Mechanisms and optimization of epitope presentation by HIV-infectable cell subset

HIV感染细胞亚群表位呈递的机制和优化

• 批准号: 8318037
• 负责人: Sylvie Le Gall
• 金额: $ 43.37万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318037
• 关键词: Accounting; Acute; Address; Affect; Antigens; Antiviral Agents; Area; Biochemical; Biological Assay; Biomedical Engineering; Bypass; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Computational Science; Computer Analysis; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Detection; Epitopes; Gagging; HIV; HIV Infections; Immune response; Individual; Infection; Kinetics; Lead; Lymphocyte Function; Pathway interactions; Pattern; Peptides; Peripheral Blood Mononuclear Cell; Persons; Physiologic pulse; Play; Population; Process; Production; Property; Proteins; RNA; Role; Specificity; T cell response; T-Lymphocyte; Testing; Vaccine Design; Vaccines; Variant; Viral; Viral Load result; Viremia; Virus; abstracting; antigen processing; cell killing; cohort; design; innovation; killings; macrophage; monocyte; nanoparticle; novel; protein degradation; response; synthetic peptide; tool; vaccine candidate

Project summary/abstract HIV-specific cytotoxic T-lymphocytes (CTL) play a critical role in containing HIV viremia in acute infection or in situation of spontaneous control, rendering them attractive candidates for vaccine strategies. However vaccines developed so far have failed to protect against HIV infection, this despite generating CTL responses. The fact that CTL responses against certain areas of the virus may be more effective at controlling HIV replication than CTL with other specificities suggests that vaccine should elicit selected CTL responses associated with protection. Effective presentation of the cognate epitopes by HIV-infected cells is a crucial condition for protective CTL responses. However, there is still surprisingly little understanding of intracellular mechanisms governing the presentation of HIV epitopes recognized by CD8 T cells. Most studies on HIV- specific CTL functions utilize cognate epitopes in the form of synthetic peptides, thus bypassing all intracellular steps of protein degradation leading to the presentation of epitopes. HIV infects several CD4-expressing subsets (CD4 T cells, monocyte/macrophages and dendritic cells) that will present HIV epitopes. Whether these subsets present similar epitopes with identical kinetics is unknown. Variations in epitope presentation between subsets may affect the antiviral efficacy of CTL. Conversely identifying areas of HIV that are efficiently processed into epitopes in all subsets is of highest importance for the identification of protective CTL responses and selection of immunogens. Building on novel epitope processing assays, we showed preferential processing of some HIV epitopes, a property that relies on motifs we used to alter the production of irrelevant epitopes. We also identified a novel factor involved in epitope processing efficiency, namely the highly variable intracellular stability of optimal HIV epitopes, also driven by specific motifs. Finally we show that CD4 T cells have lower processing activities than monocytes, which affects the kinetics and antigenicity of degradation products from HIV proteins. These data suggest that epitope production is controlled by rules that could be exploited to design customized immunogens. Specifically we propose to: 1) Determine whether CTL responses associated with spontaneous control of HIV viremia efficiently recognize and kill all HIV-infectable cell subsets. Taking advantage of a large cohort of controllers and progressors, we will assess the functionality of CD8 T cells stimulated by various HIV-infected subsets. 2) Identify peptides commonly produced in distinct antigen processing pathways of infectable subsets contributing to spontaneous controlled viremia. Using nanoparticles to target HIV proteins inside cell subsets, we will identify antigenic peptides produced by all subsets. 3) Design and test sequence signatures leading to the selective presentation of protective HIV epitopes. This proposal relies on a cross-disciplinary collaborative approach involving computational science, bioengineered tools and biochemical and immunological assays of epitope processing and CTL functions designed for primary cells.

项目摘要/摘要 HIV特异性细胞毒性T淋巴细胞（CTL）在含有HIV病毒血症的急性感染或在 自发控制的情况，使他们成为疫苗策略的有吸引力的候选人。然而 到目前为止，迄今为止开发的疫苗未能防止艾滋病毒感染，尽管产生了CTL反应。 CTL针对病毒某些区域的反应可能更有效地控制HIV的事实 复制比CTL具有其他特殊性，表明疫苗应引起选定的CTL反应 与保护有关。通过HIV感染的细胞对同源表位的有效表现至关重要 保护性CTL响应的条件。但是，对细胞内的了解仍然很少 介绍CD8 T细胞识别的HIV表位的机制。大多数关于HIV的研究 特定的CTL功能利用合成肽的形式使用同源表位，从而绕过所有细胞内 蛋白质降解的步骤导致表现出现。 HIV感染了几种CD4表达 子集（CD4 T细胞，单核细胞/巨噬细胞和树突状细胞），将呈现HIV表位。无论 这些子集具有相似的表位，具有相同的动力学是未知的。表位表现的变化 子集之间可能会影响CTL的抗病毒功效。相反，识别有效的艾滋病毒区域 在所有子集中加工成表位，对于识别保护性CTL至关重要 免疫原子的反应和选择。基于新型表位加工测定法，我们显示了优先 处理某些艾滋病毒表位的处理，这是一种依赖于图案的特性，我们用来改变无关的产生 表位。我们还确定了表位处理效率涉及的新因素，即高度可变的因素 最佳HIV表位的细胞内稳定性也由特定基序驱动。最后，我们表明CD4 T细胞 与单核细胞相比，处理活动较低，这会影响降解的动力学和抗原性 来自HIV蛋白的产品。这些数据表明，表位生产受可能是规则控制的 利用设计定制的免疫原。具体提议：1）确定CTL是否响应 与自发控制HIV病毒血症有关，有效地识别并杀死所有可感染HIV的细胞亚群。 利用大量的控制器和进步者，我们将评估CD8 T的功能 由各种HIV感染的子集刺激的细胞。 2）鉴定通常在不同抗原中产生的肽 可感染子集的处理途径有助于自发控制的病毒血症。使用纳米颗粒 为了靶向细胞子集中的HIV蛋白，我们将确定所有亚群产生的抗原肽。 3）设计 和测试序列特征，导致保护性HIV表位的选择性表现。这个建议 依靠涉及计算科学，生物工程工具和的跨学科协作方法 表位加工和CTL功能的生化和免疫学测定专为原代细胞设计。