Optimizing CD8+ T Cell Vaccine Responses Against HIV

优化 CD8 T 细胞疫苗对 HIV 的反应

基本信息

批准号：
8492547
负责人：
TODD M ALLEN
金额：
$ 40.2万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-07 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8492547
关键词：
AIDS/HIV problem Address Adenoviruses Adjuvant Alleles Animal Model B-Lymphocytes Biological Models Bone Marrow CD8B1 gene Cells Cellular Immunity Controlled Study Cytomegalovirus DNA Data Development Dose Epitopes Evolution Frequencies Gagging Genetic Genomics HIV HIV Antigens HIV Infections HIV vaccine Heterogeneity Homing Human Humoral Immunities Immune Immune response Immunity Immunologics Infection Instruction Kinetics Lipids Liver Macaca Macaca mulatta Mediating Membrane Memory Micelles Modeling Mus Mutation Pathway interactions Regimen SIV Site Specificity System T cell response T-Lymphocyte Testing Thymus Gland Time Translating Translational Research Ursidae Family Vaccination Vaccine Adjuvant Vaccine Design Vaccines Variant Viral Viremia Virus Work base cost fitness immunogenicity impaired capacity improved lymph nodes mouse model nanocapsule nanoparticle novel prevent programs protective effect response vaccine development vaccine efficacy vector

项目摘要

Project 1 seeks to apply a rational approach to the optimization of an effective CD8+ T cell response to HIV, capitalizing on viral fitness constraints to exploit the natural limits of HIV sequence evolution and CD8 immunodominance hierarchies and the plasticity of the immune response to block viral escape pathways. It also brings to bear recent advances in high throughput genomic sequencing to tackle the enormous sequence diversity of HIV, while applying novel and potent nanoparticle-based vaccine adjuvant systems. Most importantly, it serves to translate identified correlates of immune control of HIV into a novel humanized mouse model capable of recapitulating HIV infection as well as human HIV-specific immune responses. Thus, this work will enable for the first time the direct study of human (not rhesus monkey) immune responses against HIV (not SIV) in order to define the mechanisms of this protection and interatively improve vaccine approaches to optimize these effects. Project 1 responds to five specific objectives of the HIVRAD Program: 1) Identifying correlates of vaccineinduced immune protection to HIV/AIDS; 2) How vaccine design can better address the heterogeneity of HIV; 3) Improved animal model systems (and challenge viruses) to address vaccine efficacy; 4) Approaches to increase the immunogenicity of HIV antigens (e.g., novel adjuvants), and 5) Determining how immune cells can be mobilized to the portal of infection, and will address the following specific aims: Aim 1: Characterize the magnitude, kinetics, specificity and efficacy of HIV-specific CD8+ T cell responses in the humanized BLT mouse model to facilitate studies of HIV-specific vaccine immunity. Aim 2: Determine whether vaccination can overcome natural CD8+ T cell immunodominance hierarchies to avoid targeting of 'decoy' CD8 epitopes, and induce variant-specific CD8+ T cell responses. Aim 3: Determine whether the induction of strong, mucosal-homing CD8+ T cell responses by novel nanoparticle delivery systems can prevent the early systemic dissemination of HIV in BLT mice.

项目 1 寻求应用合理的方法来优化 CD8+ T 细胞对 HIV 的有效反应，利用病毒适应度限制来利用 HIV 序列进化和 CD8 的自然限制免疫优势层次和阻止病毒逃逸途径的免疫反应的可塑性。它还带来了高通量基因组测序的最新进展，以解决巨大的问题 HIV 的序列多样性，同时应用新颖且有效的基于纳米颗粒的疫苗佐剂系统。最重要的是，它有助于将已确定的 HIV 免疫控制相关性转化为新型人源化药物小鼠模型能够重现艾滋病毒感染以及人类艾滋病毒特异性免疫反应。因此，这项工作将首次能够直接研究人类（而非恒河猴）免疫针对 HIV（而非 SIV）的应对措施，以确定这种保护机制并交互改进疫苗方法可以优化这些效果。项目 1 响应 HIVRAD 计划的五个具体目标： 1) 确定疫苗诱导的相关性对艾滋病毒/艾滋病的免疫保护； 2）疫苗设计如何更好地解决疫苗的异质性艾滋病病毒; 3）改进动物模型系统（和挑战病毒）以解决疫苗功效问题； 4）方法增加 HIV 抗原的免疫原性（例如新型佐剂），以及 5) 确定免疫效果细胞可以被动员到感染门户，并将实现以下具体目标：目标 1：表征 HIV 特异性 CD8+ T 细胞反应的强度、动力学、特异性和功效人源化 BLT 小鼠模型，以促进 HIV 特异性疫苗免疫的研究。目标 2：确定疫苗接种是否可以克服天然 CD8+ T 细胞免疫优势等级避免靶向“诱饵”CD8 表位，并诱导变体特异性 CD8+ T 细胞反应。目标 3：确定新型药物是否能诱导强烈的粘膜归巢 CD8+ T 细胞反应纳米颗粒输送系统可以防止 BLT 小鼠体内 HIV 的早期全身传播。