RNA DELIVERY FOR DENDRITIC CELL HIV ANTIGEN PREVENTION

但前提是。 与全世界的艾滋病作斗争，迫切需要一种安全有效的艾滋病毒疫苗。同时， 免疫保护的相关性还没有明确的定义，无论是保护性疫苗还是治疗性疫苗，它都是广泛的 认为CD4*和CD8细胞以及体液免疫都很重要。有多宽泛， 能否引发有效和持久的反应尚未确定，这代表着我们的关键算法 了解如何产生一种有效的预防措施，确保能够实现保护性免疫。树突状细胞 (DC)代表先天免疫和获得性免疫之间的接口，是最有效和最重要的 因此，我们一直在关注操纵DC的新方法 以开发其在抗HIV免疫反应中的潜在作用。一种最新开发的，特别是 利用抗原编码的信使核糖核酸(MRNAs)感染DC是一种很有前途的方法。为此，我们开发了 一种新的、高效的树突状细胞mRNA负载方法，并利用该方法最大化树突状细胞的免疫 响应生成能力。在我们的初步研究中，我们已经表明编码抗原负载的DC的mRNAs 都能引发两种CD4 CD8反应。此外，抗原编码的信使核糖核酸可以直接感染 并产生初级和次级T细胞和B细胞免疫反应。此外，我们的试点数据表明 除了提供一种抗原递送方式外，RNA还具有激活DC的独特内在能力。我们的 假设基于rna的树突状细胞抗原递送提供了一种独特的灵活和有效的方法。 对于免疫，可以操纵RNA递送的机制来调节应答的类型 产生的(包括助手免疫、细胞毒性免疫和体液免疫)，并且这种方法可以被用于 艾滋病疫苗的开发。这项提议的目的是为了更好地理解RNA 编码的抗原由DC处理，定义了特定的抗原提呈途径可能通过的因素 以RNA编码的抗原为靶点，并建立治疗艾滋病毒有效性的概念验证证据。我们预计这将是 工作将增强我们对DC免疫功能的理解，使我们能够差异化地操纵特定的元素 在免疫反应中，并最终允许我们利用编码抗原的信使核糖核酸产生树突状细胞 潜在的保护和治疗目的的免疫反应，除了为 合理开发HIV疫苗，我们希望这些研究也能提供 这是疫苗开发的新途径。

PROVIDED. A safe andeffectivevaccinefor HIV is criticallyneededto combatthe worldwidescourgeof AIDS. Whilethe correlatesof immuneprotectionhave yet to be clearlydefined,eitherforprotectiveor therapeuticvaccines,it is widely believed that both CD4* and CD8 cell as well as humoralimmunityare all important. How sufficientlybroad, potent,and sustainedresponsescan be elicitedhas yet to be determined,and this representsa criticalgap in our understandingof howto generatean effectivevaccinesuchthat protectiveimmunitycan be achieved. Dendriticcells (DC) representthe interfacebetween innate and adaptiveimmunityand are amongthe most potentand important componentsin generatingimmune responses.Therefore,we havefocusedon novelapproachesto manipulatingDC in order to exploit their potential role in anti-HIV immune responses. One recently developed and particularly promising approach to priming DC is using transfection of antigen encoded mRNA. Towards this end, we developed a novel, high-efficiency method of loading DC with mRNA, and utilized this approach to maximize DC immune response generation capacity. In our preliminary studies, we have shown that mRNA encoding antigen-loaded DC are able to elicit both CD4 CD8 responses. In addition, antigen-encoded mRNA can be directly iniected into mice and generate both primary and secondary T and B cell immune responses. Furthermore, our pilot data suggest that in addition to providing a mode of antigen delivery, RNA has a unique intrinsic ability to activate DC. Our hypotheseis is that RNA-based dendritic cell antigen delivery offers a uniquely flexible and potent approach to immunization, that the mechanism of RNA delivery can be manipulated to regulate the types of response generated (including helper, cytotoxic and humoral immunity), and that this approach can be exploited for the development of HIV vaccines. The aim of this proposal is to better understand the mechanisms by which RNA encoded antigen is processed by DC, define the factors by which specific antigen presentation pathways may be targeted by RNA-encoded antigen, and establish proof-of-concept evidence for efficacy in HIV. We anticipate that this work will enhance our understanding of DC immune function, enable us to differentially manipulate specific elements in the immune response, and, ultimately, allow us to exploit mRNA encoded antigen loaded dendritic cell-generated immune responses for potentially protective and therapeutic purposes, in addition to providing a foundation for the rational development of a now._lapproach to HIV vaccine development, it is our hope that these studies may also offer a new avenuefor vaccine development in general.