器，增加了podosomes的稳定性，大小和蛋白水解功能。总之，HIV-1重新编程巨噬细胞迁移，这可能解释了几种患者组织中的巨噬细胞积聚，这是病毒传播和发病的关键步骤。此外，Nef指出，podosomes和Hck/WASP信号通路是控制巨噬细胞组织浸润的良好候选者，巨噬细胞是几种疾病中的有害现象。
Macrophages are motile leukocytes, targeted by HIV-1, thought to play a critical role in host dissemination of the virus. However, whether infection impacts their migration capacity remains unknown. We show that 2-dimensional migration and the 3-dimensional (3D) amoeboid migration mode of HIV-1-infected human monocyte-derived macrophages were inhibited, whereas the 3D mesenchymal migration was enhanced. The viral protein Nef was necessary and sufficient for all HIV-1-mediated effects on migration. In Nef transgenic mice, tissue infiltration of macrophages was increased in a tumor model and in several tissues at steady state, suggesting a dominant role for mesenchymal migration in vivo. The mesenchymal motility involves matrix proteolysis and podosomes, cell structures constitutive of monocyte-derived cells. Focusing on the mechanisms used by HIV-1 Nef to control the mesenchymal migration, we show that the stability, size, and proteolytic function of podosomes are increased via the phagocyte-specific kinase Hck and Wiskott-Aldrich syndrome protein (WASP), 2 major regulators of podosomes. In conclusion, HIV-1 reprograms macrophage migration, which likely explains macrophage accumulation in several patient tissues, which is a key step for virus spreading and pathogenesis. Moreover, Nef points out podosomes and the Hck/WASP signaling pathway as good candidates to control tissue infiltration of macrophages, a detrimental phenomenon in several diseases.