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

描述（由申请人提供）：该多项目 HIVRAD 计划申请的总体目标是引发针对初级 HIV-1 包膜 (Env) 糖蛋白的 CD4 结合位点 (CD4bs) 的中和抗体。该 P01 计划提案由三个主要项目以及两个支持主要项目活动的核心组成。以下是本计划不同项目/核心中提议的主要活动的摘要。目标 1：组织和管理一支高度互动且富有成效的研究团队（核心 B）。目标 2：了解 HIV-1 R5 Env 的变异如何影响趋向性、中和作用和疫苗开发（项目 1）。 HIV-1 R5 包膜感染巨噬细胞的能力差异很大。我们建议研究巨噬细胞向性（mac-tropism）的变化对与 Env 相关的其他生物学特性（包括中和敏感性）的影响。目标 3：研究 CD4b 抗原性的变化如何影响初级 Env 蛋白的中和敏感性和免疫原性（项目 2）。几组初级包膜的 CD4bs 抗原性，每组都有其独特的生物学特征，将通过 mAb 进行探测。我们将使用 DMA 引发蛋白加强免疫方法检查高 CD4bs 抗原性和对 CD4bs mAb 介导的中和的高敏感性是否会导致关键代表性 Env 的高免疫原性。目标 4：研究受体结合位点的修饰作为 HIV-1 疫苗设计的方法（项目 3）。我们将测试由特定聚糖修饰引起的变化是否会导致受体结合位点中保守表位的稳定性或可接近性增加，以及这些保守位点的更大可接近性是否会增强它们作为免疫原的功能以引发交叉反应性 NAb 反应。目标5：为Env结构分析、新型抗原结构和抗原抗体相互作用研究等重大项目提供支持（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).