Characterization of immunogenic and structural properties of HIV-1 envelope

全球迫切需要开发针对HIV-1的保护性疫苗。中和抗体（Nabs）可以有效预防HIV-1感染。然而，诱导对许多抗原多样性HIV-1分离株具有广泛交叉反应性的Nab一直是一个重大挑战，它仍然是HIV-1疫苗开发的关键障碍。这些研究的主要目标是产生能够引发这种Nab的新型抗原，长期目标是开发针对该病毒的疫苗。 该提议的基本假设是，我们将能够通过改变HIV-1包膜蛋白的抗原组成来增强可以引发广泛反应性Nab的关键表位的免疫原性，只要免疫原在结构上是完整的并且表位在抗原性上是正确的。为了验证这一假设，我们已经产生了基于gp 41膜近端外部区域（MPER）和gp 120外部结构域（gp 120 OD）的原型抗原。这两种蛋白质都具有免疫原性，可以引发针对多种主要HIV-1分离株的Nab。我们的目标是利用目前和不断发展的理解的原型抗原的生化，结构和免疫原性，以设计第二代抗原，可以诱导更有效的Nab。拟议的研究是重点突出和假设驱动的，有明确界定的里程碑和时间表。成功完成拟议的研究将是在研制艾滋病保护性疫苗方面取得的重大进展。 拟议的研究计划包括两个项目和一个核心：项目1的作用是设计亚单位包膜抗原，生产它们，并评估其免疫原性。项目2的作用是确定抗原的高分辨率结构，目的是促进抗原设计过程和了解其免疫学特性。行政核心负责提供组织管理和维护支持财政监测的基础设施。

There is a global urgency to develop a protective vaccine against HIV-1. Neutralizing antibodies (Nabs) can provide effective prophylaxis against HIV-1 infections. However, eliciting Nabs that are broadly cross-reactive against many antigenically diverse HIV-1 isolates has been a major challenge and it remains a critical roadblock to HIV-1 vaccine development. The primary objective of the studies being proposed is to generate novel antigens that are able to elicit such Nabs, with a long-term goal of developing a vaccine against the virus. The underlying hypothesis of this proposal is that we will be able to enhance immunogenicity of key epitopes that can elicit broadly reactive Nabs by altering the antigenic composition of HIV-1 envelope protein, as long as the immunogen is structurally intact and the epitopes are antigenically correct. To test this hypothesis, we have generated prototypic antigens based on gp41 membrane-proximal external region (MPER) and gp120 outer domain (gp120OD). Both proteins are immunogenic and can elicit Nabs against multiple primary HIV-1 isolates. Our goal is to use current and evolving understanding of biochemical, structural and immunogenic properties of the prototypic antigens to design second-generation antigens that could induce even more potent Nabs. The proposed studies are focused and hypothesis-driven, with clearly defined milestones and timelines. Successful completion of the proposed studies would represent a major advancement towards developing a protective AIDS vaccine. The proposed research Program consists of two Projects and one Core: The role of Project 1 is to design subunit envelope antigens, to produce them, and to evaluate their immunogenic properties. The role of Project 2 is to determine high-resolution structures of the antigens with a goal of facilitating the antigen design process and understanding of their immunological properties. The Administrative Core is responsible for providing the organizational management and maintaining infrastructure to support the fiscal monitoring.