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

项目摘要/摘要 艾滋病毒一直是对人类健康的主要威胁，迄今尚未开发出保护性艾滋病疫苗。 可重复地诱导中和和非中和保护产生的设计策略 通过接种疫苗产生的抗体一直是阻止艾滋病毒传播的高价值目标。然而，该设计 的疫苗没有利用免疫系统激活机制来 最大限度地刺激与产生保护性抗体有关的关键免疫细胞(即辅助T细胞)。一个 迫切需要从新的角度来研究艾滋病毒疫苗。在这里，我们提出了一种创新的方法， 建立一种新的范例的可能性，即人类CD4+T细胞谱系包含一个 识别gp120的N-糖膜的碳水化合物特异性T细胞(即T细胞)。HIV-1表面是 装饰着一种被称为gp120的高度糖基化的包膜蛋白，它与CD4分子相互作用 是病毒进入CD4+T细胞的关键一步。利用这种糖类及其多糖的发现 表位，我们可以设计和开发基于知识的新一代艾滋病毒疫苗，这将引发强大的 和持久的适应性免疫反应，以保护免受艾滋病毒感染。我们假设TCAB的招募将会 不仅能诱导T细胞的增殖和记忆，还会诱导产生保护性的、高亲和力的 B细胞通过亲和力成熟和抗体类型转换等机制产生抗体。我们相信 我们提议的研究将为开发新一代保护性未来艾滋病毒疫苗提供一个平台。

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.