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

• 批准号: 8788494
• 负责人: TODD M ALLEN
• 金额: $ 246.18万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-07 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788494
• 关键词: AIDS/HIV problem; Address; Adjuvant; Animal Model; Animals; Antibody Response; 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 response; vaccine trial; vaccine-induced immunity; vector

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）：本P01计划项目资助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B细胞和T细胞抗HIV应答的诱导。虽然SIV感染的猕猴模型已被证明对HIV疫苗开发是非常宝贵的，但猕猴和人类宿主遗传学（例如MHC、TCR、BCR）之间的差异以及SIV和HIV之间的序列差异导致人类和猕猴对这些病原体的完全不同的病毒特异性应答。同样，人类HIV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善有希望的结果的能力。 调查结果。因此，我们研究，优化和翻译人类免疫体液和细胞免疫反应控制人类HIV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，我们确定最佳诱导人类这些精确类型反应的方法的能力也受到限制。该提案建立在研究人员在了解针对HIV的中和抗体和CD 8 + T细胞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的基础上。此外，它将这些努力转化为新开发的BLT（骨髓，肝脏，胸腺）人源化HIV感染小鼠模型，该模型有力地支持HIV感染，并概括了人类细胞和体液免疫应答，特异性和特征，这些特征对于准确定义免疫控制的相关性和引发保护性疫苗诱导免疫的方法至关重要。 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。人源化BLT小鼠模型的最新发展提供了独特的机会来探索针对HIV的免疫保护的相关性，并快速测试迭代疫苗设计方法以优化人类对HIV的反应。 项目1：优化针对HIV的CD 8 + T细胞疫苗应答 项目负责人（PL）：艾伦、托德M. 描述（如申请人所提供）：项目1旨在应用合理的方法来优化有效的CD 8 + T细胞对HIV的应答，利用病毒适应性约束来利用HIV序列进化和CD 8免疫优势等级的自然限制以及免疫应答的可塑性来阻断病毒逃逸途径。它还带来了高通量基因组测序的最新进展，以解决HIV的巨大序列多样性，同时应用新型和有效的基于纳米颗粒的疫苗佐剂系统。 最重要的是，它用于将识别的HIV免疫控制相关物转化为能够重现HIV感染以及人类HIV特异性免疫应答的新型人源化小鼠模型。因此，这项工作将首次直接研究人类（而不是恒河猴）对HIV（而不是SIV）的免疫反应，以确定这种保护的机制，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对HIV/AIDS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; 4）增加HIV抗原免疫原性的方法（例如，新的佐剂），和5）确定免疫细胞如何被动员到感染的入口，并将解决以下具体目标：目标1：表征人源化BLT小鼠模型中HIV特异性CD 8 + T细胞应答的幅度、动力学、特异性和功效，以促进HIV特异性疫苗免疫的研究。 目标二：确定疫苗接种是否可以克服天然CD 8 + T细胞免疫优势等级，以避免靶向“诱饵”CD 8表位，并诱导变异特异性CD 8 + T细胞应答。 目标三：确定通过新型纳米颗粒递送系统诱导强烈的粘膜归巢CD 8 + T细胞应答是否可以预防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来探索在能够支持HIV感染和安装人类HIV特异性类型应答的系统内通过细胞免疫应答对HIV的免疫保护的相关性。该模型还将使我们能够快速测试迭代疫苗设计方法，以进一步优化对HIV的细胞免疫反应。