Eliciting tyrosine-sulfated neutralizing antibodies recognizing the Env apex

引发识别 Env 顶点的酪氨酸硫酸化中和抗体

• 批准号: 10013483
• 负责人: Michael R. Farzan
• 金额: $ 23.13万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-06 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013483
• 关键词: Abbreviations; Affinity; Antibodies; Antibody Diversity; Antigen Targeting; Antigens; B-Lymphocytes; Binding; Binding Sites; Characteristics; Data; Engineering; Epitopes; Foundations; Genes; Glycoproteins; Goals; HIV; HIV-1; HIV-1 vaccine; Hemocyanin; Human; Immune Sera; Immunization; Immunize; Immunoglobulin Somatic Hypermutation; Individual; Keyhole Limpet Hemocyanin; Knowledge; Light; Modeling; Mutation; Polysaccharides; Population; Property; Protein Family; Rattus; Receptors, Antigen, B-Cell; Side; Sulfate; Testing; Transferase; Vaccines; Wistar Rats; Work; base; complementarity-determining region 3; crosslink; design; disulfide bond; interest; nanoparticle; neutralizing antibody; nonhuman primate; novel strategies; prevent; protein-tyrosine sulfotransferase; scaffold; success; transmission process; tyrosine O-sulfate

PROJECT SUMMARY An effective HIV-1 remains an important but elusive goal. One promising approach to such a vaccine uses sequential immunization to guide B-cell receptor (BCR) maturation. To do so, one first amplifies immature unmutated precursors of a particular class of broadly neutralizing antibodies (bNAbs). These precursor BCR are then shepherded to recognize HIV-1 envelope glycoprotein (Env) using increasingly native Env antigens. Sequential immunization strategies for both VRC01- and V3-glycan-classes of bNAbs are being developed. Here we establish the foundations for using the same general strategy to elicit V2-glycan/apex antibodies. Apex bNAbs have properties that both complicate such an approach but ultimately make success more likely. Specifically these bNAbs bind Env largely through their long, acidic and tyrosine-sulfated heavy-chain CDR3 region. Thus there is less need for extensive somatic hypermutaion characteristic of V3-glycan and VRC01-class bNAbs. However, apart from their long sulfated CDR3 regions, apex bNAbs have few distinguishing features. Here we show that we can elicit antibodies in rats with long tyrosine-sulfated CDR3 regions using anti-sulfotyrosine antibodies as antigens. We propose to optimize this approach and use it in concert with oligomeric forms of Env trimers to elicit anti-apex antibodies. These studies will develop a potentially easier approach to generating broad and potent anti-HIV-1 antisera.

项目摘要 有效的HIV-1仍然是一个重要但难以实现的目标。一种有希望的疫苗方法 使用顺序免疫来引导B细胞受体（BCR）成熟。要做到这一点，首先要放大 特定类别的广泛中和抗体（bNAb）的未成熟的未突变的前体。这些 前体BCR然后被引导识别HIV-1包膜糖蛋白（Env）， 天然Env抗原。针对VRC 01-和V3-聚糖类的顺序免疫策略 BNAB正在开发中。在这里，我们建立了使用相同的一般策略的基础， 引发V2-聚糖/顶点抗体。Apex bNAb具有使这种方法复杂化的性质 但最终使成功更有可能。具体地说，这些bNAb主要通过它们的长， 酸性和酪氨酸硫酸化重链CDR 3区。因此，不太需要广泛的体细胞 V3-聚糖和VRC 01-类bNAb超突变特征。然而，除了他们的长期 在硫酸化的CDR 3区中，顶端bNAb具有很少的区别特征。这里我们展示了我们可以引出 使用抗磺基酪氨酸抗体， 抗原我们建议优化这种方法，并将其与Env三聚体的寡聚形式一起使用 来引发抗顶点抗体这些研究将开发一种潜在的更容易的方法来产生 广泛和有效的抗HIV-1抗血清。