HIV-1 Nef Disrupts CD4+ T Lymphocyte Polarity, Extravasation, and Homing to Lymph Nodes via Its Nef-Associated Kinase Complex Interface
HIV-1 Nef Disrupts CD4+ T Lymphocyte Polarity, Extravasation, and Homing to Lymph Nodes via Its Nef-Associated Kinase Complex Interface
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DOI：
10.4049/jimmunol.1701420
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发表时间：
2018-11-01
影响因子：
4.4
通讯作者：
Fackler, Oliver T.
中科院分区：
文献类型：
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作者：
Lamas-Murua, Miguel;Stolp, Bettina;Fackler, Oliver T.
HIV-1 Nef是一种多功能蛋白，可优化病毒传播，促进感染细胞的免疫逃避，加速艾滋病患者的疾病进展。作为其活性之一，Nef降低了受感染的CD 4（+）T淋巴细胞在密闭空间中的运动性。在体内，Nef限制T淋巴细胞归巢到淋巴结，因为它降低了渗出步骤的外渗能力。Nef对T淋巴细胞运动性的影响通常通过其减少肌动蛋白重塑的能力介导。然而，与渗出干扰不依赖于Nef中的残留物所需的抑制宿主细胞肌动蛋白动力学。在寻找Nef可以改变T淋巴细胞外渗的替代机制时，我们注意到病毒蛋白干扰HIV-1感染后原代人CD 4（+）T淋巴细胞的极化。Nef的单独表达足以破坏T细胞极化，并且这种作用在慢病毒Nef蛋白中是保守的。Nef通过阻止CD 4（+）T细胞在极化和非极化形态之间的振荡而起作用。定位研究确定Nef相关激酶复合物（NAKC）的结合位点是Nef活性的关键决定因素，NAKC结合缺陷型Nef变体不能损害CD 4（+）T淋巴细胞外渗和归巢淋巴结。因此，这些结果意味着通过其NAKC结合位点破坏T淋巴细胞极性是慢病毒Nef蛋白改变体内T淋巴细胞迁移的一种新机制。
HIV-1 Nef is a multifunctional protein that optimizes virus spread and promotes immune evasion of infected cells to accelerate disease progression in AIDS patients. As one of its activities, Nef reduces the motility of infected CD4(+) T lymphocytes in confined space. In vivo, Nef restricts T lymphocyte homing to lymph nodes as it reduces the ability for extravasation at the diapedesis step. Effects of Nef on T lymphocyte motility are typically mediated by its ability to reduce actin remodeling. However, interference with diapedesis does not depend on residues in Nef required for inhibition of host cell actin dynamics. In search for an alternative mechanism by which Nef could alter T lymphocyte extravasation, we noted that the viral protein interferes with the polarization of primary human CD4(+) T lymphocytes upon infection with HIV-1. Expression of Nef alone is sufficient to disrupt T cell polarization, and this effect is conserved among lentiviral Nef proteins. Nef acts by arresting the oscillation of CD4(+) T cells between polarized and nonpolarized morphologies. Mapping studies identified the binding site for the Nef-associated kinase complex (NAKC) as critical determinant of this Nef activity and a NAKC-binding-deficient Nef variant fails to impair CD4(+) T lymphocyte extravasation and homing to lymph nodes. These results thus imply the disruption of T lymphocyte polarity via its NAKC binding site as a novel mechanism by which lentiviral Nef proteins alter T lymphocyte migration in vivo.