Role of HLA-G on HIV Evasion of NK Cells

HLA-G 在 NK 细胞逃避 HIV 中的作用

• 批准号: 8138941
• 负责人: Edward Barker
• 金额: $ 6.28万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8138941
• 关键词: Affinity; Autologous; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cell surface; Cells; Cytotoxic T-Lymphocytes; Data; Down-Regulation; Endoplasmic Reticulum; Enzyme-Linked Immunosorbent Assay; Event; Fetal Tissues; G Cells; HIV; HIV Antigens; HIV Infections; HIV-1; HLA Antigens; HLA G antigen; Histocompatibility Antigens Class I; Immune response; Immunologic Surveillance; Lymphocyte; Membrane; Modeling; Molecular; Natural Killer Cells; Peptides; Population; Production; Proteins; RNA Interference; Refractory; Reporting; Resistance; Role; Signal Transduction; Small Interfering RNA; Surface; T-Lymphocyte; TAC1 gene; Testing; Transcript; Up-Regulation; Viral; base; cell killing; cytotoxic; infected B cell; insight; killings; lymphoblast; prevent; receptor; response; trophoblast

DESCRIPTION (provided by applicant): HIV-1 avoids destruction by HIV-antigen specific cytotoxic T-lymphocytes (CTL) by decreasing the cell surface expression of human leukocyte antigen (HLA)-A and HLA-B, which are needed to trigger CTL. Natural killer (NK) cells, however, can destroy cells lacking MHC class I molecules since these molecules inhibit NK cell killing. Despite this fact, NK cells are unable to kill HIV-infected cells. Our long-term objective is to determine how HIV prevents NK cells from destroying the infected cells, even though the conditions for the NK cell cytotoxic response appear optimal. One explanation for the inability of NK cells to kill HIV- infected cell is the presence of HLA-C and HLA-E on the infected cell surface. However, HLA-C and HLA-E only prevent a subset of NK cells from killing HIV-infected cells. Another explanation for the lack of NK cell killing is that HIV-1 induces the expression of HLA-G on activated CD4+ T-cells. HLA-G inhibits NK cell cytotoxic responses. The central hypothesis of this proposal is that HIV prevents NK from killing infected cells and controlling viral replication by inducing the expression of HLA-G. To evaluate our objective, we will determine the role of HLA-G cell surface expression, in the context of HIV infection, in disabling NK cell function, and to dissect the required signaling events. This will be accomplished by directing small interfering (si)RNA to HLA-G in HIV-infected cells, and determining the ability of NK cells to become activated and kill HIV-infected cells with decreased HLA-G surface expression. We will also determine the mechanisms by which HIV infection of CD4+ cells induces surface expression of HLA-G. Finally, we will determine the effect of soluble HLA-G secreted by HIV-infected cells on NK cell cytotoxic responses. The overall significance of this study is to provide insight into the mechanism important for allowing HIV to counter cellular immune responses that are differentially regulated by MHC class I molecules.

描述（由申请人提供）：HIV-1通过降低人类白细胞抗原（HLA）-A和HLA-B的细胞表面表达来避免HIV抗原特异性细胞毒性T淋巴细胞（CTL）的破坏，而人类白细胞抗原（HLA）-A和HLA-B是触发CTL所必需的。然而，自然杀伤（NK）细胞可以破坏缺乏MHC I类分子的细胞，因为这些分子抑制NK细胞杀伤。尽管如此，NK细胞无法杀死HIV感染的细胞。我们的长期目标是确定HIV如何阻止NK细胞破坏受感染的细胞，即使NK细胞细胞毒性反应的条件似乎是最佳的。NK细胞不能杀死HIV感染的细胞的一种解释是在感染的细胞表面上存在HLA-C和HLA-E。然而，HLA-C和HLA-E只能阻止一部分NK细胞杀死HIV感染的细胞。缺乏NK细胞杀伤的另一种解释是HIV-1诱导活化的CD 4 + T细胞上HLA-G的表达。HLA-G抑制NK细胞的细胞毒性应答。该建议的中心假设是，HIV通过诱导HLA-G的表达来阻止NK杀死感染的细胞并控制病毒复制。为了评估我们的目标，我们将确定HLA-G细胞表面表达的作用，在HIV感染的背景下，在禁用NK细胞功能，并剖析所需的信号事件。这将通过将小干扰（si）RNA定向到HIV感染细胞中的HLA-G，并确定NK细胞变得活化并杀死具有降低的HLA-G表面表达的HIV感染细胞的能力来实现。我们还将确定HIV感染CD 4+细胞诱导HLA-G表面表达的机制。最后，我们将确定HIV感染细胞分泌的可溶性HLA-G对NK细胞细胞毒性反应的影响。这项研究的总体意义是提供了重要的机制，让艾滋病毒对抗细胞免疫反应的差异调节的MHC I类分子的洞察。