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

描述(由申请人提供)：本P01计划资助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细胞对HIV的反应。虽然SLV感染的猕猴模型已被证明对HIV疫苗的开发具有重要价值，但猕猴与人类宿主遗传学(如MHC、TCR、BCR)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产生完全不同的病毒特异性反应。同样，人类艾滋病毒疫苗研究的成本和持续时间限制了快速进行迭代研究以改进前景的能力。 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，我们识别最佳地在人类中诱导这些精确类型反应的方法的能力也是有限的。这一建议建立在研究人员在了解中和抗体和CD8+T细胞对艾滋病毒的反应，以及开发新的纳米颗粒递送方法以诱导高水平的粘膜归巢反应方面的良好记录。此外，它将这些努力转化为新开发的BLT(骨髓、肝脏、胸腺)人源化的HIV感染小鼠模型，该模型有力地支持了HIV感染，并概括了人类细胞和体液免疫反应、特异性和特征，这些反应、特异性和特征对于准确定义免疫控制的相关性和诱导保护性疫苗诱导免疫的方法至关重要。 相关性：了解艾滋病毒免疫控制的精确机制对于开发能够概括这些反应的有效艾滋病毒疫苗至关重要。人源化BLT小鼠模型的最新发展为探索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细胞疫苗对艾滋病毒的反应 项目负责人(PL)：Allen，Todd M. 描述(由申请人提供)：项目1寻求应用一种合理的方法来优化有效的CD8+T细胞对艾滋病毒的反应，利用病毒适应性限制来利用艾滋病毒序列进化和CD8免疫优势等级的自然限制以及免疫反应的可塑性来阻断病毒的逃逸途径。它还带来了高通量基因组测序的最新进展，以应对艾滋病毒巨大的序列多样性，同时应用新的和有效的基于纳米颗粒的疫苗佐剂系统。最重要的是，它将已确定的艾滋病毒免疫控制相关因素转化为一种新的人源化小鼠模型，能够概括艾滋病毒感染和人类艾滋病毒特异性免疫反应。因此，这项工作将首次直接研究人类(不是恒河猴)对HIV(不是SIV)的免疫反应，以确定这种保护的机制，并反复改进疫苗方法，以优化这些效果。项目1响应HIVRAD计划的五个具体目标：1)确定疫苗诱导的对艾滋病毒/艾滋病的免疫保护的相关因素；2)疫苗设计如何更好地解决艾滋病毒的异质性；3)改进动物模型系统(和挑战病毒)以解决疫苗效力问题；4)提高HIV抗原(如新型佐剂)免疫原性的方法，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：目的1：在人源化的BLT小鼠模型中表征HIV特异性CD8+T细胞反应的大小、动力学、特异性和有效性，以促进HIV特异性疫苗免疫的研究。目的2：确定疫苗接种能否克服天然的CD8+T细胞免疫优势等级，避免以“诱饵”CD8表位为靶标，诱导变异型特异性CD8+T细胞应答。目的：确定新型纳米颗粒递送系统诱导强烈的粘膜归巢CD8+T细胞反应是否能阻止HIV在BLT小鼠体内的早期系统性传播。 相关性：新开发的人源化小鼠模型提供了独特的机会，通过在能够支持艾滋病毒感染的系统中通过细胞免疫反应来探索艾滋病毒免疫保护的相关性，并建立人类艾滋病毒特异性类型反应。该模型还将使我们能够快速测试迭代疫苗设计方法，以进一步优化对艾滋病毒的细胞免疫反应。

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.