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捉摸的目标。这种疫苗的一种有希望的方法 使用顺序免疫来指导B细胞受体（BCR）成熟。为此，第一个放大 特定类别的广泛中和抗体（BNABS）的未成熟的未成熟前体。这些 然后将前体BCR牧羊人使用越来越多的 本地env抗原。 VRC01-和V3-Glycan类的顺序免疫策略 正在开发BNAB。在这里，我们为使用相同的一般策略建立了基础 引起V2-Glycan/Apex抗体。 Apex BNAB具有使这种方法复杂化的属性 但最终使成功更有可能。具体而言，这些bnabs在很大程度上结合了Env 酸性和酪氨酸硫磺的重链CDR3区域。因此，较少的躯体需要很少 V3-Glycan和VRC01级BNAB的超毛体特征。但是，除了他们的长期 硫酸化的CDR3区域，Apex BNAB几乎没有区别特征。在这里，我们证明我们可以引起 使用抗磺胺酪氨酸抗体作为长酪氨酸硫化CDR3区域大鼠的抗体 抗原。我们建议优化这种方法并与寡聚形式的env trimers一起使用 引起抗Apex抗体。这些研究将开发一种可能更轻松的方法来产生 广泛而有效的抗HIV-1抗血清。