CCR5 structural plasticity shapes HIV-1 phenotypic properties
CCR5 structural plasticity shapes HIV-1 phenotypic properties
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DOI：
10.1371/journal.ppat.1007432
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发表时间：
2018-12-01
期刊：
影响因子：
6.7
通讯作者：
Lagane, Bernard
中科院分区：
文献类型：
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作者：
Colin, Philippe;Zhou, Zhicheng;Lagane, Bernard
CCR5具有免疫功能，是R5 HIV-1毒株的辅助受体。它以不同的构象和寡聚化状态存在。我们探究了CCR5结构多样性在HIV-1感染中的意义。我们发现来自不同HIV-1毒株的包膜糖蛋白（gp120）在细胞系和原代细胞上与CCR5的结合水平不同，但与CD4或CD4i单克隆抗体E51的结合水平不同。这是由于gp120与不同CCR5群体的不同结合，CCR5在细胞表面的数量不同，在不同细胞类型之间的表达也不同。这些群体中的一些，但不是全部，在抗原性上是不同的辅助受体构象。gp120的不同结合水平也对应于它们结合CCR5二聚体/低聚物能力的差异。CCR5二聚化界面的突变改变了CCR5二聚体的构象，并对不同gp120的结合进行了不同的调节。env假型病毒也使用特定的CCR5构象进入，这可能在不同的病毒之间有所不同，并且代表了结合gp120的一个子集。特别是，即使gp120s可以结合CCR5单体和低聚物，CCR5寡聚物的损伤也可以改善病毒的进入，这表明HIV-1更倾向于单体进入。从功能的角度来看，我们说明了gp120/HIV-1结合的CCR5分子的性质决定了对CCR5配体抑制和细胞趋向性的敏感性。t细胞和巨噬细胞之间的CCR5群体存在差异，这与结合gp120和支持病毒进入的能力不同有关。在巨噬细胞中，CCR5的结构可塑性对于血液来源的R5分离株的进入至关重要，与来自脑组织的典型嗜m型菌株相比，CCR5分离株不能从增强的CD4亲和力中获益。总之，我们的研究结果支持CCR5异质性在HIV-1分离株表型特性多样化中的作用，并为开发CCR5靶向药物提供了新的线索。
CCR5 plays immune functions and is the coreceptor for R5 HIV-1 strains. It exists in diverse conformations and oligomerization states. We interrogated the significance of the CCR5 structural diversity on HIV-1 infection. We show that envelope glycoproteins (gp120s) from different HIV-1 strains exhibit divergent binding levels to CCR5 on cell lines and primary cells, but not to CD4 or the CD4i monoclonal antibody E51. This owed to differential binding of the gp120s to different CCR5 populations, which exist in varying quantities at the cell surface and are differentially expressed between different cell types. Some, but not all, of these populations are antigenically distinct conformations of the coreceptor. The different binding levels of gp120s also correspond to differences in their capacity to bind CCR5 dimers/oligomers. Mutating the CCR5 dimerization interface changed conformation of the CCR5 homodimers and modulated differentially the binding of distinct gp120s. Env-pseudotyped viruses also use particular CCR5 conformations for entry, which may differ between different viruses and represent a subset of those binding gp120s. In particular, even if gp120s can bind both CCR5 monomers and oligomers, impairment of CCR5 oligomerization improved viral entry, suggesting that HIV-1 prefers monomers for entry. From a functional standpoint, we illustrate that the nature of the CCR5 molecules to which gp120/HIV-1 binds shapes sensitivity to inhibition by CCR5 ligands and cellular tropism. Differences exist in the CCR5 populations between T-cells and macrophages, and this is associated with differential capacity to bind gp120s and to support viral entry. In macrophages, CCR5 structural plasticity is critical for entry of blood-derived R5 isolates, which, in contrast to prototypical M-tropic strains from brain tissues, cannot benefit from enhanced affinity for CD4. Collectively, our results support a role for CCR5 heterogeneity in diversifying the phenotypic properties of HIV-1 isolates and provide new clues for development of CCR5-targeting drugs.