Potentiation Immune Resp vs HIV vacc Modula Innate Resp

描述：(改编自申请者摘要)一种避孕药的成功 针对艾滋病毒感染的疫苗取决于它能否诱导出一种有效的和 长寿的免疫反应。最近对小鼠模型的研究表明， 导致急性感染的全身性病毒感染会导致强大的原发 和记忆免疫反应。这突显了探索 活体感染诱导有效免疫反应的机制 将这一原则应用于艾滋病毒疫苗接种战略。主要区别是 活体感染和亚单位疫苗之间的关系包括高抗原量和 低水平抗原性持续存在的可能性。另一个主要区别是 活体感染会引发强大的先天反应，而作为亚单位 疫苗不起作用。现在有越来越多的证据表明，先天免疫反应 可能影响获得性免疫反应的下游事件。我们开始了 探索活体感染引发的先天反应，并研究如何 这些事件影响适应性反应的产生。我们发现了I型 在感染后早期诱导的干扰素在这两种疾病中都扮演着意想不到的角色 调节早期先天反应，增强免疫原性 疫苗的价值。我们假设，类似的规则也可能适用于 产生对艾滋病毒疫苗的免疫反应。这个项目的总体目标是 努力是找到增强对艾滋病毒的初级和记忆反应的方法 疫苗，同时对内在决定因素有了新的见解 这增强了免疫原性，这也可以为其他艾滋病毒提供指导 疫苗即将问世。这项提议旨在利用第一类人的作用 干扰素增强针对候选HIV/SIV疫苗的免疫记忆和 探索将我们通过啮齿动物获得的知识转化为 把模特变成恒河猴模特。具体而言，我们建议探索 掺入产生DNA的I型干扰素(干扰素α/β)的可行性 增强HIV/SIV免疫原性的基因佐剂构建 疫苗。该方法将首先在小鼠模型中进行优化，然后 在猕猴身上进行了测试。其规模、广度、持续时间和保护能力 针对HIV/SIV疫苗的免疫反应将使用新的 现有的高分辨率免疫学方法，如MHC四聚体结合 单细胞细胞因子分析。

DESCRIPTION: (Adapted from Applicant's Abstract) The success of a prophylactic vaccine against HIV infection depends upon its ability to elicit a potent and long-lived immune response. Recent studies in murine models have shown that systemic viral infections, that cause acute infection, induce a robust primary and memory immune response. This highlights the urgency for exploring the mechanisms by which live infections induce efficient immune responses and for applying this principle to HIV vaccination strategies. The major differences between live infections and subunit vaccines include high antigenic load and the possibility of low-level antigenic persistence. Another major difference is that live infections induce a potent innate response, where as sub-unit vaccines do not. Now there is growing evidence that the innate immune responses may shape the downstream events of adaptive immune response. We started exploring the innate reactions elicited by live infections and examine how these events affect the generation of adaptive response. We found that type-I interferons, induced early after infection, play an unexpected role in both modulating the early innate responses as well as enhancing the immunogenicity of the vaccine. We hypothesize that similar rules may also govern the generation of immune response against HIV vaccines. The overall goal of this effort is to derive ways to enhance primary and memory responses against HIV vaccines, and at the same time gaining new insights into innate determinants that enhance immunogenicity which could also provide guide lines for other HIV vaccine approaches. This proposal is aimed at exploiting the role of type-I interferons in enhancing immune memory against candidate HIV/SIV vaccines and explores the possibility of translating our knowledge gained through rodent models into rhesus macaque models. Specifically we propose to explore the feasibility of incorporating type-I interferon (IFN alpha/beta) producing DNA constructs as genetic adjuvants for enhancing immunogenicity of HIV/SIV vaccines. The approach will first be optimized in murine models and then be tested in macaques. The magnitude, breadth, duration and protective ability of immune responses against HIV/SIV vaccines will be quantitated using newly available high-resolution immunological methods such as MHC tetramer binding and single cell cytokine assays.