Tracking the evolutionary trajectory of neutralizing antibodies following BG505 SOSIP immunization

项目摘要/摘要 稳定的HIV-1包膜gp140三聚体，如BG505 SOSIP，提供了一个可行的平台来诱导保护性 中和抗体，可通过各种方法改进以诱导异源 中和的广度。BG505 SOSIP三聚体免疫诱导恒河猴保护性中和抗体 目前正在几个I期临床试验中进行测试，包括HVTN 137。在这里，我们将表演 深入研究以确定仅中和自体病毒的抗体和那些也具有 恒河猴BG505 SOSIP免疫过程中对异源病毒变异株的平行抑制作用 猕猴使用超低温保存的样本。然后我们将追踪这些病毒的抗体胚系前体 其他具有相同等位基因的免疫猕猴中的中和抗体，以了解为什么它们 有时无法开展这些活动。我们还将比较中和抗体的靶标 BG505 SOSIP免疫受试者对恒河猴模型中识别的那些反应。这个 HVTN 137试验也在使用不同佐剂的BG505 SOSIP，我们将调查这些 影响人体志愿者中和抗体的特异性。最后，我们将分离中和单抗 从选定的BG505 SOSIP免疫恒河猴和人类受试者的抗体比较 抗原识别的结构和生物物理性质。这些广泛的临床前和临床资源 与我们的多学科专业知识相结合，提供了一种新的环境，在其中解决阻碍 制定有效的艾滋病毒疫苗接种战略。如果成功，这些研究将阐明新的战略。 改进HIV-1三聚体包膜免疫原和佐剂。

PROJECT SUMMARY/ABSTRACT Stabilized HIV-1 envelope gp140 trimers such as BG505 SOSIP provide a viable platform to elicit protective neutralizing antibodies that can be improved upon through various approaches to induce heterologous neutralizing breadth. BG505 SOSIP trimer immunization elicits protective neutralizing antibodies in rhesus macaques and is now being tested in several phase I clinical trials, including HVTN 137. Here we will perform in-depth studies to determine how antibodies that neutralize only the autologous virus and those that also have activity against heterologous viral variants developed in parallel during BG505 SOSIP immunization of rhesus macaques using cryopreserved samples. We will then track the antibody germline precursors for these neutralizing antibodies in other immunized rhesus macaques that share the allele to understand why they sometimes failed to develop these activities. We will also compare the targets of the neutralizing antibody responses in BG505 SOSIP immunized human subjects to those recognized in the rhesus macaque model. The HVTN 137 trial is also administering BG505 SOSIP with different adjuvants and we will investigate how these impact neutralizing antibody specificities in the human volunteers. Finally, we will isolate neutralizing monoclonal antibodies from selected BG505 SOSIP immunized rhesus macaques and human subjects to compare the structural and biophysical properties of antigen recognition. These extensive pre-clinical and clinical resources combined with our multidisciplinary expertise provides a novel setting in which to address barriers that impede the development of effective HIV vaccination strategies. If successful, these studies will illuminate new strategies to improve upon HIV-1 trimer envelope immunogens and adjuvants.