Human immunodeficiency virus 1 Nef protein downmodulates the ligands of the activating receptor NKG2D and inhibits natural killer cell-mediated cytotoxicity
Human immunodeficiency virus 1 Nef protein downmodulates the ligands of the activating receptor NKG2D and inhibits natural killer cell-mediated cytotoxicity
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DOI：
10.1099/vir.0.82125-0
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发表时间：
2007-01-01
影响因子：
3.8
通讯作者：
Doria, Margherita
中科院分区：
文献类型：
--
作者：
Cerboni, Cristina;Neri, Francesca;Doria, Margherita
自然杀伤（NK）细胞是宿主针对各种病原体的先天免疫防御的主要组分。包括人类免疫缺陷病毒1（HIV-1）在内的几种病毒已经发展出逃避NK细胞应答的策略。本研究旨在评估HIV-1是否可以干扰NK细胞活化配体的表达，特别是与NKG 21 D（所有NK细胞表达的活化受体）结合的人类白细胞抗原（HLA）-I样云母和ULBP分子。结果表明，HIV-1 Nef蛋白下调了云母、ULBP 1和ULBP 2的细胞表面表达，对后者分子的影响更大。对云母和ULBP 2的活性在来自HIV-1感染患者的Nef蛋白变体中是很保守的。在HIV-1感染的细胞中，与野生型病毒相比，Nef缺陷型病毒的NKG 2D配体的细胞表面表达增加程度更高。Nef的突变分析表明，NKG 2D配体下调的结构要求不同于其他报道的Nef活性，包括HLA-I下调。最后，数据表明Nef表达对NK细胞识别具有功能性后果，导致对NK细胞介导的裂解的易感性降低。这些发现为HIV-1逃避NK细胞反应的机制提供了新的见解。
Natural killer (NK) cells are a major component of the host innate immune defence against various pathogens. Several viruses, including Human immunodeficiency virus 1 (HIV-1), have developed strategies to evade the NK-cell response. This study was designed to evaluate whether HIV-1 could interfere with the expression of NK cell-activating ligands, specifically the human leukocyte antigen (HLA)-I-like MICA and ULBP molecules that bind NKG21D, an activating receptor expressed by all NK cells. Results show that the HIV-1 Nef protein downmodulates cell-surface expression of MICA, ULBP1 and ULBP2, with a stronger effect on the latter molecule. The activity on MICA and ULBP2 is well conserved in Nef protein variants derived from HIV-1-infected patients. In HIV-1-infected cells, cell-surface expression of NKG2D ligands increased to a higher extent with a Nef-deficient virus compared with wild-type virus. Mutational analysis of Nef showed that NKG2D ligand downmodulation has structural requirements that differ from those of other reported Nef activities, including HLA-I downmodulation. Finally, data demonstrate that Nef expression has functional consequences on NK-cell recognition, causing a decreased susceptibility to NK cell-mediated lysis. These findings provide a novel insight into the mechanisms evolved by HIV-1 to escape from the NK-cell response.