Optimizing Human B and T Cell Vaccines Against HIV Using Humanized BLT Mice

使用人源化 BLT 小鼠优化针对 HIV 的人类 B 和 T 细胞疫苗

基本信息

批准号：
8616335
负责人：
TODD M ALLEN
金额：
$ 246.52万
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/8616335
关键词：
AIDS/HIV problem Address Adjuvant Animal Model Animals Antibody Formation Antigens Autologous Avidity B-Lymphocytes Biological Models Bone Marrow CD34 gene CD4 Positive T Lymphocytes CD8B1 gene Cells Cellular Immunity Characteristics Communicable Diseases Complement Development Epitopes Evolution Generations Genetic Genomics HIV HIV Antigens HIV Infections HIV vaccine Helper-Inducer T-Lymphocyte Hematopoietic stem cells Heterogeneity Homing Human Humoral Immunities Immune Immune response Immune system Immunity Immunization Immunology Implant Infection Infection prevention Instruction Kinetics Lipids Liver Macaca Macaca mulatta Membrane Micelles Modeling Mus Pathway interactions Peptide Vaccines Phenotype Program Research Project Grants Proteins Records Research Personnel SIV Site Specificity Structure of germinal center of lymph node System T cell response T-Cell Depletion T-Lymphocyte Testing Thymic Tissue Thymus Gland Time Translating Transplantation Ursidae Family Vaccination Vaccine Adjuvant Vaccine Design Vaccines Variant Viral Viremia Virus Work arm base cost data modeling design fetal fitness immunogenicity improved lymph nodes mouse model mucosal site nanocapsule nanoparticle neutralizing antibody novel pathogen prevent programs response vaccine development vaccine efficacy vaccine-induced immunity vector

项目摘要

DESCRIPTION (provided by applicant): This P01 Program Project Grant is focused on optimizing the induction of vaccine-elicited human B cell and T cell responses against HIV utilizing the recently developed BLT (bone marrow, liver, thymus) humanized mouse model. While the SlV-infected macaque model has proven invaluable to HIV vaccine development, differences between macaque and human host genetics (e.g. MHC, TCR, BCR), as well as sequence differences between SIV and HIV, results in entirely distinct virus-specific responses in humans and macaques to these pathogens. Similarly, the cost and duration of HIV vaccine studies in humans limits the ability to rapidly conduct iterative studies to improve upon promising findings. As such, our ability to study, optimize and translate specific mechanisms by which human immune humoral and cellular immune responses control HIV in humans, especially with respect to immune specificity, remains restricted, as does our ability to identify approaches to best induce these precise types of responses in humans. This proposal builds on the investigators' strong track records in understanding neutralizing antibody and CD8+ T cell responses against HIV, and in developing novel nanoparticle delivery approaches to induce high levels of mucosal homing responses. Moreover, it translates these efforts into a newly developed BLT (bone marrow, liver, thymus) humanized mouse model of HIV infection that robustly supports HIV infection, and recapitulates human cellular and humoral immune responses, specificities, and characteristics critical to accurately defining the correlates of immune control and approaches to elicit protective vaccine-induced immunity. RELEVANCE: Understanding the precise mechanisms of immune control of HIV will be critical to the development of an effective HIV vaccine capable of recapitulating these responses. The recent development of the humanized BLT mouse model provides the unique opportunity to explore the correlates of immune protection against HIV and rapidly test iterative vaccine design approaches to optimize human responses to HIV. Project 1: Optimizing CD8+ T Cell Vaccine Responses Against HIV Project Leader (PL): Allen, Todd M. DESCRIPTION (as provided by applicant): Project 1 seeks to apply a rational approach to the optimization of an effective CD8+ T cell response to HIV, capitalizing on viral fitness constraint 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 nove 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 iteratively improve vaccine approaches to optimize these effects. Project 1 responds to five specific objectives of the HIVRAD Program: 1) Identifying correlates of vaccine-induced 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. RELEVANCE: The newly developed humanized mouse model provides the unique opportunity to explore the correlates of immune protection of HIV by cellular immune responses within a system capable of supporting HIV infection and mounting human HIV-specific type responses. This model will also enable us to rapidly test iterative vaccine design approaches to further optimize cellular immune responses to HIV.

描述（由申请人提供）：该 P01 计划项目拨款的重点是利用最近开发的 BLT（骨髓、肝脏、胸腺）人源化小鼠模型，优化疫苗诱导的人类 B 细胞和 T 细胞针对 HIV 的反应。虽然SIV感染的猕猴模型已被证明对HIV疫苗的开发非常有价值，但猕猴和人类宿主遗传学之间的差异（例如MHC、TCR、BCR）以及SIV和HIV之间的序列差异导致了完全不同的病毒特异性反应人类和猕猴对这些病原体。同样，人类艾滋病毒疫苗研究的成本和持续时间限制了快速进行迭代研究以改进有希望的能力的能力发现。因此，我们研究、优化和转化人类免疫体液和细胞免疫反应控制人类艾滋病毒的特定机制的能力，特别是在免疫特异性方面，仍然受到限制，我们识别最佳诱导这些精确类型的方法的能力也受到限制。人类的反应。该提议建立在研究人员在了解中和抗体和 CD8+ T 细胞针对 HIV 的反应以及开发新型纳米颗粒递送方法以诱导高水平粘膜归巢反应方面的良好记录基础上。此外，它将这些努力转化为新开发的 HIV 感染 BLT（骨髓、肝脏、胸腺）人源化小鼠模型，该模型有力地支持 HIV 感染，并概括了对于准确定义相关性至关重要的人类细胞和体液免疫反应、特异性和特征免疫控制和引发保护性疫苗诱导免疫的方法。相关性：了解 HIV 免疫控制的精确机制对于开发能够重现这些反应的有效 HIV 疫苗至关重要。最近开发的人源化 BLT 小鼠模型为探索 HIV 免疫保护的相关性和快速测试迭代疫苗设计方法以优化人类对 HIV 的反应提供了独特的机会。项目 1：优化 CD8+ T 细胞疫苗对 HIV 的反应项目负责人 (PL)：Allen, Todd M. 描述（由申请人提供）：项目 1 寻求采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 免疫优势层次结构的自然限制以及可塑性阻止病毒逃逸途径的免疫反应。它还带来了高通量基因组测序的最新进展，以解决 HIV 巨大的序列多样性问题，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，它可以将已确定的 HIV 免疫控制相关性转化为新型人源化小鼠模型，该模型能够重现 HIV 感染以及人类 HIV 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）针对 HIV（而非 SIV）的免疫反应，以确定这种保护机制，并迭代改进疫苗方法以优化这些效果。项目 1 响应 HIVRAD 计划的五个具体目标： 1) 确定疫苗诱导的免疫保护与艾滋病毒/艾滋病的相关性； 2）疫苗设计如何更好地解决HIV的异质性； 3）改进动物模型系统（和挑战病毒）以解决疫苗功效问题； 4) 提高 HIV 抗原免疫原性的方法（例如新型佐剂），以及 5) 确定如何将免疫细胞动员到感染门户，并将解决以下具体目标：目标 1：表征规模、动力学、人源化 BLT 小鼠模型中 HIV 特异性 CD8+ T 细胞反应的特异性和功效，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 细胞免疫优势层次，以避免靶向“诱饵”CD8 表位，并诱导变体特异性 CD8+ T 细胞反应。目标 3：确定新型纳米颗粒递送系统诱导强烈的粘膜归巢 CD8+ T 细胞反应是否可以预防 BLT 小鼠中 HIV 的早期全身传播。相关性：新开发的人源化小鼠模型提供了独特的机会，可以在能够支持 HIV 感染并产生人类 HIV 特异性类型反应的系统内，通过细胞免疫反应来探索 HIV 免疫保护的相关性。该模型还将使我们能够快速测试迭代疫苗设计方法，以进一步优化针对 HIV 的细胞免疫反应。