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: 8127882
• 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/8127882
• 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; antigen processing; cell killing; cohort; design; innovation; killings; macrophage; monocyte; nanoparticle; novel; protein degradation; response; synthetic peptide; tool; vaccine candidate

DESCRIPTION (provided by applicant): 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. HIV-specific CD8 T cells are able to kill HIV-infected cells because infected cells display pieces of virus called epitopes. Deciphering the mechanisms of production and presentation of HIV epitopes stimulating efficient immune responses is key to rational vaccine design. This project seeks to identify immune responses and epitopes presented by HIV-infected cell subsets from persons with spontaneously undetectable viremia (controllers) and to define factors governing the efficiency of epitope processing that will enable selected presentation of protective epitopes in immunogens.

描述（由申请人提供）：HIV特异性的细胞毒性T淋巴细胞（CTL）在含有HIV病毒血症的急性感染或自发控制的情况下起着至关重要的作用，使它们对疫苗策略的候选者有吸引力。然而，到目前为止，尽管产生了CTL反应，但迄今为止开发的疫苗仍未预防艾滋病毒感染。与其他特异性相比，针对病毒某些区域的CTL反应可能比CTL更有效地控制HIV复制，这表明疫苗应引起与保护相关的选定CTL反应。通过HIV感染的细胞对同源表位的有效表示是保护性CTL反应的关键条件。然而，令人惊讶的是，人们对管理CD8 T细胞识别的HIV表位的细胞内机制几乎没有理解。大多数关于HIV特异性CTL功能的研究都以合成肽的形式使用同源表位，因此绕过了蛋白质降解的所有细胞内步骤，导致表现出现。 HIV感染了将呈现HIV表位的几种表达CD4的亚群（CD4 T细胞，单核细胞/巨噬细胞和树突状细胞）。这些子集是否具有相同动力学的相似表位是未知的。子集之间的表位表现的变化可能会影响CTL的抗病毒功效。相反，在所有子集中有效地识别有效加工成表位的艾滋病毒区域对于鉴定保护性CTL反应和免疫原子的选择至关重要。在新型表位加工测定的基础上，我们展示了某些HIV表位的优先处理，该特性依赖于我们用来改变无关表位的产生的图案。我们还确定了参与表位加工效率的新因素，即最佳HIV表位的高度可变的细胞内稳定性，这也是由特定基序驱动的。最后，我们显示CD4 T细胞的加工活性比单核细胞低，这会影响HIV蛋白质降解产物的动力学和抗原性。这些数据表明，表位生产受可能利用用于设计定制免疫原的规则。具体而言，我们建议：1）确定与自发控制HIV病毒血症有关的CTL反应是否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队列，我们​​将评估各种HIV感染的子集刺激的CD8 T细胞的功能。 2）鉴定有助于自发控制病毒血症的可感染子集的不同抗原加工途径中通常产生的肽。我们将使用纳米颗粒靶向细胞子集中的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。该提案依赖于涉及计算科学，生物工程工具以及为主细胞设计的表位处理和CTL功能的生化和免疫学测定的跨学科协作方法。 HIV特异性CD8 T细胞能够杀死感染HIV的细胞，因为感染的细胞显示了称为表位的病毒部分。解释生产机制和艾滋病毒表位的表现刺激有效免疫反应是理性疫苗设计的关键。该项目旨在识别来自艾滋病毒感染的细胞子集给出的免疫反应和表位，这些细胞子群来自具有自发不可检测的病毒血症（控制器）的人，并定义了负责表位加工效率的因素，这些因素将使免疫原中的保护性表位呈现。