A participant-derived xenograft mouse model to study T-cell-mediated viral control and mRNA vaccine strategies

项目概要/摘要 虽然现代疗法已经大大改善了艾滋病毒感染者的前景， 治疗感染，使这些人终身承担抗逆转录病毒（ARV）药物的负担。 对于任何特定的个人，保持终身坚持服药可能会带来巨大的挑战。 此外，许多人无法获得这些昂贵的药物，特别是那些生活在 资源有限的环境。此外，为结束艾滋病毒流行病所作的努力因缺乏有效的 预防性或治疗性疫苗-在消除其他疾病方面发挥了关键作用的生物医学工具 流行病，如天花。近年来，在利用抗体臂方面取得了重要进展， 免疫系统实现这些目标，尽管仍然存在重大挑战。免疫系统的T细胞分支 专门识别和消除病毒感染细胞的系统， 这些国家都为这些努力做出了贡献，但在发展方面却落后了。这可以部分归因于 目前可用的临床前动物模型用于研究T细胞应答的适用性存在局限性。为 例如，主要组织相容性（MHC）限制的特性意味着病毒- 恒河猴的受感染细胞将识别出与它们原本识别方式不同的病毒感染细胞， 被一个特定的人所认识。目前的建议旨在以令人信服的初步结果为基础，其中 我们已经观察到，对人源化小鼠模型的相对简单但强大的修改解决了许多问题， 到目前为止，这些关键问题的效用有限。也就是说，我们提出了一种小鼠模型，可以稳定地移植 与来自HIV感染或未感染成人的免疫细胞（PBMC），而不诱导移植物抗宿主病 （GvHD）。使用成体细胞既避免了对胎儿组织的需要。在这个项目中，我们将测试艾滋病毒- 在这种小鼠模型中，特异性T细胞应答自然产生，以及这些应答是否在抑制病毒中发挥作用， 复制的然后，我们将测试我们是否能够在未感染的动物中诱导HIV特异性T细胞反应 使用mRNA疫苗技术，类似于用于对抗COVID-19的技术。最后，我们将测试 疫苗诱导的反应可以控制病毒复制。如果成功，这将导致一种新的小动物 我们可以使用mRNA平台快速测试和优化HIV疫苗接种策略。我们认为 这将有助于将最佳方法转化为临床试验。

PROJECT SUMMARY/ABSTRACT Although modern therapies have dramatically improved the outlooks for people living with HIV they are unable to cure infection, leaving these individuals burdened by a lifelong commitment to antiretroviral (ARV) medication. For any given individual, maintaining lifelong adherence to medication can present substantial challenges. Moreover, many people do not have access to these expensive medications - in particular those living in resource-limited settings. Furthermore, efforts to end the HIV epidemic have suffered from the lack of effective preventative or therapeutic vaccines – biomedical tools which have played critical roles in the elimination of other epidemics, such as smallpox. Recent years have seen important advances in harnessing the antibody arm of the immune system towards these aims, though substantial challenges still exist. The T-cell arm of the immune system, which specializes in the recognition and elimination of virus infected cells, holds great promise to contribute to these efforts, but has lagged behind in development. This can be attributed – in part – to substantial limitations in the suitability of currently available pre-clinical animal models for the study of T-cell responses. For example, the property of major histocompatibility (MHC) restriction means that the ways in which the virus- infected cells of a rhesus macaque will recognize a virus-infected cell differ from the way they would be recognized by a given human. The current proposal aims to build upon compelling preliminary results, in which we have observed that a relatively simple, but powerful, modification of a humanized mouse model solves many of the key issues that have limited utility to date. Namely, we present a mouse model that can be stably engrafted with immune cells (PBMC) from HIV-infected or uninfected adults, without inducing graft versus host disease (GvHD). The use of adult cells both avoids the need for fetal tissue. In this project, we will test whether HIV- specific T-cell responses arise naturally in this mouse model, and whether these play a role in suppressing viral replication. We will then test whether we are able to induce HIV-specific T-cell responses in uninfected animals using an mRNA vaccine technology, similar to that employed against COVID-19. Finally, we will test whether vaccine-induced responses can control viral replication. If successful, this will result in a novel small animal model in which we can rapidly test and optimize HIV vaccination strategies using a mRNA platform. We believe that this will facilitate the translation of optimal approaches to clinical trials.