Vpu inhibits NK cell function through down regulation of NTB-A

Vpu 通过下调 NTB-A 抑制 NK 细胞功能

• 批准号: 8975113
• 负责人: Edward Barker
• 金额: $ 33.45万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8975113
• 关键词: Activated Natural Killer Cell; Antigens; Antiviral Agents; B-Lymphocytes; Binding; CD4 Positive T Lymphocytes; Cell Degranulation; Cell Line; Cell membrane; Cell physiology; Cell surface; Cells; Cytolysis; Cytoplasmic Granules; Cytoplasmic Tail; Detection; Down-Regulation; Effectiveness; Event; Family; HIV; HIV Infections; HIV-1; HLA-A gene; Histocompatibility Antigens Class I; Human; Immune; Immune response; Immune system; Immunologic Surveillance; Individual; Infection; K-562; KIR3DS1; Knowledge; Lead; Ligands; Lymphocyte; Lytic; Major Histocompatibility Complex; Methods; NK Cell Activation; NK cell receptor NKB1; Natural Killer Cells; Proteins; Receptor Activation; Reporting; SIV; Signal Transduction; Stream; Subfamily lentivirinae; Surface; T-Lymphocyte; TRAPP transport protein particle; Testing; Transmembrane Domain; Virus; adaptive immunity; insight; mutant; novel therapeutic intervention; prevent; protein transport; receptor; response; trans-Golgi Network; treatment strategy

DESCRIPTION (provided by applicant): Natural killer (NK) cells are innate lymphocytes that are crucial in the immune surveillance against viruses. However, NK cells fail to control HIV-1. NK cells do not effectively lyse HIV-infected cells despite the ability of HIV-1 Nef to down modulate the ligands for NK cell inhibitory receptors, HLA-A and -B. Moreover, HIV-1 Vpr induces ligands, ULBP-1 and -2, to the activation receptor, NKG2D. The actions of Nef and Vpr are sufficient to activate NK cells but insufficient to trigger NK cells to release their cytolytic granules. For NK cells to degranulate they require the engagement of two receptors, NKG2D and NTB-A. Under normal conditions, NTB-A on NK cells is triggered by NTB-A on CD4+ T-cells. However, HIV-1 Vpu is able to down modulate NTB-A from the infected cells surface and in doing so prevents the responding NK cells from degranulating. Thus, Vpu protects the infected cell from lysis by NK cells. In order to understand Vpu's modulation of NTB-A and its consequence on the NK cell cytolytic response we will: 1) determine the mechanism by which Vpu, through NTB-A down modulation, suppresses NK cytolytic response, 2) determine how Vpu down modulates NTB-A and 3) determine whether and how Vpu from various subtypes and groups of HIV-1 and SIV strains are able to down modulate NTB-A. In the first aim, we will test the hypothesis that Vpu down modulation of NTB-A on HIV-infected target cells prevents the ability of specific intracellular signals originating from NTB-A on NK cells from inducing down stream signaling events involved in facilitating the release of lytic granules. In Aim 1 we will alo examine whether the activation ligands to NK cell activation receptor, KIR3DS1 is able to trigger degranulation in the context of NTB-A down modulation. In the second aim, we will test the hypothesis that Vpu's cytoplasmic tail interferes with host cell proteins that are involved in transporting NTB-A from the trans-Golgi network to the plasma membrane. In the second Aim we will also determine whether and how the transmembrane (TM) portion of Vpu interacts with the TM portion of NTB-A. In the last aim, we will test the hypothesis that Vpu from specific HIV-1 subtypes and groups will have different efficiencies in modulating NTB-A. Moreover, we will determine whether Vpu's down modulation of NTB-A is limited to HIV-1 or whether SIV Vpu down modulates simian and human NTB-A as well. Knowledge of these mechanisms will undoubtedly lead to novel therapeutic interventions aimed at restoring the effectiveness of the NK compartment during HIV- 1 infection.

描述（由申请人提供）：天然杀手（NK）细胞是先天淋巴细胞，对于针对病毒的免疫监测至关重要。但是，NK细胞无法控制HIV-1。尽管HIV-1 NEF能够调节NK细胞抑制受体HLA-A和-B，但NK细胞没有有效地裂解HIV感染的细胞。此外，HIV-1 vpr诱导配体ULBP-1和-2，激活受体NKG2D。 NEF和VPR的作用足以激活NK细胞，但不足以触发NK细胞释放其细胞溶解度 颗粒。为了使NK细胞脱脂，它们需要两个受体NKG2D和NTB-A的参与。在正常条件下，NTB-A上的NTB-A在CD4+ T细胞上触发NTB-A触发。但是，HIV-1 VPU能够从受感染的细胞表面调节NTB-A，从而防止反应的NK细胞脱粒。因此，VPU可保护被感染的细胞免受NK细胞的裂解。为了了解VPU对NTB-A的调节及其对NK细胞溶解响应的影响，我们将：1）确定通过NTB-A下降调节的VPU的机制，抑制NK细胞溶解响应，2）确定VPU如何调节NTB-A和3）确定vpu and siv str and sTR and sTRES和SIV是否能够向下sTRES和SIV，以下siv stry and sTRES和SIV是否能够下部和SIV组模式。 NTB-A。在第一个目的中，我们将检验以下假设：HIV感染的靶细胞对NTB-A的VPU下降调节可防止源自NK细胞上NTB-A源自NTB-A的特定细胞内信号的能力，从而诱导了促进裂解颗粒释放的降低流信号传导事件。在AIM 1中，我们将ALO检查NK细胞激活受体的激活配体是否能够在NTB-A下降调制的背景下触发脱粒。在第二个目标中，我们将检验以下假设：VPU的细胞质尾部会干扰与将NTB-A从反式高尔基网络运输到质膜的宿主细胞蛋白。在第二个目标中，我们还将确定VPU的跨膜（TM）部分是否与NTB-A的TM部分相互作用。在最后一个目标中，我们将检验以下假设：来自特定HIV-1亚型和组的VPU在调节NTB-A时具有不同的效率。此外，我们将确定VPU对NTB-A的下降调制是否仅限于HIV-1，或者SIV VPU下降是否也调节了Simian和Human NTB-A。这些机制的知识无疑会导致新的治疗干预措施，旨在恢复HIV-1感染期间NK室的有效性。