Glycopeptide-specific helper T cells eliciting protective humoral immunity against HIV - Resubmission

项目总结/摘要 艾滋病毒一直是人类健康的主要威胁，迄今尚未研制出保护性艾滋病疫苗。 设计可重复诱导中和和非中和保护性抗体产生的策略 通过接种疫苗产生抗体是阻止艾滋病毒传播的一个高价值目标。然而，设计 目前这一代疫苗中的大多数没有利用免疫系统激活机制， 使关键免疫细胞的刺激最大化（即，辅助性T细胞）参与产生保护性抗体。一 艾滋病疫苗研究需要新的视角。在这里，我们提出了一种创新的方法， 建立一种新的范式的潜力，即人CD 4 + T细胞库包含一群 碳水化合物特异性T细胞（即，Tcarbs）识别gp 120的N-聚糖屏蔽。HIV-1的表面是 用一种称为gp 120的高度糖基化的包膜蛋白修饰，它与CD 4分子相互作用， 是病毒进入CD 4 + T细胞的关键步骤。利用这种Tcarbs及其聚糖的发现， 表位，我们可以设计和开发基于知识的新一代HIV疫苗， 和持久的适应性免疫反应，以保护免受艾滋病毒。我们假设Tcarbs的招募将 不仅诱导T细胞增殖和记忆，而且还将诱导产生保护性的、高亲和力的 通过亲和力成熟和抗体类别转换等机制，由B细胞产生抗体。我们认为 我们提出的研究将产生一个平台，开发新一代的保护性未来艾滋病毒疫苗。

PROJECT SUMMARY/ABSTRACT HIV has been a major threat to human health and a protective AIDS vaccine has not as yet been developed. Designing strategies for reproducibly inducing the production of neutralizing and non-neutralizing protective antibodies through vaccination has been a high-value target for halting the spread of HIV. However, the design of the current generation of vaccines does not make use of immune system activation mechanisms to maximize stimulation of critical immune cells (i.e., helper T cells) involved in producing protective antibodies. A new perspective to HIV vaccine research is much needed. Here, we propose an innovative approach with the potential of establishing a new paradigm that the human CD4+ T cell repertoire contains a population of carbohydrate-specific T cells (i.e., Tcarbs) that recognize the N-glycan shield of gp120. The HIV-1 surface is decorated with a heavily glycosylated envelope protein called gp120, whose interaction with the CD4 molecule is the key step for the virus’s entry into CD4+ T cells. Using the discovery of such Tcarbs and their glycan epitopes, we can design and develop knowledge-based, new-generation HIV vaccines that will elicit a strong and long lasting adaptive immune response to protect from HIV. We hypothesize that recruitment of Tcarbs will not only induce T cell proliferation and memory, but will also induce production of protective, high-affinity antibodies by B cells through mechanisms such as affinity maturation and antibody class-switch. We believe our proposed studies will yield a platform to develop a new-generation of protective future HIV vaccines.