Structure of HIV-2 Nef Reveals Features Distinct from HIV-1 Involved in Immune Regulation
Structure of HIV-2 Nef Reveals Features Distinct from HIV-1 Involved in Immune Regulation
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DOI：
10.1016/j.isci.2019.100758
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发表时间：
2020-01-24
期刊：
影响因子：
5.8
通讯作者：
Maenaka, Katsumi
中科院分区：
文献类型：
--
作者：
Hirao, Kengo;Andrews, Sophie;Maenaka, Katsumi
人类免疫缺陷病毒 (HIV) 辅助蛋白 Nef 在建立和维持感染中发挥着重要作用，特别是通过免疫逃避。许多 HIV-2 感染者经历了长期的病毒控制和生存，类似于 HIV-1 精英控制。 HIV-2 Nef 与 HIV-1 Nef 具有重叠但又不同的功能。在这里，我们报告了 HIV-2 Nef 核心的晶体结构。双亮氨酸分选基序形成与邻近分子结合的螺旋，此外，等温滴定量热法证明CD3内吞基序可以直接与HIV-2 Nef结合，确保AP-2介导的CD3内吞作用。高度保守的 C 末端区域形成了 HIV-1 中不存在的 α 螺旋。我们进一步确定了包含该区域的猿猴免疫缺陷病毒 (SIV) Nef 的结构，证明了相似的 C 末端 a 螺旋，这可能有助于 AP-1 结合从而下调 MHC-I。这些结果为了解 HIV-2 感染的独特发病机制提供了见解。
The human immunodeficiency virus (HIV) accessory protein Nef plays a major role in establishing and maintaining infection, particularly through immune evasion. Many HIV-2-infected people experience long-term viral control and survival, resembling HIV-1 elite control. HIV-2 Nef has overlapping but also distinct functions from HIV-1 Nef. Here we report the crystal structure of HIV-2 Nef core. The di-leucine sorting motif forms a helix bound to neighboring molecules, and moreover, isothermal titration calorimetry demonstrated that the CD3 endocytosis motif can directly bind to HIV-2 Nef, ensuring AP-2-mediated endocytosis for CD3. The highly conserved C-terminal region forms a alpha-helix, absent from HIV-1. We further determined the structure of simian immunodeficiency virus (SIV) Nef harboring this region, demonstrating similar C-terminal a-helix, which may contribute to AP-1 binding for MHC-I downregulation. These results provide insights into the distinct pathogenesis of HIV-2 infection.