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

切割、稳定的 HIV-1 包膜三聚体的结构和免疫原性

• 批准号: 7867916
• 负责人: WILLIAM C OLSON
• 金额: $ 278.12万
• 依托单位: PROGENICS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7867916
• 关键词: Structure; Immunogenicity; Cleaved; Stabilized; HIV

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.

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疫苗提供根本性的进步，而不是引发广泛中和抗体（NAb）。该创新项目包括两个研究项目：HIV-1 Env疫苗设计（John摩尔博士，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）。这些项目得到了科学和行政核心（William Olson博士，Progenies Pharmaceuticals）的支持。该计划利用了我们最近在产生稳定的、蛋白水解成熟的gp 140三聚体（SOSIP gp 140 s）方面的成功，该三聚体在拓扑结构和抗原性上模拟病毒体相关的Env。作为免疫原，SOSIP三聚体已被证明在动物中诱导NAb方面上级匹配的gp 120。在HIVRAD中，将定制SOSIP模板用于结构研究和进一步改善动物免疫原性。我们的HIVRAD的总体目标反映在三个主要里程碑中：1）确定<4 A分辨率的切割的env三聚体的结构，2）证明克服HIV-1 Env的免疫抑制特性的方法，和3）鉴定增强不同HIV-1分离株的异源中和的SOSIP三聚体疫苗。鉴于目前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三聚体的初步研究提供了高度的热情和谨慎的乐观。平行研究将评估已经修饰的SOSIP三聚体，以改善NAb表位的呈递和/或去除Env免疫抑制特征。动物免疫原性研究将补充体外研究，比较修饰和未修饰形式的Env在人DC中引发免疫抑制应答的能力。除了主要的项目和核心之外，HIVRAD还包括其他领先的学术和企业合作者，他们在疫苗交付领域提供专业知识（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）。我们的共同目标是克服关键的结构和免疫挑战，以开发成功的基于Env的HIV-1疫苗。