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:
    8788494
  • 负责人:
  • 金额:
    $ 246.18万
  • 依托单位:
  • 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 2016-01-31
  • 项目状态:
    已结题

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计划项目赠款旨在优化疫苗引起的人类B细胞和T细胞反应,利用最近开发的BLT(骨髓,肝脏,胸骨)人性化小鼠模型,以抗HIV。尽管SLV感染的猕猴模型已被证明对HIV疫苗的发育而言是无价的,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,导致人类和对这些病原体的人类和麦克虫的完全不同的病毒反应。同样,人类艾滋病毒疫苗研究的成本和持续时间限制了迅速进行迭代研究的能力,以改善有希望的能力 发现。因此,我们研究,优化和翻译特定机制的能力,通过这种机制,人类免疫体液和细胞免疫反应控制人类的艾滋病毒,尤其是在免疫特异性方面,仍然受到限制,我们的能力也受到限制,我们鉴定出最能识别人类中这些精确反应类型的方法的能力也受到限制。该提案基于研究人员在理解针对HIV的中和抗体和CD8+ T细胞反应以及开发新型的纳米颗粒输送方法以诱导高水平粘膜归巢反应的方法的强大记录。此外,它将这些努力转化为新开发的BLT(骨髓,肝脏,胸腺)HIV感染的人源化小鼠模型,该模型强烈支持HIV感染,并概括了人类的细胞和体液免疫反应,特异性和特征,对于准确地定义了免疫控制和对免疫的相关性,以实现免疫的免疫接种效果。 相关性:了解HIV免疫控制的精确机制对于能够概括这些反应的有效HIV疫苗的开发至关重要。人性化BLT小鼠模型的最新发展提供了独特的机会,可以探索免疫保护抗HIV的相关性,并迅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CD8+ T细胞疫苗反应 项目负责人(PL):艾伦,托德·M。 描述(如申请人提供):项目1试图采用合理的方法来优化有效的CD8+ T细胞对艾滋病毒的反应,利用病毒适应性约束,以利用HIV序列演化的自然限制和CD8免疫质量层次结构以及对阻断病毒逃生途径的免疫反应的可变性。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,同时应用新颖且有效的基于纳米粒子的疫苗辅助系统。 最重要的是,它可以将艾滋病毒免疫控制的已鉴定的相关性转化为能够概括HIV感染以及人类HIV特异性免疫反应的Nove人性化小鼠模型。因此,这项工作将首次实现对艾滋病毒(而非SIV)的人类(不是恒河猴)免疫反应的直接研究,以定义这种保护的机制,并迭代地改善了疫苗的方法来优化这些作用。 项目1响应Hivrad计划的五个特定目标:1)识别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艾滋病毒的异质性; 3)改善动物模型系统(和挑战病毒)以解决疫苗功效; 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免疫力。 AIM 2:确定疫苗接种是否可以克服天然CD8+ T细胞免疫优势层次结构,以避免靶向“诱饵” CD8表位,并诱导变异特异性的CD8+ T细胞反应。 AIM 3:确定新型纳米粒子递送系统诱导强,粘膜含有CD8+ T细胞的反应是否可以防止BLT小鼠中HIV的早期全身传播。 相关性:新开发的人性化小鼠模型为探索能够支持HIV感染和安装人类HIV特异性类型反应的系统中的细胞免疫反应提供了独特的机会来探索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,以进一步优化细胞免疫反应对HIV。

项目成果

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TODD M ALLEN其他文献

TODD M ALLEN的其他文献

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{{ truncateString('TODD M ALLEN', 18)}}的其他基金

Development of Allogeneic CAR T Cell Therapy for a Functional Cure of HIV Infection
开发同种异体 CAR T 细胞疗法以功能性治愈 HIV 感染
  • 批准号:
    10480991
  • 财政年份:
    2022
  • 资助金额:
    $ 246.18万
  • 项目类别:
Development of Allogeneic CAR T Cell Therapy for a Functional Cure of HIV Infection
开发同种异体 CAR T 细胞疗法以功能性治愈 HIV 感染
  • 批准号:
    10581704
  • 财政年份:
    2022
  • 资助金额:
    $ 246.18万
  • 项目类别:
HCV Ghost Sequencing Center
HCV Ghost 测序中心
  • 批准号:
    10649195
  • 财政年份:
    2017
  • 资助金额:
    $ 246.18万
  • 项目类别:
Next-Generation Sequencing Center for GHOSTing Hepatitis C Virus: Transforming Community Based Molecular Surveillance and Outbreak Investigation
丙型肝炎病毒重影的下一代测序中心:改变基于社区的分子监测和疫情调查
  • 批准号:
    10241239
  • 财政年份:
    2017
  • 资助金额:
    $ 246.18万
  • 项目类别:
Leveraging Genetic Engineering Towards a Functional Cure of HIV Infection
利用基因工程实现艾滋病毒感染的功能性治愈
  • 批准号:
    8897540
  • 财政年份:
    2015
  • 资助金额:
    $ 246.18万
  • 项目类别:
Administrative and Biostatistics Core
行政和生物统计核心
  • 批准号:
    8492617
  • 财政年份:
    2013
  • 资助金额:
    $ 246.18万
  • 项目类别:
Animal and Laboratory Core
动物和实验室核心
  • 批准号:
    8492624
  • 财政年份:
    2013
  • 资助金额:
    $ 246.18万
  • 项目类别:
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:
    8994707
  • 财政年份:
    2013
  • 资助金额:
    $ 246.18万
  • 项目类别:
Optimizing CD8+ T Cell Vaccine Responses Against HIV
优化 CD8 T 细胞疫苗对 HIV 的反应
  • 批准号:
    8492547
  • 财政年份:
    2013
  • 资助金额:
    $ 246.18万
  • 项目类别:
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:
    8487593
  • 财政年份:
    2013
  • 资助金额:
    $ 246.18万
  • 项目类别:

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