Glycopeptide evolution targeting antibodies of the PGT128 lineage.

项目摘要/摘要 近年来对HIV+个体的广泛研究揭示了许多抗体的例子，这些抗体 可以中和广泛的HIV毒株，并在动物模型中保护免受病毒挑战 感染。现在已知病毒表面最常被这种抗体靶向的部分是 “高甘露糖贴片”：在产生广谱中和抗体的患者中，38%的患者瞄准了这一点 病毒的一个区域。最有效的高甘露糖片抗体之一，PGT128，与一个 高甘露糖的特殊排列和保守的多肽残基。我们的目标是发展 精确模拟这种排列并用于诱导类似PGT128的疫苗免疫原 抗体。 我们的方法将利用独特的定向进化方法来开发糖肽免疫原 正确重组了哪些PGT128表位元件。也有可能是额外的 将需要免疫原来通过刺激生殖系前体来正确启动免疫反应 PGT128。因此，我们将开发针对成熟和种系PGT128的糖肽 抗体。在斯克里普斯与David Nemazee的合作中，我们将调查这些 糖肽组合，激活生殖系PGT128反应，该反应可成熟为反应 具有广谱中和PGT128样的特异性。

Project Summary/Abstract Extensive study of HIV+ individuals in recent years has brought to light many examples of antibodies that can neutralize a broad range of HIV strains and protect against viral challenge in animal models of infection. The portion of viral surface most commonly targeted by such antibodies is now known to be the “high-mannose patch”: among patients producing broadly-neutralizing antibodies, 38% target this one region of the virus. One of the most potent high mannose patch antibodies, PGT128, binds to a particular arrangement of high-mannose glycans and conserved peptide residues. Our goal is to develop vaccine immunogens which mimic this arrangement precisely and be used to elicit PGT128-like antibodies. Our approach will utilize unique directed evolution methods to develop glycopeptide immunogens in which PGT128 epitope elements are correctly reconstituted. It is also possible that additional immunogens will be required to correctly prime the immune response by stimulating germline precursors of PGT128. Therefore, we will develop glycopeptides targeting both mature and germline PGT128 antibodies. In collaboration with David Nemazee at Scripps, we will investigate the ability of these glycopeptides in combination, to activate a germline PGT128 response that can mature into a response with broadly-neutralizing PGT128-like specificity.