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结构受限形式的 HIV-1 包膜 (Env) 蛋白，以开发 HIV-1 疫苗。病毒包膜蛋白 gp120 的配方可以对人类免疫系统进行编程，以识别和阻断 HIV-1 包膜蛋白，这一直是艾滋病疫苗开发的主要目标。然而，gp120被发现能够逃避免疫监视，这主要归功于其构象灵活性。确定诱导结构稳定性增加的方法，特别是通过保守表位聚焦，被视为提高包膜疫苗引发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，它们可以与病毒 gp120 强烈结合，从而将 gp120 捕获在三维结构中，该结构在功能上受到抑制，但具有可接近的 CD4 Phe 43 结合口袋。我们假设变构双位点拮抗剂可以诱导 HIV-1 包膜蛋白免疫原性景观的改变，并且这种改变的景观可能会导致针对保守受体结合位点（包括 CD4 的）的中和免疫反应增强。我们将在 PIA 项目的 R21 阶段测试这个假设，有两个主要目标。 (R21-Aim1) 利用重组蛋白工程和肽合成，我们的目标是生产 HIV-1 Env 免疫原，其中 HNG-156 类变构双位点拮抗剂与 HIV-1 gp120 的重组三聚体和单体形式非共价或共价结合。 (R21-Aim2) 使用小动物模型，我们旨在测试以下假设：将变构 gp120 抑制剂与重组三聚体和单体形式的 HIV-1 gp120 复合物和共价融合疫苗接种，将引发增强的抗 HIVgp120 特异性抗体和 T 细胞表位宽度、大小以及 B 细胞的中和能力。 R21项目的关键里程碑将是证明HIV-1 Env gp120变构双位点拮抗剂促进的血清中和活性增强。 这一里程碑的实现将导致 R33 开发阶段，包括鉴定先进的免疫原，以及与变构抑制剂非共价和共价结合的 HIV-1 Env 的优化组合物 (R33-Aim1)；使用具有粘膜攻击的非人类灵长类动物模型来测试免疫原（R33-Aim2）；以及由Env变构抑制剂免疫原引发的潜在中和单克隆抗体的产生，其特征在于Env结合表位和中和广度（R33-Aim3）。 总体而言，该项目将通过构象约束使用表位聚焦来了解变构配体如何以免疫原性有效的方式对 HIV-1 Env 蛋白的构象进行控制，识别 HIV-1 Env 中的中和位点以实现保护性免疫，开发用于非人类灵长类动物功效/毒性评估的 Env 构建体，并将免疫原配方推进到灵长类动物并最终进行人体试验。 公共健康相关性：该项目旨在测试新发现的 HIV-1 病毒外壳蛋白形式，作为设计可用于为人类提供免疫保护的艾滋病疫苗的工具。