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

诱导针对 HIV-1 Env 的 CD4 结合区的中和抗体

• 批准号: 8118542
• 负责人: Shan Lu
• 金额: $ 197.58万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-07 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118542
• 关键词: Induction; neutralizing; antibodies; targeting; CD4

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).

描述（由申请人提供）：该多项目Hivrad程序应用的总体目标是引起靶向主要HIV-1 Invelope（ENG）糖蛋白的CD4结合位点（CD4B）的中和抗体。该P01计划提案包括三个主要项目，以及两个核心，以支持主要项目的活动。以下是该计划的不同项目/核心中提出的重大活动的摘要。目标1：组织和管理一个高度互动和富有成效的研究团队（Core B）。目标2：了解HIV-1 R5 ENV中的变化如何影响鹿，中和和疫苗的发展（项目1）。 HIV-1 R5包膜在感染巨噬细胞的能力方面差异很大。我们建议研究巨噬细胞对巨噬细胞主义（MAC-Tropism）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CD4BS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）。 MAB将探测几个主要Envs的CD4BS抗原性，每个Envs具有其独特的生物学特征。我们将检查使用DMA Prime蛋白增强免疫方法的关键代表性ENV的高CD4BS抗原性和对CD4BS mAb介导的中和的高灵敏度是否会导致高免疫原性。目标4：研究受体结合位点作为HIV-1疫苗设计方法的修饰（项目3）。我们将测试特定的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及性的提高，以及这些保守位点的更大可及性是否会增强其作为免疫原的功能，以引起交叉反应性NAB反应。目标5：为ENV结构分析的主要项目提供支持，并研究新型抗原和抗原抗体相互作用的结构（核心A）。