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

描述（由申请人提供）：该 HIVRAD 计划融合了领先的 HIV-1 研究人员的互补专业知识，以便为 HIV-1 疫苗提供比可引发广泛中和抗体（NAb）的根本性进步。该创新计划包括两个研究项目：HIV-1 包膜疫苗设计（John Moore 博士，康奈尔大学）和 HIV-1 三聚体晶体学（Ian Wilson 博士，斯克里普斯研究所）。这些项目得到科学和行政核心（Progenies Pharmaceuticals 的 William Olson 博士）的支持。该计划利用了我们最近在生成稳定、蛋白水解成熟的 gp140 三聚体 (SOSIP gp140s) 方面取得的成功，该三聚体在拓扑结构和抗原性方面模仿病毒粒子相关的 Env。作为免疫原，SOSIP 三聚体已被证明在动物体内引发 NAb 方面优于匹配的 gp120。在 HIVRAD 中，SOSIP 模板将针对结构研究和进一步提高动物免疫原性进行定制。我们的 HIVRAD 总体目标体现在三个主要里程碑中：1）以 <4A 分辨率确定切割的 env 三聚体的结构，2）展示克服 HIV-1 Env 免疫抑制特性的方法，以及 3）确定可引发不同 HIV-1 分离株异源中和的 SOSIP 三聚体疫苗。鉴于目前对三聚体结构的基本了解，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，并且我们对结晶SOSIP三聚体的初步研究提供了高度的热情和对成功的谨慎乐观。平行研究将评估经过修饰的 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，这些研究比较修饰和未修饰形式的 Env 在人类 DC 中引发免疫抑制反应的能力。除了主要项目和核心之外，HIVRAD 还包括其他领先的学术和企业合作者，他们在疫苗递送 (Aldevron, Inc.)、NAb 分析 (Monogram 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) 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，成功开发基于 Env 的 HIV-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.