Glycoantigen evolution targeting antibodies of the PGT 128 lineage

项目总结/摘要 近年来对HIV+个体的广泛研究揭示了许多抗体的例子， 可以中和广泛的HIV毒株，并在动物模型中保护免受病毒攻击。 感染现在已知病毒表面最常被此类抗体靶向的部分是 “高甘露糖斑块”：在产生广泛中和抗体的患者中，38%的人以此为目标。 病毒的一个区域。最有效的高甘露糖补丁抗体之一PGT 128结合于一种 高甘露糖聚糖和保守肽残基的特殊排列。我们的目标是开发 疫苗免疫原，其精确模拟这种排列，并用于引发PGT 128样 抗体的 我们的方法将利用独特的定向进化方法来开发糖免疫原， PGT 128表位元件正确重构。另外的免疫原也可能 需要通过刺激PGT 128的生殖系前体来正确引发免疫应答。 因此，我们将开发靶向成熟和生殖系PGT 128抗体的糖肽。在 与Scripps的大卫·内马齐合作，我们将研究这些糖肽在 组合，以激活生殖系PGT 128应答，所述生殖系PGT 128应答可以成熟为具有广泛免疫应答的应答。 中和PGT 128样特异性。

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 glycoimmunogens 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.