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

总体摘要 本HIVRAD计划项目更新申请是为了响应PAR-18-319。它包含两个研究 项目，一个科学核心和一个行政核心，在首席研究员，约翰P。 摩尔博士（威尔康奈尔医学院; WCMC）和共同首席研究员伊恩A.威尔逊博士（The Wilson，PhD） Scripps研究所; TSRI）。该项目的目标是进一步开发稳定的，可溶的，切割的三聚体 天然Env刺突（SOSIP三聚体）的模拟物作为抗原用于结构研究和作为免疫原用于 开发旨在诱导广泛中和抗体（bNAb）的疫苗。 我们的中心假设是，HIV-1 Env的蛋白水解切割的可溶性三聚体形式是一种免疫缺陷病毒。 用于高分辨率X射线晶体学和电子显微镜研究的适当结构抗原，以及 用于旨在诱导bNAb的疫苗研究的合适的免疫原。我们的目的是使用基于结构的 有助于开发有效的预防性HIV-1疫苗（或更复杂疫苗的组成部分）的信息 其基于诱导足够滴度的bNAb的概念。我们相信实现这一目标的一个方法 目的是制备存在于病毒体上的天然三聚体Env刺突的可溶性重组蛋白模拟物， 它介导病毒进入细胞，是所有已知bNAb的靶点。SOSIP三聚体具有所需的 这些化合物具有良好的生物学特性，并且可以有效地生产，包括人类临床所需的量和质量。 审判 这个艾滋病毒防治项目小组在过去4年中取得了很大进展，现在寻求支持 继续合作其研究计划包括以下子组成部分。 项目1：约翰P.摩尔（和罗吉尔W. Sanders）：SOSIP三聚体的设计 项目2：Ian A.威尔逊（和安德鲁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：John P.摩尔：行政支助 罗吉尔·W阿姆斯特丹大学医学中心的桑德斯将指导 项目1。 安德鲁B。斯克里普斯研究所的沃德将担任项目2的联合领导人。 除了HIVRAD小组的组成部分外，我们建议维持和扩大一个广泛的 研究合作网络，我们将继续提供SOSIP三聚体和相关试剂， 许多科学家请求我们的支持

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.