Understanding the mechanism(s) of systemic antibody delivery, distribution, and localization to mucosal sites in the in vivo macaque model

到目前为止，尽管由于抗逆转录病毒和其他生物医学药物，与艾滋病毒相关的死亡人数正在下降 干预措施，仍然缺乏针对艾滋病毒的疫苗。最近，人们对这一问题越来越感兴趣 利用广谱中和抗体(BNAbs)作为疫苗策略，已被证明结合 在非人类灵长类动物模型中灭活慢病毒颗粒。不仅有对bNAb被动迁移的研究 恒河猴证明了对慢病毒感染的保护作用，但也导致了第一个bNAb 人体临床试验，抗体介导的保护(AMP)研究。尽管这些都是英勇的努力， 阻止艾滋病毒感染，目前仍不清楚这些抗体是如何传递到艾滋病毒感染的粘膜部位 就会发生传播。更好地了解这些抗体是如何在解剖上分布的 在努力开发预防艾滋病毒感染的疫苗方面有很大的影响。为了实现这一目标 目的：我一直致力于开发一种新的平台来跟踪体内荧光标记的抗体。 恒河猴活体模型。到目前为止，利用这项技术，我已经揭示了抗体可以 在输液后大约一周达到稳定状态--这一观察结果可能具有一定的意义 正在进行的AMP试验。此外，我还观察到bNAb在组织驻留细胞中的独特定位。 那些在艾滋病毒传播和发病机制中很重要的区域，如直肠和阴道粘膜以及大脑。 基于这些初步数据，我建议在目标1中确定抗体运输和 使用体内非人灵长类动物模型进行定位。在目标2中，我将描述(S)的机制 全身应用后，抗体与不同解剖部位的特定组织驻留细胞相关联。 最后，在目标3中，我将使用前两个目标的数据来确定抗体亚类是否会影响组织 运输和本地化。总体而言，这一奖项对于实现这些目标是不可或缺的，以理解 抗体分布和定位事件背后的机理和基础科学基础。有了这个 机会，再加上托马斯·霍普博士和罗纳德·维兹博士提供的指导，我可以开始 解开如何将保护性抗体传递到涉及艾滋病毒传播的部位的复杂性 和发病机制。这一知识对于推动疫苗开发的努力至关重要 能够提供免受艾滋病毒感染的保护，特别是在粘膜部位。此外，培训 阐明这些机制的机会对我作为一名研究人员的发展非常宝贵，因为它 也将为我提供重要的技能和未来的实验，我可以将其发扬光大 独立。

To date, although the number HIV-related deaths are on the decline due to antiretroviral and other biomedical interventions, there is still a vaccine lacking for HIV. Recently, there has been increased interest in the utilization of broadly neutralizing antibodies (bNAbs) as a vaccine strategy, which have been illustrated to bind and inactivate lentiviral particles in non-human primate models. Not only have bNAb passive transfer studies in rhesus macaques demonstrated protection against lentiviral infection, but have also led to the first bNAb human clinical trial, the Antibody Mediated Protection (AMP) study. Although these are valiant efforts towards blocking HIV infection, it is still unknown how these antibodies are delivered to mucosal sites where HIV transmission occurs. Gaining a better understanding of how these antibodies are anatomically distributed will have a great impact in the effort to develop a vaccine to prevent HIV acquisition. In order to accomplish this objective, I have been working to develop a novel platform to track fluorescently labeled antibodies in the in vivo rhesus macaque model. To date, utilizing this technique, I have revealed that antibodies take approximately one week to reach a steady state after infusion — an observation that could have implications for the ongoing AMP trial. Additionally, I have observed unique bNAb localization within tissue resident cells in those areas important in HIV transmission and pathogenesis, such as the rectal and vaginal mucosa, and brain. Based on these preliminary data, I propose in Aim 1 to identify the mechanisms of antibody transport and localization using the in vivo nonhuman primate model. In Aim 2, I will characterize the mechanism(s) of antibody association with specific, tissue resident cells at distinct anatomical sites after systemic application. Finally, in Aim 3, I will use the data from the first two aims to determine if antibody subclass influences tissue transport and localization. Overall, this award is integral to the completion of these aims in understanding the foundation of the mechanistic, basic science behind antibody distribution and localization events. With this opportunity, combined with the mentorship provided by Dr. Thomas Hope and Dr. Ronald Veazey, I can start to unravel the complexities of how protective antibodies are delivered to those sites involved in HIV transmission and pathogenesis. This knowledge is critical to advance the effort in the development of a vaccine that is able to provide protection from HIV infection, especially at mucosal sites. Additionally, the training opportunities to elucidate these mechanisms are extremely valuable to my development as a researcher, as it will also provide me with an important skillset and future experimentation that I can carry forward to academic independence.