HIV Envelope gp120-induced immunosuppression

HIV包膜gp120诱导的免疫抑制

• 批准号: 8786350
• 负责人: Catarina E Hioe
• 金额: $ 22.48万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-17 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8786350
• 关键词: Address; Adenoviruses; Adhesions; Affect; Antibody Formation; Antigen-Presenting Cells; Antigens; Apoptosis; Binding; CD3 Antigens; CD4 Positive T Lymphocytes; Cell Communication; Cell physiology; Cells; Characteristics; Collaborations; Cytotoxic T-Lymphocytes; DNA; DNA Sequence Rearrangement; DNA Viruses; Data; Development; Disease; Elements; Epidemic; Event; Fluorescence Microscopy; Glass; Goals; HIV; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; Helper-Inducer T-Lymphocyte; Hour; Image; Immune; Immune response; Immunosuppression; Immunosuppressive Agents; Induction of Apoptosis; Institutes; Intercellular adhesion molecule 1; Intercept; Letters; Ligands; Literature; MHC Interaction; Maintenance; Mediating; Membrane; Modeling; Molecular; Morphology; Natural Killer Cells; Pathway interactions; Pattern; Peptide/MHC Complex; Peripheral; Physiological; Preventive; Production; Reading; Regulatory T-Lymphocyte; Reporting; Resolution; Signal Transduction; Signaling Molecule; Surface; System; T cell differentiation; T cell response; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Up-Regulation; Vaccines; Viral; Viral Tumor Antigens; Viral Vector; Virus; Virus Diseases; base; cell type; chemokine receptor; crosslink; cytokine; cytotoxicity; design; env Gene Products; immunological synapse; immunological synapse formation; innovative technologies; memory CD4 T lymphocyte; receptor; response; spatiotemporal; vaccinia virus vector; vector vaccine; virus envelope

PROJECT SUMMARY/ABSTRACT The capacity of HIV envelope gp120 to cause immune suppression has been well documented in the literatures. These suppressive effects can be triggered by gp120 independent of virus infection. Recent data also demonstrate suppression of CD4 T cell activation by gp120 delivered via vaccine vectors. However, very little is known about the molecular mechanisms for this suppressive activity. In fact, the read-outs for gp120- mediated suppression have been based mainly on the standard T cell responses such as proliferation, cytotoxicity, cytokine production. The effects of gp120 on the upstream events essential for T cell activation are not at all clear. It is important to note that, upon engagement of CD4 and/or chemokine receptors, gp120 triggers unique gp120/CD4 supramolecular rearrangements and activation signals that involve many components of the T cell signaling machinery, but how the gp120-triggered clustering and signaling actually intersect with and alter the physiologic T cell receptor-mediated activation pathway remains unknown. The goal of this application is to investigate the consequences of CD4 T cell interaction with gp120 on the early events in T cell activation, i.e. the formation of immunological synapse and the subsequent signaling events. Our main hypothesis is that gp120 interferes with T cell receptor-mediated immunological synapse assembly and signaling to cause suppression of downstream T cell responses. To test this hypothesis, the synthetic glass-supported planar bilayer system will be utilized to mimic antigen-presenting cells bearing the cognate T cell receptor ligands (peptide-MHC complexes or anti-CD3), the costimulatory molecules, and gp120. Together with the state-of-the-art fluorescence microscopy, this experimental system enables acquisition of high-resolution and dynamic images of immunological synapse and its specific component. Hence, we will employ this innovative technology to explore the effects of gp120 interaction on two types of CD4 T cells, memory and naive, which display different immunological synapse characteristics and activation requirements. For each cell type, we will evaluate four parameters known to be critical for full CD4 T cell activation: a) immunological synapse assembly, morphology, and stability, b) T cell receptor-proximal signal activation, c) the immediate cellular responses (Ca2+ flux and CD69 upregulation), and d) the downstream effector functions (cytokine production and proliferation). HIV gp120 is an important target for anti-HIV antibodies. Since it has become clearer that induction of antibody responses is an indispensable element for HIV vaccines, we must understand better not only the immune responses to gp120 but also the immunosuppressive potential of this antigen, especially on CD4 T cells that provide help for the development and maintenance of both humoral and cellular responses. The data generated from this study will be valuable for designing gp120-based preventive and therapeutic strategies that are effective to block HIV infection and disease.

项目摘要/摘要 HIV信封GP120引起免疫抑制的能力已在 文献。这些抑制作用可以由与病毒感染无关的GP120触发。最新数据 还证明了通过疫苗向量传递的GP120抑制CD4 T细胞的激活。但是，非常 关于这种抑制活性的分子机制知之甚少。实际上，GP120-的读出 介导的抑制主要基于标准T细胞反应，例如增殖， 细胞毒性，细胞因子产生。 GP120对T细胞激活必不可少的上游事件的影响 根本不清楚。重要的是要注意，在CD4和/或趋化因子受体的参与后，GP120 触发独特的GP120/CD4超分子重排和激活信号，涉及许多 T细胞信号机械的组件，但实际上是GP120触发的聚类和信号传导 与生理T细胞受体介导的活化途径相交并改变并改变了未知。 该应用的目的是研究CD4 T细胞与GP120在 T细胞激活中的早期事件，即免疫突触的形成和随后的信号传导 事件。我们的主要假设是GP120干扰了T细胞受体介导的免疫突触 组装和信号传导引起下游T细胞反应的抑制。为了检验这一假设， 合成玻璃支持的平面双层系统将用于模仿带有抗原的细胞 同名T细胞受体配体（肽-MHC复合物或抗CD3），共刺激分子和 GP120。与最先进的荧光显微镜一起，该实验系统可以实现 获得免疫突触及其特定成分的高分辨率和动态图像的获取。 因此，我们将采用这项创新技术来探索GP120相互作用对两种类型的影响 CD4 T细胞，记忆和天真，它们显示出不同的免疫突触特征和激活 要求。对于每种单元格类型，我们将评估四个已知对完整CD4 T细胞至关重要的参数 激活：a）免疫突触组件，形态和稳定性，b）T细胞受体 - 透明信号 激活，c）立即的细胞反应（Ca2+通量和CD69上调），d）下游 效应子功能（细胞因子的产生和增殖）。 HIV GP120是抗HIV抗体的重要靶标。由于已经变得更加清楚地归纳了 抗体反应是HIV疫苗必不可少的元素，我们不仅必须更好地了解 对GP120的免疫反应，但也具有该抗原的免疫抑制潜力，尤其是在CD4 T上 为开发和维持体液和细胞反应提供帮助的细胞。数据 这项研究产生的将对设计基于GP120的预防和治疗策略很有价值 有效阻止HIV感染和疾病。