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

项目摘要/摘要 尽管现代疗法极大地改善了艾滋病毒携带者的前景，但它们无法 为了治愈感染，这些人背负着终身服用抗逆转录病毒(ARV)药物的负担。 对于任何特定的个人来说，保持终生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 资源受限设置。此外，结束艾滋病毒流行病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关键作用的生物医学工具 流行病，如天花。近年来，在利用猪细小病毒抗体臂方面取得了重要进展 免疫系统朝着这些目标前进，尽管仍然存在重大挑战。免疫的T细胞臂 专门识别和消除受病毒感染的细胞的系统，拥有巨大的希望 为这些努力做出了贡献，但在发展方面一直落后。这可以部分归因于实质性的 目前可用的临床前动物模型在T细胞反应研究中的适用性的局限性。为 例如，主要组织相容性(MHC)限制的性质意味着病毒- 恒河猴的感染细胞会识别不同于病毒感染细胞的方式 被一个特定的人类识别的。目前的提案旨在以令人信服的初步结果为基础，其中 我们观察到，对人性化的小鼠模型进行相对简单但强大的修改可以解决许多问题 到目前为止，这些关键问题的效用有限。也就是说，我们提出了一种可以稳定嫁接的小鼠模型 与来自艾滋病毒感染或未感染的成人的免疫细胞，不会引发移植物抗宿主病(GvHD)。 成人细胞的使用既避免了对胎儿组织的需要，又允许在体内测试抗病毒药物 免疫效应器的活动--如包括CD8+T细胞和自然杀伤细胞--从这些细胞产生 人类捐赠者，以自体的方式。这些效应器可以：i)直接进行体外研究 自然控制病毒的个体与不自然控制病毒的个体之间的差异II)体外接种 人类志愿者的疫苗接种III)或体外增强--就像基于细胞疗法的方法模型一样。 我们提出了实验，我们期望该模型将用于测试控制病毒的策略 复制，以及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--朝着治愈感染的目标迈进。

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.