Structure and Immunogenicity of Cleaved, Stabilized HIV-1 Envelope Trimers

描述(由申请人提供)：这一HIVRAD计划融合了领先的HIV-1研究人员的互补专业知识，以提供比引发广泛中和抗体(NAB)更好的HIV-1疫苗的根本性进展。这一创新项目包括两个研究项目：艾滋病毒-1环境疫苗设计(约翰·摩尔博士，康奈尔大学)和艾滋病毒-1三聚体结晶学(伊恩·威尔逊博士，斯克里普斯研究所)。这些项目得到了科学和行政核心的支持(威廉·奥尔森博士，后代制药公司)。该计划利用我们最近在产生稳定的、蛋白水解性成熟的gp140三聚体(SOSIP Gp140)方面的成功，在拓扑和抗原性上模拟病毒粒子相关的环境蛋白。作为免疫原，SOSIP三聚体在动物体内诱导NAB方面优于匹配的gp120。在HIVRAD中，SOSIP模板将被定制用于结构研究和进一步改善动物的免疫原性。我们HIVRAD的总体目标反映在三个主要里程碑中：1)在4A分辨率下确定切割的环境三聚体的结构，2)展示克服HIV-1环境病毒免疫抑制特性的方法，以及3)发现一种能够诱导不同HIV-1毒株的异源中和的SOSIP三聚体疫苗。鉴于目前对三聚体结构的基本知识，原子水平的观点有可能刺激新一代合理设计的Env疫苗的开发，我们对结晶SOSIP三聚体的初步研究为成功提供了高度的热情和谨慎的乐观情绪。平行研究将评估已被修改的SOSIP三聚体，以改善NAB表位的呈现和/或消除Env免疫抑制特征。动物免疫原性研究将与体外研究相补充，比较修饰和未修饰形式的Env在人类DC中诱导免疫抑制反应的能力。除了主要项目和核心，HIVRAD还包括其他领先的学术和企业合作者，他们在疫苗交付(Aldevron，Inc.)、NAB分析(Mongraph Biosciences)、NAB特异性分析(James Binley博士)、体外免疫原性研究(VaxDesign)和探索性免疫遗传学(Sunil Ahuja博士)等领域提供专业知识。我们的共同目标是克服关键的结构和免疫学挑战，开发成功的基于环境的艾滋病毒-1疫苗。

DESCRIPTION (provided by applicant): This HIVRAD program merges the complementary expertise of leading HIV-1 researchers in order to provide a fundamental advance towards an HIV-1 vaccine than can elicit broadly neutralizing antibodies (NAbs). This innovative program comprises two Research Projects: HIV-1 Env Vaccine Design (Dr. John Moore, Cornell University) and HIV-1 Trimer Crystallography (Dr. Ian Wilson, The Scripps Research Institute). The Projects are supported by scientific and administrative Cores (Dr. William Olson, Progenies Pharmaceuticals). This program leverages our recent successes in generating stable, proteolytically mature gp140 trimers (SOSIP gp140s) that mimic virion-associated Env in topology and antigenicity. As immunogens, SOSIP trimers have proven to be superior to matched gp120s in eliciting NAbs in animals. In the HIVRAD, the SOSIP template will be tailored for structural studies and for further improvements in immunogenicity in animals. Our overall goals of the HIVRAD are reflected in three major milestones: 1) determine the structure of cleaved env trimers at <4A resolution, 2) demonstrate methods to overcome HIV-1 Env's immunosuppressive properties, and 3) identify a SOSIP trimer vaccine that elicits heterologous neutralization of diverse HIV-1 isolates. Given the present rudimentary knowledge of trimer structure, an atomic-level view has the potential to spur development of a new generation of rationally designed Env vaccines, and our preliminary studies on crystallizing SOSIP trimers provide high enthusiasm and guarded optimism for success. Parallel studies will evaluate SOSIP trimers that have been modified so as to improve presentation of NAb epitopes and/or remove Env immunosuppressive features. Animal immunogenicity studies will be complemented with in vitro studies that compare modified and unmodified forms of Env for their ability to elicit immunosuppressive responses in human DCs. In addition to the primary Projects and Cores, the HIVRAD includes additional leading academic and corporate collaborators who lend specialized expertise in the areas of vaccine delivery (Aldevron, Inc.), NAb analyses (Monogram Biosciences), NAb specificity analyses (Dr. James Binley), in vitro immunogenicity studies (VaxDesign), and exploratory immunogenetics (Dr. Sunil Ahuja). Our shared goal is to overcome key structural and immunological challenges to developing a successful Env-based HIV-1 vaccine.