Potentiation Immune Resp vs HIV vacc Modula Innate Resp

描述：（改编自申请人摘要）预防性治疗的成功 针对HIV感染的疫苗依赖于其引发有效的， 长期免疫反应。最近在小鼠模型中的研究表明， 引起急性感染全身性病毒感染， 和记忆免疫反应这凸显了探索 活感染诱导有效免疫应答的机制， 将这一原则应用于艾滋病毒疫苗接种策略。的主要差异 活感染和亚单位疫苗之间的差异包括高抗原负荷， 低水平抗原持久性的可能性。另一个主要区别是 肝脏感染诱导了一种强有力的先天反应， 疫苗没有。现在有越来越多的证据表明先天免疫反应 可能会影响适应性免疫反应的下游事件。我们开始 探索由活体感染引起的先天反应， 这些事件影响适应性反应的产生。我们发现I型糖尿病 在感染后早期诱导的干扰素在这两种疾病中都发挥了意想不到的作用， 调节早期先天性应答以及增强免疫原性 的疫苗。我们假设，类似的规则也可能适用于 产生针对HIV疫苗的免疫应答。这个项目的总体目标是 一项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，同时获得对先天决定因素的新见解 增强免疫原性，这也可以为其他艾滋病毒提供指导 疫苗接近。这一建议旨在利用第一类的作用， 干扰素增强对候选HIV/SIV疫苗的免疫记忆， 探索将我们通过啮齿动物获得的知识转化为 模型转化为恒河猴模型。具体而言，我们建议探讨 掺入产生I型干扰素（IFN α/β）的DNA的可行性 作为增强HIV/SIV免疫原性的遗传佐剂的构建体 疫苗。该方法将首先在小鼠模型中进行优化，然后在 在猕猴身上做了测试的规模、广度、持续时间和保护能力 针对HIV/SIV疫苗的免疫应答将使用新的 可用的高分辨率免疫学方法如MHC四聚体结合 和单细胞细胞因子测定。

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.