HIV-1 Vpu Downregulates Tim-3 from the Surface of Infected CD4+ T Cells.
HIV-1 Vpu Downregulates Tim-3 from the Surface of Infected CD4+ T Cells.
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HIV-1 Vpu 下调受感染 CD4 T 细胞表面的 Tim-3。
DOI：
10.1128/jvi.01999-19
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发表时间：
2020
影响因子：
5.4
通讯作者：
Dikeakos,JimmyD
中科院分区：
文献类型：
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作者：
Prévost,Jérémie;Edgar,CassandraR;Richard,Jonathan;Trothen,StevenM;Jacob,RajeshAbraham;Mumby,MitchellJ;Pickering,Suzanne;Dubé,Mathieu;Kaufmann,DanielE;Kirchhoff,Frank;Neil,StuartJD;Finzi,Andrés;Dikeakos,JimmyD
与其他免疫检查点一样，T 细胞免疫球蛋白和含粘蛋白结构域的蛋白 3 (Tim-3) 在耗竭的 CD4+ 和 CD8+T 细胞上表达，并在被人类免疫缺陷病毒 1 型 (HIV-1) 感染后在这些细胞表面上表达上调。最近的报告表明 Tim-3 具有抗病毒作用。然而，调节细胞表面 Tim-3 水平的 HIV-1 分子决定因素尚未确定。在这里，我们证明 HIV-1 Vpu 下调受感染原代 CD4+T 细胞表面的 Tim-3，从而减弱 HIV-1 诱导的 Tim-3 上调。我们还提供证据表明 Vpu 的跨膜结构域是 Tim-3 下调所必需的。使用免疫荧光显微镜，我们确定 Vpu 与 Tim-3 非常接近，并通过将其引导至 Rab 5 阳性 (Rab 5+) 囊泡并将其靶向隔离在反式高尔基体网络 (TGN) 内来改变其亚细胞定位。有趣的是，Tim-3 敲低和 Tim-3 阻断增加了 HIV-1 在原代 CD4+T 细胞中的复制，从而表明 Tim-3 表达可能代表了限制病毒传播的天然免疫机制。 重要性 HIV 感染调节 Tim-3 的表面表达，但其分子决定因素仍知之甚少。在这里，我们发现 HIV-1 Vpu 通过其跨膜结构域下调受感染原代 CD4+T 细胞表面的 Tim-3，并改变其亚细胞定位。 Tim-3 阻断会增加 HIV-1 复制，表明该蛋白在病毒传播中具有潜在的负面作用，而 Vpu 可以抵消这种作用。
Along with other immune checkpoints,Tcellimmunoglobulin andmucin domain-containing protein3(Tim-3) is expressed on exhausted CD4+and CD8+T cells and is upregulated on the surface of these cells upon infection byhumanimmunodeficiencyvirus type1(HIV-1). Recent reports have suggested an antiviral role for Tim-3. However, the molecular determinants of HIV-1 which modulate cell surface Tim-3 levels have yet to be determined. Here, we demonstrate that HIV-1 Vpu downregulates Tim-3 from the surface of infected primary CD4+T cells, thus attenuating HIV-1-induced upregulation of Tim-3. We also provide evidence that the transmembrane domain of Vpu is required for Tim-3 downregulation. Using immunofluorescence microscopy, we determined that Vpu is in close proximity to Tim-3 and alters its subcellular localization by directing it to Rab 5-positive (Rab 5+) vesicles and targeting it for sequestration within thetrans-Golginetwork (TGN). Intriguingly, Tim-3 knockdown and Tim-3 blockade increased HIV-1 replication in primary CD4+T cells, thereby suggesting that Tim-3 expression might represent a natural immune mechanism limiting viral spread.IMPORTANCEHIV infection modulates the surface expression of Tim-3, but the molecular determinants remain poorly understood. Here, we show that HIV-1 Vpu downregulates Tim-3 from the surface of infected primary CD4+T cells through its transmembrane domain and alters its subcellular localization. Tim-3 blockade increases HIV-1 replication, suggesting a potential negative role of this protein in viral spread that is counteracted by Vpu.