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: 8513885
• 负责人: Shan Lu
• 金额: $ 202.66万
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8513885
• 关键词: Affect; Antibodies; Antigens; Binding; Binding Sites; Biological; Epitopes; Glycoproteins; Goals; HIV-1; Immunization; Lead; Mediating; Modification; Polysaccharides; Program Research Project Grants; Property; Proteins; Research; Site; Structure; Testing; Tropism; Vaccine Design; Variant; env Gene Products; immunogenicity; macrophage; neutralizing antibody; novel; programs; receptor binding; response; vaccine development

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（由申请方提供）：该多项目HIVRAD项目申请的总体目标是引发靶向HIV-1主要包膜（Env）糖蛋白的CD 4结合位点（CD 4 bs）的中和抗体。本P01计划建议书包括三个主要项目，以及两个支持主要项目活动的核心。以下是本计划不同项目/核心中提出的主要活动的摘要。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-1 R5 Envs的变异如何影响嗜性、中和和疫苗开发（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嗜性（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CD 4 bs抗原性的变化如何影响一级Env蛋白的中和敏感性和免疫原性（项目2）。将通过mAb探测几组原代Env的CD 4 bs抗原性，每种Env都有自己独特的生物学特征。我们将使用DMA初免-蛋白加强免疫方法检查高CD 4 bs抗原性和对CD 4 bs 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）。我们将测试由特异性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增加，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，以引发交叉反应性NAb应答。目标5：为Env结构分析、新抗原结构和抗原抗体相互作用研究（核心A）等重大项目提供支持。

项目成果

Structural Analysis of the Glycosylated Intact HIV-1 gp120-b12 Antibody Complex Using Hydroxyl Radical Protein Footprinting.

• DOI: 10.1021/acs.biochem.6b00888
• 发表时间: 2017-02-21
• 期刊: Biochemistry
• 影响因子: 2.9
• 作者: Li X;Grant OC;Ito K;Wallace A;Wang S;Zhao P;Wells L;Lu S;Woods RJ;Sharp JS
• 通讯作者: Sharp JS

Contribution of TLR4 and MyD88 for adjuvant monophosphoryl lipid A (MPLA) activity in a DNA prime-protein boost HIV-1 vaccine.

• DOI: 10.1016/j.vaccine.2014.07.010
• 发表时间: 2014-09-03
• 期刊: Vaccine
• 影响因子: 5.5
• 作者: Pouliot K;Buglione-Corbett R;Marty-Roix R;Montminy-Paquette S;West K;Wang S;Lu S;Lien E
• 通讯作者: Lien E

The dynamics of immunoglobulin V-gene usage and clonotype expansion in mice after prime and boost immunizations as analyzed by NGS.

通过 NGS 分析小鼠初免和加强免疫后免疫球蛋白 V 基因使用和克隆型扩展的动态。

• DOI: 10.1080/21645515.2017.1379638
• 发表时间: 2017
• 期刊: Human vaccines & immunotherapeutics
• 影响因子: 4.8
• 作者: Farfán-Arribas,DiegoJ;Liu,Shuying;Wang,Shixia;Lu,Shan
• 通讯作者: Lu,Shan

A cGAS-Independent STING/IRF7 Pathway Mediates the Immunogenicity of DNA Vaccines.

• DOI: 10.4049/jimmunol.1501836
• 发表时间: 2016-01-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Suschak JJ;Wang S;Fitzgerald KA;Lu S
• 通讯作者: Lu S

Functional and Structural Characterization of Human V3-Specific Monoclonal Antibody 2424 with Neutralizing Activity against HIV-1 JRFL.

具有抗 HIV-1 JRFL 中和活性的人 V3 特异性单克隆抗体 2424 的功能和结构表征。

• DOI: 10.1128/jvi.01280-15
• 发表时间: 2015
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Kumar,Rajnish;Pan,Ruimin;Upadhyay,Chitra;Mayr,Luzia;Cohen,Sandra;Wang,Xiao-Hong;Balasubramanian,Preetha;Nádas,Arthur;Seaman,MichaelS;Zolla-Pazner,Susan;Gorny,MiroslawK;Kong,Xiang-Peng;Hioe,CatarinaE
• 通讯作者: Hioe,CatarinaE