The Human Immunodeficiency Virus Type 2 Vpx Protein Usurps the CUL4A-DDB1DCAF1 Ubiquitin Ligase To Overcome a Postentry Block in Macrophage Infection
The Human Immunodeficiency Virus Type 2 Vpx Protein Usurps the CUL4A-DDB1DCAF1 Ubiquitin Ligase To Overcome a Postentry Block in Macrophage Infection
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DOI：
10.1128/jvi.00187-09
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发表时间：
2009-05-15
影响因子：
5.4
通讯作者：
Transy, Catherine
中科院分区：
文献类型：
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作者：
Bergamaschi, Anna;Ayinde, Diana;Transy, Catherine
人类免疫缺陷病毒（HIV）和猿猴免疫缺陷病毒（SIV）基因组编码的几种辅助蛋白，越来越显示出它们在病毒-宿主关系中的重要性。这些蛋白质之一Vpx是HIV-2/SIVsm谱系所特有的，并且对于巨噬细胞中的病毒复制至关重要。这一要求的功能基础以及Vpx的作用模式仍然无法解释，并且没有Vpx对应物的HIV 1型（HIV-1）可以感染巨噬细胞更加神秘。在这里，我们强调DCAF 1作为Vpx的关键宿主效应子，能够介导HIV-2在人巨噬细胞中的感染和长期复制。Vpx通过DCAF 1募集与CUL 4A-DDB 1泛素连接酶组装。阻止进入的病毒体中存在的Vpx在靶巨噬细胞中招募DCAF 1，导致以HIV-2逆转录物的缺陷性积累为特征的植入后阻断。此外，来自SIVsm的Vpx以DCAF 1结合依赖性方式在功能上补充Vpx缺陷型HIV-2。总而言之，我们的数据指出了Vpx将Cul 4A-DDB 1（DCAF 1）连接酶转移到一种进化上保守的因子上的机制，该因子限制了HIV-2和密切相关的猿猴病毒对巨噬细胞的感染。
The human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) genomes encode several auxiliary proteins that have increasingly shown their importance in the virus-host relationship. One of these proteins, Vpx, is unique to the HIV-2/SIVsm lineage and is critical for viral replication in macrophages. The functional basis for this requirement, as well as the Vpx mode of action, has remained unexplained, and it is all the more enigmatic that HIV type 1 (HIV-1), which has no Vpx counterpart, can infect macrophages. Here, we underscore DCAF1 as a critical host effector of Vpx in its ability to mediate infection and long-term replication of HIV-2 in human macrophages. Vpx assembles with the CUL4A-DDB1 ubiquitin ligase through DCAF1 recruitment. Precluding Vpx present in the incoming virions from recruiting DCAF1 in target macrophages leads to a postentry block characterized by defective accumulation of HIV-2 reverse transcripts. In addition, Vpx from SIVsm functionally complements Vpx-defective HIV-2 in a DCAF1-binding-dependent manner. Altogether, our data point to a mechanism in which Vpx diverts the Cul4A-DDB1(DCAF1) ligase to inactivate an evolutionarily conserved factor, which restricts macrophage infection by HIV-2 and closely related simian viruses.