The Nef protein of the macrophage tropic HIV-1 strain AD8 counteracts human Bst-2/tetherin
The Nef protein of the macrophage tropic HIV-1 strain AD8 counteracts human Bst-2/tetherin
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巨噬细胞嗜性 HIV-1 病毒株 AD8 的 Nef 蛋白对抗人类 Bst-2/tetherin
DOI：
10.1101/2020.02.07.938464
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Giese S
中科院分区：
文献类型：
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作者：
Giese S
骨髓基质细胞抗原2（BST-2）/tetherin通过在病毒从细胞表面出芽的过程中将新生颗粒物理束缚到受感染的细胞上来抑制许多包膜病毒的释放。Tetherin也限制人类免疫缺陷病毒（HIV），流行性主要（M）组HIV 1型（HIV-1）被认为完全依赖于其Vpu蛋白来克服Tetherin介导的病毒释放限制。然而，至少有一种M组HIV-1毒株，即嗜巨噬细胞的主要AD 8分离株，由于其翻译起始密码子的突变而不能表达Vpu。在这里，使用原代单核细胞衍生的巨噬细胞（MDM），我们表明AD 8 Nef蛋白可以补偿Vpu的缺乏，并将病毒释放恢复到野生型水平。我们证明，HIV-1 AD 8 Nef降低了内源性细胞表面连接蛋白水平，将其与病毒出芽部位物理分离，从而防止HIV滞留。从机制上讲，AD 8 Nef增强了人栓蛋白长同种型的内化，导致限制因子的核周积累。最后，我们表明，Nef蛋白从其他艾滋病毒株也表现出不同程度的tetherin拮抗作用。总的来说，我们表明M组HIV-1可以使用辅助蛋白而不是Vpu来拮抗人类tetherin。
Bone Marrow Stromal Cell Antigen 2 (BST-2)/tetherin inhibits the release of numerous enveloped viruses by physically tethering nascent particles to infected cells during the process of viral budding from the cell surface. Tetherin also restricts human immunodeficiency virus (HIV), and pandemic main (M) group HIV type 1s (HIV-1s) are thought to rely exclusively on their Vpu proteins to overcome tetherin-mediated restriction of virus release. However, at least one M group HIV-1 strain, the macrophage-tropic primary AD8 isolate, is unable to express Vpu due to a mutation in its translation initiation codon. Here, using primary monocyte-derived macrophages (MDMs), we show that AD8 Nef protein can compensate for the absence of Vpu and restore virus release to wild type levels. We demonstrate that HIV-1 AD8 Nef reduces endogenous cell surface tetherin levels, physically separating it from the site of viral budding, thus preventing HIV retention. Mechanistically, AD8 Nef enhances internalisation of the long isoform of human tetherin, leading to perinuclear accumulation of the restriction factor. Finally, we show that Nef proteins from other HIV strains also display varying degrees of tetherin antagonism. Overall, we show that M group HIV-1s can use an accessory protein other than Vpu to antagonise human tetherin.