Targeting neutralizing epitopes in the MPER of HIV Env

靶向 HIV 包膜 MPER 中的中和表位

• 批准号: 8846024
• 负责人: CHINGLAI YANG
• 金额: $ 65.41万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-06 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846024
• 关键词: AIDS Vaccines; AIDS vaccine development; Achievement; Address; Adenoviruses; Adjuvant; Antibodies; Antibody Formation; Antigens; B-Lymphocytes; Binding Sites; Biological Markers; Cavia; Cell Separation; Cell surface; Chimeric Proteins; Cloning; DNA; Development; Drug Formulations; Epitope Mapping; Epitopes; Exhibits; Failure; Foundations; Frequencies; Genes; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV vaccine; Hemagglutinin; Immunization; Immunology; Infection; Influenza A virus; Knowledge; Mediating; Membrane; Modeling; Molecular Conformation; Monoclonal Antibodies; Nature; Peptides; Phenotype; Plasma; Production; Proteins; Public Health; Recombinants; Regimen; Replicon; Reporting; Research Personnel; Research Project Grants; SIV; Serum; Site; Structure; Surface; Testing; V3 Loop; Vaccination; Vaccine Adjuvant; Vaccine Design; Vaccine Research; Vaccines; Viral; base; compare effectiveness; design; env Gene Products; glycosylation; immunogenic; immunogenicity; improved; interdisciplinary approach; meetings; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; novel vaccines; prevent; protective efficacy; public health relevance; response; simian human immunodeficiency virus; success; vaccine development; vaccine-induced immunity; virology

DESCRIPTION (provided by applicant): The spread of HIV infection is a major threat to public health worldwide and the development of an effective vaccine strategy is of the highest significance. Currently, the greatest and most pressing challenge to AIDS vaccine research is to develop a vaccine strategy that can induce strong and broadly neutralizing antibodies (bNAbs) against HIV. We have assembled a team of investigators who possess specialized expertise in antigen design, B cell analysis, virology, and vaccine immunology to develop an effective vaccine strategy to induce bNAbs against the conserved epitopes in the membrane-proximal external region (MPER) of the HIV envelope glycoprotein (Env), which are targets for several potent and broadly neutralizing monoclonal antibodies against HIV. This collaborative effort will explore strategies to overcome major obstacles that hinder the induction of bNAbs against the MPER of the HIV Env. Specifically, we will explore different vaccine strategies to present the MPER in its neutralization-competent structure and investigate alternative approaches to overcome the weak antigenicity of MPER for inducing strong bNAbs against HIV. Building on our recent success in eliciting MPER-specific HIV NAbs by a HA/gp41 chimeric antigen and employing multidisciplinary approaches, we will: 1) modify vaccine design and develop new chimeric protein antigens to selectively augment induction of bNAbs against the conserved epitopes in the HIV Env MPER; 2) determine the targets of vaccine-induced MPER-specific neutralizing antibodies and modify vaccine design to selectively augment induction of such antibodies; and 3) optimize the immunization regimens and investigate the use of adjuvant for inducing strong neutralizing antibodies against MPER of the HIV Env. The successful development of these vaccine strategies will be of great significance for HIV vaccine development, and knowledge gained through these studies could also be applied to vaccine design against other conserved neutralizing epitopes in the HIV Env, which are very likely to be conformational sensitive, cryptic, and weakly immunogenic like the epitopes in the MPER.

描述（申请人提供）：艾滋病毒感染的传播是全球公共卫生的主要威胁，开发有效的疫苗策略具有最高的意义。目前，艾滋病疫苗研究面临的最大和最紧迫的挑战是开发一种疫苗策略，能够诱导针对艾滋病毒的强效和广泛中和抗体（bNAb）。我们组建了一支研究人员团队，他们在抗原设计、B 细胞分析、病毒学和疫苗免疫学方面拥有专业知识，以开发有效的疫苗策略，诱导针对 HIV 近膜外部区域 (MPER) 保守表位的 bNAb包膜糖蛋白 (Env)，它是几种有效且广泛中和的抗 HIV 单克隆抗体的靶标。这项合作将探索克服阻碍针对 HIV Env 的 MPER 诱导 bNAb 的主要障碍的策略。具体来说，我们将探索不同的疫苗策略，以具有中和能力的结构呈现 MPER，并研究替代方法来克服 MPER 的弱抗原性，从而诱导针对 HIV 的强 bNAb。基于我们最近通过 HA/gp41 嵌合抗原诱导 MPER 特异性 HIV NAb 的成功，并采用多学科方法，我们将：1) 修改疫苗设计并开发新的嵌合蛋白抗原，以选择性地增强针对 MPER 特异性 HIV NAb 的诱导。 HIV 包膜 MPER； 2) 确定疫苗诱导的 MPER 特异性中和抗体的靶标，并修改疫苗设计以选择性地增强此类抗体的诱导； 3)优化免疫方案并研究使用佐剂诱导针对HIV Env的MPER的强中和抗体。这些疫苗策略的成功开发将对HIV疫苗的开发具有重要意义，通过这些研究获得的知识也可以应用于针对HIV包膜中其他保守的中和表位的疫苗设计，这些表位很可能是构象敏感的、神秘的。 ，并且像 MPER 中的表位一样具有弱免疫原性。