Optimizing CD8+ T Cell Vaccine Responses Against HIV

项目1试图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开发HIV序列进化和CD8的自然极限 免疫优势等级和免疫反应的可塑性，以阻断病毒逃逸途径。它 也带来了高通量基因组测序的最新进展，以应对巨大的 艾滋病毒的序列多样性，同时应用新的和有效的纳米颗粒疫苗佐剂系统。 最重要的是，它有助于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性化 能够概括HIV感染以及人类HIV特异性免疫反应的小鼠模型。 因此，这项工作将首次使直接研究人类(不是恒河猴)免疫成为可能。 对艾滋病毒(不是SIV)的反应，以确定这种保护的机制并以互动的方式改进 优化这些效果的疫苗方法。 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因素 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 艾滋病毒；3)改进动物模型系统(和挑战病毒)，以解决疫苗效力问题；4)方法 提高HIV抗原(如新型佐剂)的免疫原性，以及5)确定如何免疫 细胞可以被动员到感染的门户，并将解决以下具体目标： 目的1：研究HIV特异性CD8+T细胞应答的大小、动力学、特异性和有效性。 人源化的BLT小鼠模型，以促进艾滋病毒特异性疫苗免疫的研究。 目的2：确定疫苗接种是否可以克服自然的CD8+T细胞免疫优势等级 避免以“诱饵”CD8表位为靶标，并诱导变异型特异性CD8+T细胞反应。 目的3：确定新诺明是否能诱导强烈的粘膜归巢CD8+T细胞反应 纳米颗粒递送系统可以防止艾滋病毒在BLT小鼠体内的早期系统性传播。

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.