Identifying, Characterizing and Inducing Effective Anti-HIV T Cell Responses

识别、表征和诱导有效的抗 HIV T 细胞反应

• 批准号: 7989095
• 负责人: HELEN HORTON
• 金额: $ 64.77万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7989095
• 关键词: Acute; Address; Antigens; Area; Biological Assay; CD8B1 gene; Cell Line; Clinical; Clinical Trials; Clinical Trials Design; Data; Dendritic Cells; Disease; Effectiveness; Epitopes; Escape Mutant; Flow Cytometry; Frequencies; Genetic Transcription; HIV; HIV Infections; HIV vaccine; HIV-1; HIV-1 vaccine; Hepatitis C virus; Human; Immune system; Immunoglobulin Variable Region; In Vitro; Individual; Infection; Infectious Agent; Length; Leukapheresis; Macaca mulatta; Measures; Mediating; Modeling; Mutate; Mutation; Oligopeptides; Outcome; Patients; Proteins; Sampling; Specificity; T cell response; T-Cell Immunologic Specificity; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Translations; Vaccinated; Vaccination; Vaccines; Variant; Viral; Viral Load result; Viral Vector; Virus; base; cytokine; design; in vitro Assay; insight; monocyte; multicatalytic endopeptidase complex; novel; pressure; prototype; response; theories; vaccine candidate; vaccine development; vaccine effectiveness

DESCRIPTION (provided by applicant): Current candidate HIV-1 vaccines induce T cells that (i) possess restricted breadth; i.e. recognize only a few different epitopes; and (ii) predominantly target variable regions of HIV-1. Furthermore, during acute HIV-1 infection individuals who possess T cells targeting variable HIV-1 epitopes progress to disease faster than individuals possessing T cells targeting conserved HIV-1 epitopes. These data support the views that an effective T cell-based immunogen will contain only conserved regions of HIV-1 (the conserved immunogen approach). An alternative approach (the mosaic immunogen approach) has been to design immunogens to include multiple variants. This approach is based upon the theory that inclusion of multiple variants would enable responses to a broader range of circulating variants and could prime the immune system against common escape mutants. This proposal seeks to test the hypothesis that the conservation (as measured by conservation score) rather than the diversity of response against non-conserved epitopes correlates with effectiveness of vaccine-induced T cell responses. This hypothesis will be addressed in the following three Specific Aims: 1) To assess the effectiveness of T cells targeting conserved vs. variable HIV-1 epitopes to suppress viral replication in vitro, 2) To determine if T cells induced using conserved or mosaic immunogens will be activated in the context of natural HIV-1 infection and assess their ability to control viral replication; and 3) To determine if fragmentation of HIV immunogens will increase breadth of induced T cell response by increasing the pool of epitopes derived from defective ribosomal products (DRiPs). This proposal will utilize a novel in vitro priming assay to predict the epitope specificities that will be recognized by induced T cells upon vaccination with candidate vaccines. This assay could be used as a first screen of other candidate T cell based immunogens allowing only those candidates that show the most promise to move forward into more costly human clinical trials. The proposed studies have far reaching implications for design of T cell-based HIV vaccines. Determining whether effective anti-viral T cell responses induced by vaccination are due to (i) increasing the number of HIV-1 variants that are recognized or (ii) increasing specificity such that only conserved regions of HIV-1 are targeted (or both) will also have implications for the development of vaccines for other infectious organisms with high mutation rates e.g. Hepatitis C Virus (HCV).

描述（由申请人提供）： 当前的候选HIV-1疫苗诱导（i）具有受限广度的T细胞；即仅认识几个不同的表位； （ii）主要针对HIV-1的变量区域。此外，在急性HIV-1感染中，具有可变HIV-1表位的T细胞的个体比具有靶向保守的HIV-1表位的T细胞的个体更快地发展为疾病。这些数据支持这样的观点，即有效的基于T细胞的免疫原仅包含HIV-1的保守区域（保守的免疫原方法）。另一种方法（马赛克免疫原方法）是设计免疫原料以包括多种变体。这种方法基于这样的理论，即包含多种变体将使对更广泛的循环变体的响应产生响应，并可以针对共同逃生突变体启用免疫系统。该提案旨在检验以下假设：保护（按保护评分衡量），而不是针对非保存表位的反应多样性与疫苗诱导的T细胞反应的有效性相关。该假设将在以下三个具体目的中解决：1）评估靶向保守的T细胞与可变的HIV-1表位以抑制体外抑制病毒复制的有效性，2）确定使用保守或镶嵌性免疫剂诱导的T细胞在天然HIV-1感染和评估其控制能力的情况下会激活其诱导的T细胞。 3）为了确定HIV免疫原的碎片化是否会通过增加源自有缺陷的核糖体产物（滴水）的表位池来增加诱导的T细胞反应的广度。该建议将利用一种新型的体外启动测定法来预测用候选疫苗疫苗接种后诱导的T细胞识别的表位特异性。该测定法可以用作其他候选T细胞免疫原的第一个屏幕，仅允许那些表现出最有望进入更昂贵的人类临床试验的候选者。拟议的研究对基于T细胞的HIV疫苗的设计具有很大的影响。确定疫苗接种引起的有效抗病毒T细胞反应是否是由于（i）增加识别的HIV-1变体数量，或者（ii）增加特异性，因此仅针对HIV-1的保守区域（或两者）也将对其他高突变率的疫苗开发（或两者）都有意义。丙型肝炎病毒（HCV）。