Characterization of immunogenic and structural properties of HIV-1 envelope

全球迫切需要开发一种针对HIV-1的保护性疫苗。中和抗体(NAB)能有效预防HIV-1感染。然而，诱导对许多抗原性不同的HIV-1分离株产生广泛交叉反应的NAb一直是一个重大挑战，并且仍然是HIV-1疫苗开发的关键障碍。正在提议的研究的主要目标是产生能够引发这种NAB的新抗原，长期目标是开发针对该病毒的疫苗。 这一提议的基本假设是，只要免疫原结构完整，表位抗原性正确，我们就能够通过改变HIV-1包膜蛋白的抗原组成来增强关键表位的免疫原性，这些表位可以引发广泛的反应性NAB。为了验证这一假设，我们基于gp41膜近端外区(MPER)和gp120外区(Gp120OD)产生了原型抗原。这两种蛋白都是免疫原性的，可以诱导针对多个HIV-1初级分离株的NAb。我们的目标是利用当前和不断发展的对原型抗原的生化、结构和免疫原性的了解来设计能够诱导更强大的NAB的第二代抗原。拟议的研究是有重点的和假设驱动的，有明确定义的里程碑和时间表。拟议研究的成功完成将代表着朝着开发保护性艾滋病疫苗的方向取得的重大进展。 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，并评估它们的免疫原性。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基础设施，以支持财政监测。

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.