Induction of neutralizing antibodies targeting CD4 binding region of HIV-1 Env

描述(由申请人提供)：这个多项目HIVRAD计划应用的总体目标是诱导针对主要HIV-1包膜(Env)糖蛋白的CD4结合位点(CD4bs)的中和抗体。这份P01计划提案由三个重大项目组成，外加两个支持重大项目活动的核心。以下是该计划不同项目/核心中提议的主要活动的摘要。目标1：组织和管理一个高度互动和富有成效的研究团队(核心B)。目标2：了解HIV-1R5 env基因变异如何影响趋向性、中和性和疫苗开发(项目1)。HIV-1R5囊膜感染巨噬细胞的能力差异很大。我们建议研究巨噬细胞嗜性的变化对与Env相关的其他生物学特性的影响，包括中和敏感性。目标3：研究CD4b抗原性的变化如何影响原代Env蛋白的中和敏感性和免疫原性(项目2)。单抗将检测几组初级包膜病毒的CD4b抗原性，每组包膜病毒都有自己独特的生物学特性。我们将使用DMA Prime-Protein Boost免疫方法研究高CD4b抗原性和对CD4bs单抗介导的中和高敏感性是否会导致关键代表病毒的高免疫原性。目标4：研究受体结合位点的修饰作为HIV-1疫苗设计的一种方法(项目3)。我们将测试特定的多糖修饰引起的变化是否会导致受体结合部位保守表位的稳定性或可及性增加，以及这些保守表位的可及性是否会增强它们作为免疫原的功能，以引发交叉反应的NAB反应。目标5：为环境病毒结构分析和研究新抗原的结构以及抗原-抗体相互作用的主要项目提供支助(核心A)。

DESCRIPTION (provided by applicant): The overall objective of this multi-project HIVRAD program application is to elicit neutralizing antibodies that target the CD4 binding site (CD4bs) of primary HIV-1 envelope (Env) glycoproteins. This P01 program proposal consists of three major projects, plus two cores to support the activities of major projects. The following is a summary of major activities as proposed in different Projects/Cores of this program. Goal 1: To organize and manage a highly interactive and productive research team (Core B). Goal 2: To understand how the variation in HIV-1 R5 Envs affect tropism, neutralization and vaccine development (Project 1). HIV-1 R5 envelopes vary extensively in their capacity to infect macrophages. We propose to investigate the impact of variation in macrophage tropism (mac-tropism) on other biological properties associated with Env including neutralization sensitivity. Goal 3: To study how the variation of antigenicity of CD4bs will affect the neutralization sensitivity and immunogenicity of primary Env proteins (Project 2). The CD4bs antigenicity of several panels of primary Envs, each with their own unique biological features, will be probed by mAbs. We will examine whether high CD4bs antigenicity and high sensitivity to CD4bs mAb mediated neutralization will lead to high immunogenicity for key representative Env using the DMA prime-protein boost immunization approach. Goal 4: To study the modification of receptor binding site as an approach to HIV-1 vaccine design (Project 3). We will test whether changes resulting from specific glycan modifications will lead to increased stability or accessibility of conserved epitopes in the receptor binding site and whether greater accessibility of these conserved sites will enhance their function as immunogen to elicit cross-reactive NAb responses. Goal 5: To provide support to major projects on structure analysis of Env and to study the structure of novel antigens, and antigen-antibody interactions (Core A).