Epitope-Focused HIV-1 Envelope Vaccine for HIV-1/AIDS

针对 HIV-1/AIDS 的针对表位的 HIV-1 包膜疫苗

• 批准号: 8012619
• 负责人: IRWIN M CHAIKEN
• 金额: $ 25万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012619
• 关键词: AIDS Vaccines; AIDS vaccine development; Achievement; Acquired Immunodeficiency Syndrome; Adjuvant; Animal Model; Antibodies; Antigens; B-Lymphocytes; Binding; Binding Sites; CCR5 gene; CXCR4 gene; Capsid Proteins; Cell fusion; Cells; Complex; Development; Drug Formulations; Epitopes; Evaluation; Glycoproteins; Goals; HIV Envelope Protein gp120; HIV-1; HIV-1 vaccine; Human; Immune response; Immune system; Immunity; Immunization; Immunologic Surveillance; Lead; Learning; Ligands; Modeling; Molecular Conformation; Monoclonal Antibodies; Peptide Synthesis; Phase; Primates; Production; Protein Engineering; Proteins; Recombinant Proteins; Recombinants; Serum; Site; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Toxic effect; Vaccination; Vaccines; Viral; Viral Envelope Proteins; Virus; Virus-like particle; design; env Gene Products; flexibility; immunogenic; improved; inhibitor/antagonist; macrophage; neutralizing monoclonal antibodies; nonhuman primate; programs; public health relevance; receptor; receptor binding; three dimensional structure; tool

DESCRIPTION (provided by applicant): The overall goal of this project is to explore and advance structurally constrained forms of HIV-1 envelope (Env) protein for development of an HIV-1 vaccine. Formulations of viral envelope protein gp120 that could program the human immune system to recognize and block the HIV-1 envelope protein have been a major goal of AIDS vaccine development. However, gp120 has been found to be able to evade immune surveillance, due significantly to its conformational flexibility. Identifying approaches to induce increased structural stability, in particular by conserved epitope focusing, is seen as an important goal to improve the ability of envelope vaccines to elicit neutralizing immune responses. Recently, we have developed a set of molecules, called "allosteric dual site antagonists", that can bind strongly to the viral gp120 in such a way as to entrap gp120 in a three dimensional structure that is functionally suppressed but with an accessible CD4 Phe 43 binding pocket. We hypothesize that allosteric dual site antagonists can induce an altered immunogenic landscape in HIV-1 envelope protein, and that such an altered landscape can potentially lead to an enhanced neutralizing immune response against conserved receptor binding sites, including that for CD4. We will test this hypothesis in the R21 phase of this PIA project with 2 major aims. (R21-Aim1) Using recombinant protein engineering and peptide synthesis, we aim to produce HIV-1 Env immunogens in which allosteric dual site antagonists of the HNG-156 class are bound either noncovalently or covalently with recombinant trimeric and monomeric forms of HIV-1 gp120. (R21-Aim2) Using small animal models, we aim to test the hypothesis that vaccination of complexes and covalent fusions of allosteric gp120 inhibitors with recombinant trimeric and monomeric forms of HIV-1 gp120 will elicit enhanced anti-HIVgp120 specific antibody and T cell epitope breadth, magnitude and the neutralization capacity of B cells. The key milestone of the R21 project will be to demonstrate enhanced serum neutralization activities promoted by allosteric dual site antagonists of HIV-1 Env gp120. Achievement of this milestone will lead to an R33 development phase that includes identification of advanced immunogens with optimized compositions of HIV-1 Env bound noncovalently and covalently to allosteric inhibitors (R33-Aim1); testing of immunogens using a non-human primate model with mucosal challenge (R33- Aim2); and production of potential neutralizing monoclonal antibodies, elicited by Env -allosteric inhibitor immunogens, that will be characterized for Env binding epitopes and breadth of neutralization (R33-Aim3). Overall, this project will use epitope focusing through conformational constraint to learn how allosteric ligands can exert control over conformations of HIV-1 Env protein in an immunogenically productive way, identify neutralization sites in HIV-1 Env for protective immunity, develop Env constructs for non-human primate efficacy/toxicity evaluation, and advance immunogen formulations to primate and, ultimately, human trials. PUBLIC HEALTH RELEVANCE: This project seeks to test newly identified forms of the HIV-1 virus coat protein as tools for designing AIDS vaccines that could be used to provide immunoprotection in humans.

描述（由申请人提供）：该项目的总体目标是探索和推进HIV-1信封（INV）蛋白的结构约束形式，以开发HIV-1疫苗。可以对人免疫系统进行编程以识别和阻断HIV-1包膜蛋白的病毒包膜蛋白GP120的配方已成为AIDS疫苗开发的主要目标。但是，已经发现GP120能够逃避免疫监测，这是由于其构象的柔韧性而显着。识别诱导增加结构稳定性的方法，特别是通过保守的表位聚焦，被视为提高包膜疫苗引起中和免疫反应的能力的重要目标。最近，我们开发了一组称为“变构双位点拮抗剂”的分子，该分子可以与病毒GP120强烈结合，以使其在功能抑制但可访问的CD4 PHE 43结合口袋的三维结构中置于三维结构中。我们假设变构双位点拮抗剂可以诱导HIV-1包膜蛋白中的免疫原性景观改变，并且这种改变的景观可能会导致对保守受体结合位点的中和免疫反应增强，包括CD4。我们将在该PIA项目的R21阶段以2个主要目的来检验这一假设。 （R21-AIM1）使用重组蛋白工程和肽合成，我们旨在生产HIV-1 ENV免疫原子，其中HNG-156类的变构双位点拮抗剂与重组三聚体和HIV-1GP120的单体形式无偏或共价地结合。 （R21-AIM2）使用小动物模型，我们旨在检验以下假设：复合物的疫苗接种和变构GP120抑制剂与HIV-1 GP120的重组三聚体和单体形式的熔融融合，将降低抗HIVGP120特异性抗体和T细胞息肉的能力和中等的细胞，并具有抗HIV-1 GP120的形式。 R21项目的关键里程碑将是展示由HIV-1 Env120的变构双位点拮抗剂促进的增强的血清中和活性。 实现这一里程碑将导致R33发育阶段，其中包括鉴定具有优化的HIV-1 ENV成分的高级免疫原，无可比和共价为变构抑制剂（R33-AIM1）；使用粘膜挑战的非人类灵长类动物模型（R33- AIM2）测试免疫原子；以及由Env Allosteric抑制剂免疫原子引起的潜在中和单克隆抗体的潜在中和单克隆抗体的产生，这些抗体将以ENV结合表位和中和的广度为特征（R33 -AIM3）。 Overall, this project will use epitope focusing through conformational constraint to learn how allosteric ligands can exert control over conformations of HIV-1 Env protein in an immunogenically productive way, identify neutralization sites in HIV-1 Env for protective immunity, develop Env constructs for non-human primate efficacy/toxicity evaluation, and advance immunogen formulations to primate and, ultimately, human trials. 公共卫生相关性：该项目旨在测试新近确定的HIV-1病毒外套蛋白的形式，作为设计艾滋病疫苗的工具，可用于在人类中提供免疫保护。