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: 8263260
• 负责人: Edward Barker
• 金额: $ 14.62万
• 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 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8263260
• 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; 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. PUBLIC HEALTH RELEVANCE: This project will determine how HIV evades immune cells called natural killer cells. Natural killer cells are part of the first line of defense against HIV infection. The results from this study will provide insights on the mechanisms by which HIV avoids detection and destruction by the early immune response. These insights will point the way towards treatment strategies that will enhance the immune system's ability to control HIV infection.

描述（由申请方提供）：自然杀伤（NK）细胞是先天性淋巴细胞，在针对病毒的免疫监视中至关重要。然而，NK细胞无法控制HIV-1。尽管HIV-1 Nef能够下调NK细胞抑制性受体HLA-A和-B的配体，但NK细胞不能有效地裂解HIV感染的细胞。此外，HIV-1 Vpr诱导活化受体NKG2D的配体ULBP-1和ULBP-2。Nef和Vpr的作用足以激活NK细胞，但不足以触发NK细胞释放其溶细胞因子。 颗粒。对于NK细胞来说，它们需要两种受体NKG2D和NTB-A的参与。在正常条件下，NK细胞上的NTB-A由CD4 + T细胞上的NTB-A触发。然而，HIV-1 Vpu能够下调来自感染细胞表面的NTB-A，这样做可以防止应答NK细胞脱粒。因此，Vpu保护受感染的细胞免受NK细胞的裂解。为了理解Vpu对NTB-A的调节及其对NK细胞溶细胞反应的结果，我们将：1）确定Vpu通过NTB-A下调抑制NK细胞溶细胞反应的机制，2）确定Vpu如何下调NTB-A和3）确定来自HIV-1和SIV毒株的各种亚型和组的Vpu是否能够下调NTB-A以及如何下调NTB-A。在第一个目标中，我们将测试以下假设：HIV感染的靶细胞上NTB-A的Vpu下调阻止NK细胞上源自NTB-A的特异性细胞内信号诱导参与促进溶解颗粒释放的下游信号传导事件的能力。在目的1中，我们还将检查NK细胞活化受体的活化配体KIR3DS 1是否能够在NTB-A下调的情况下触发脱粒。在第二个目标中，我们将测试的假设，Vpu的胞质尾干扰宿主细胞蛋白参与运输NTB-A从trans-Golgi网络质膜。在第二个目标中，我们还将确定Vpu的跨膜（TM）部分是否以及如何与NTB-A的TM部分相互作用。在最后一个目标中，我们将测试来自特定HIV-1亚型和组的Vpu在调节NTB-A中具有不同效率的假设。此外，我们将确定Vpu对NTB-A的下调是否仅限于HIV-1，或者SIV Vpu是否也下调猿猴和人类NTB-A。这些机制的知识无疑将导致新的治疗干预措施，旨在恢复HIV-1感染期间NK隔室的有效性。 公共卫生相关性：该项目将确定艾滋病毒如何逃避称为自然杀伤细胞的免疫细胞。自然杀伤细胞是对抗艾滋病病毒的第一道防线的一部分 感染这项研究的结果将为HIV避免被早期免疫反应检测和破坏的机制提供见解。这些见解将为增强免疫系统控制艾滋病毒感染的能力的治疗策略指明方向。