Cleaved, stabilized HIV-1 Env trimers for structural and vaccine studies

总体摘要 本HIVRAD计划项目续签申请是根据PAR-18-319提出的。它包含两个研究 项目，一个科学核心和一个管理核心，由首席调查员John P. 摩尔博士(威尔·康奈尔医学院；WCMC)和联合首席调查员伊恩·A·威尔逊博士(The 斯克里普斯研究所；TSRI)。该项目的目标是进一步开发稳定的、可溶的、可裂解的三聚体 模拟天然环境蛋白刺激物(SOSIP三聚体)作为结构研究的抗原和作为免疫原 开发旨在诱导广谱中和抗体(BNAbs)的疫苗。 我们的中心假设是，一种蛋白质降解的、可溶的、三聚体形式的HIV-1env是一种 适用于高分辨率x射线结晶学和电子显微镜研究的结构抗原，以及 适合疫苗研究的免疫原，目的是诱导bNAbs。我们的意图是使用基于结构的 帮助开发有效的预防性HIV-1疫苗(或更复杂疫苗的组成部分)的信息 这是基于诱导足够效价的bNAbs的概念。我们认为，实现这一目标的一种方法 目标是使可溶的重组蛋白模拟存在于病毒粒子上的天然的三聚体Env尖峰， 它介导病毒进入细胞，是所有已知bNAb的靶标。SOSIP三聚体具有所需的 性能，并可以高效地生产，包括人类临床所需的数量和质量 审判。 这个HIVRAD项目团队在过去4年中取得了很好的进展，现在正在寻求支持 继续共同努力。其研究计划包括以下子部分。 项目1：John P.Moore(和Rogier W.Sanders)：SOSIP三聚体的设计 项目2：Ian A.Wilson(和Andrew B.Ward)：SOSIP三聚体的结构研究 核心B：PJ Klasse：SOSIP三聚体的生产 核心A：约翰·P·摩尔：行政支持 阿姆斯特丹阿姆斯特丹大学医学中心的Rogier W.Sanders将指导 项目1。 斯克里普斯研究所的安德鲁·B·沃德将是项目2的共同负责人。 以及HIVRAD团队的组成部分，我们建议维持和扩大广泛的 研究合作网络，我们将继续向 许多请求我们支持的科学家。

Overall Abstract This HIVRAD Program Project renewal application is made in response to PAR-18-319. It contains two Research Projects, one Scientific Core and an Administrative Core, under the direction of Principal Investigator, John P. Moore, PhD (Weill Cornell Medical College; WCMC) and co-Principal Investigator, Ian A. Wilson, PhD (The Scripps Research Institute; TSRI). The goal of the project is to further develop stable, soluble, cleaved trimeric mimics of the native Env spike (SOSIP trimers) as antigens for structural studies and as immunogens for the development of vaccines aimed at inducing broadly neutralizing antibodies (bNAbs). Our central hypothesis is that a proteolytically cleaved, soluble, trimeric form of HIV-1 Env is an appropriate structural antigen for high resolution x-ray crystallography and electron microscopy studies, and a suitable immunogen for vaccine research aimed at the induction of bNAbs. Our intent is to use structure-based information to help develop an effective, prophylactic HIV-1 vaccine (or component of a more complex vaccine) that is based on the concept of inducing sufficient titers of bNAbs. We believe that one way to accomplish this goal is to make soluble recombinant protein mimics of the native, trimeric Env spike that is present on virions, that mediates virus entry into cells and that is the target for all known bNAbs. SOSIP trimers have the desired properties and can be produced efficiently, including in the amounts and qualities required for human clinical trials. This HIVRAD project team has made excellent progress during the past 4 years, and now seeks support to continue to work together. Its research plan involves the following sub-components. Project 1: John P. Moore (and Rogier W. Sanders): Design of SOSIP trimers Project 2: Ian A. Wilson (and Andrew B. Ward): Structural studies of SOSIP trimers Core B: PJ Klasse: Production of SOSIP trimers Core A: John P. Moore: Administrative support Rogier W. Sanders of the Amsterdam University Medical Centers, Amsterdam will direct a sub-component of Project 1. Andrew B. Ward of The Scripps Research Institute will be the co-leader of Project 2. As well as the integral components of the HIVRAD team, we propose to maintain and expand an extensive network of research collaborations, and we will continue to provide SOSIP trimers and related reagents to the many scientists who request our support.