Characterization of a Memory CD4+ T-cell Humanized Mouse Model for the Evaluation of Autologous Cell Therapies and Studies of HIV Persistence

项目总结/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，而不诱导移植物抗宿主病（GvHD）。 成体细胞的使用既避免了对胎儿组织的需要，又允许抗病毒药物的体内测试。 免疫效应物的活性-例如包括CD 8 + T细胞和自然杀伤细胞-由这些产生 人类捐赠者，以自体的方式。这些效应物可以：i）直接离体取来研究 自然控制病毒的个体与不控制病毒的个体之间的差异ii）在以下情况下离体采集 人类志愿者的疫苗接种iii）或增强的体外-如将模拟基于细胞疗法的方法。 我们提出的实验，我们预计将效用的模型都用于测试战略，以控制病毒 复制，并研究旨在减少或消除持续存在的病毒库的疗法 通过抗逆转录病毒疗法--达到治愈感染的目标。

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 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, and allows for the in vivo testing of the antiviral activities of immune effectors - such as including CD8+ T-cells and natural killer cells - generated from these human donors, in an autologous manner. These effectors could either: i) be taken directly ex vivo – to study differences between individuals who control virus naturally vs those who do not ii) taken ex vivo following vaccination of the human volunteer iii) or enhanced in vitro – as would model cell-therapy based approaches. We propose experiments that we expect will the utility of the model both for testing strategies to control viral replication, and for studying therapies which take aim at reducing or elimination the viral reservoirs that persist through ARV therapy – towards the goal of curing infection.