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避免了通过降低人白细胞抗原（HLA）-A和HLA-B的细胞表面表达，避免了HIV-抗原特异性细胞毒性T淋巴细胞（CTL），这是触发CTL所需的。但是，天然杀伤（NK）细胞会破坏缺乏MHC I类分子的细胞，因为这些分子抑制了NK细胞的杀伤。尽管这一事实，NK细胞仍无法杀死感染HIV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细胞无法杀死HIV感染细胞的一种解释是在感染的细胞表面上存在HLA-C和HLA-E。但是，HLA-C和HLA-E仅阻止NK细胞的子集杀死HIV感染的细胞。缺乏NK细胞杀死的另一个解释是，HIV-1在活化的CD4+ T细胞上诱导HLA-G的表达。 HLA-G抑制NK细胞细胞毒性反应。该提案的中心假设是HIV可防止NK通过诱导HLA-G的表达来杀死感染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，在HIV感染的背景下，禁用NK细胞功能以及剖析所需的信号事件的作用。这将通过将小型干扰（Si）RNA引导到HIV感染的细胞中HLA-G，并确定NK细胞被激活并杀死HLA-G表面表达降低的HIV感染细胞的能力。我们还将确定CD4+细胞的HIV感染诱导HLA-G的表面表达的机制。最后，我们将确定受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洞悉允许HIV对抗由MHC I类分子差异调节的细胞免疫反应至关重要的机制。