Biomaterials and Nanovaccines

项目摘要/摘要 开发一种能够诱导保护性的广谱中和抗体的艾滋病毒疫苗将 要求制定改进的战略，以控制包膜靶抗原的抗原性和 佐剂可以通过激发足够/适当的T细胞帮助来推动高水平的亲和力成熟， 促进生发中心发育，并推动长寿浆细胞和记忆B细胞的分化 细胞以获得持久的反应。本P01计划特别关注膜-近端外膜 Gp41区域(MPER)作为几种广谱中和抗体的有效靶点，包括最近的 发现了10E8抗体，该抗体显示出高效力，但没有证据表明有自身反应。与 在Reinherz实验室(项目1)，我们最近开发了一种脂质体疫苗平台，用于传递 疏水的膜相关MPER片段，允许持久的、实质性的滴度来对抗这种糟糕的 免疫原肽将在正常小鼠中提高。基于这一有希望的初步数据和我们非常 脂质体表面抗原寡聚化状态在调节B细胞中作用的新发现 触发，我们在这里提出了一套互补的策略，旨在控制抗原性和 MPER序列的免疫原性，进一步促进TFH细胞发育和抗体亲和力成熟， 并促进体液反应的持久性。我们将与项目1密切合作，提供 脂质体疫苗和新型佐剂按需进行以结构为重点的研究，同时追求 更深入地了解抗原提呈、佐剂信号和辅助性T细胞分化如何影响 诱导针对HIV MPER序列的高亲和力抗体反应。我们的具体目标是(1) 确定MPER寡聚状态在MPER特异性B细胞和体液识别中的作用 免疫，(2)测试控制抗体接近MPER序列的角度的策略 展示在脂质体载体上，(3)开发触发刺痛的新型淋巴结靶向佐剂 有效的干扰素驱动的体液反应的途径，以及(4)测试直接调节的新型佐剂 辅助性T细胞中促进转铁蛋白分化和生发中心诱导的信号通路。什么时候 结合项目1中追求的结构进步，我们的目标是通过以下方式诱导广泛的中和抗体 以正确的配置呈现MPER序列以及适当的佐剂信号 促进MPER特异性B细胞的启动和亲和力成熟。

Project Summary/Abstract The development of a vaccine capable of eliciting protective broadly neutralizing antibodies against HIV will require the development of improved strategies to control the antigenicity of envelope target antigens and adjuvants that can drive high levels of affinity maturation by eliciting sufficient/appropriate T-cell help, promoting germinal center development, and drive differentiation of long-lived plasma cells and memory B- cells to obtain a durable response. This P01 program focuses particularly on the membrane-proximal external region (MPER) of gp41 as a validated target for several broadly neutralizing antibodies, including the recently discovered 10E8 antibody that exhibits high potency without evidence of autoreactivity. In collaboration with the Reinherz lab (Project 1), we have recently developed a liposomal vaccine platform for delivery of hydrophobic, membrane-associated MPER fragments that allows durable, substantial titers against this poorly immunogenic peptide to be raised in normal mice. Building on this promising preliminary data and our very recent discoveries regarding the role of antigen oligomerization state on liposome surfaces in regulating B-cell triggering, we propose here a set of complementary strategies aiming to control the antigenicity and immunogenicity of MPER sequences, further enhance Tfh cell development and antibody affinity maturation, and promote humoral response durability. We will work in close collaboration with Project 1, providing liposomal vaccines and novel adjuvants on demand for their structure-focused studies, while pursuing a deeper understanding of how antigen presentation, adjuvant signaling, and T helper cell differentiation impact induction of high-affinity antibody responses against the MPER sequence of HIV. Our specific aims are (1) To determine the role of MPER oligomerization state on recognition by MPER-specific B-cells and humoral immunity, (2) To test strategies for controlling the angle of approach of antibodies to MPER sequences displayed on liposomal vectors, (3) To develop novel lymph node targeted adjuvants triggering the STING pathway for potent interferon-driven humoral responses, and (4) To test novel adjuvants directly modulating signaling pathways in helper T-cells to promote Tfh differentiation and germinal center induction. When combined with the structural advances pursued in Project 1, we aim to elicit broadly neutralizing antibodies by presenting MPER sequences in a correct configuration together with appropriate adjuvant signals that will promote the priming and affinity maturation of MPER-specific B-cells.