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

用于评估自体细胞疗法和 HIV 持久性研究的记忆 CD4 T 细胞人源化小鼠模型的表征

• 批准号: 10013679
• 负责人: R. Brad Jones
• 金额: $ 25.43万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-19 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10013679
• 关键词: Address; Adherence; Adoptive Transfer; Adult; Affect; Animal Model; Anti-Retroviral Agents; Antibodies; Antiviral Agents; Autologous; Automobile Driving; Biological Assay; Blood; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Therapy; Cell model; Cells; Cellular immunotherapy; Clinical Trials; Data; Development; Discrimination; Engraftment; Epidemic; Evaluation; Fetal Tissues; Formulation; Goals; HIV; HIV Infections; Histocompatibility; Human; Human Volunteers; Immune; Immune system; Immunotherapy; In Vitro; Individual; Infection; Injections; Interruption; Intervention; Investigation; Macaca mulatta; Memory; Methods; Modeling; Modernization; Modification; Morbidity - disease rate; Mus; Mutation; Natural Killer Cells; Nature; Operative Surgical Procedures; Participant; Pattern; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Play; Preventive vaccine; Property; Proviruses; Recovery; Research; Resources; Role; Smallpox; Study models; T cell response; T cell therapy; T-Lymphocyte; T-cell receptor repertoire; Tail; Testing; TimeLine; Tissues; Vaccinated; Vaccination; Viral reservoir; Viremia; Virus; Virus Replication; antiretroviral therapy; arm; clinically relevant; cost effective; effector T cell; experimental study; graft vs host disease; human fetus tissue; humanized mouse; improved; in vivo; in vivo evaluation; memory CD4 T lymphocyte; mindfulness; mortality; mouse model; neutralizing antibody; novel; pre-clinical; prevent; sample fixation; success; therapeutic vaccine; tool; viral rebound

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.

项目摘要/摘要 尽管现代疗法极大地改善了艾滋病毒患者的前景 为了治愈感染，使这些人因对抗逆转录病毒（ARV）药物的终生承诺而燃烧。 对于任何给定的人，维持终身遵守药物可能会带来重大挑战。 此外，许多人无法使用这些昂贵的药物 - 特别是那些居住在 资源有限的设置。此外，终止艾滋病毒流行的努力遭受了缺乏有效的影响 预防性或治疗性疫苗 - 在消除其他方面起着关键作用的生物医学工具 情节，例如天花。近年来，在利用抗体臂的重要进展 尽管存在重大挑战，但针对这些目标的免疫系统仍存在。免疫的T细胞臂 专门识别和消除病毒感染细胞的系统具有很大的希望 为这些努力做出了贡献，但在发展方面落后。这可以归因于一定程度地归因于实质性 目前可用的临床前动物模型对T细胞反应的研究的适用性局限性。为了 例如，主要组织相容性（MHC）限制的特性意味着病毒的方式 恒河猴的感染细胞将识别感染病毒的细胞与它们的方式不同 被给定的人认可。当前的建议旨在以引人注目的初步结果为基础 我们已经观察到，人性化鼠标模型的相对简单但功能强大的修饰解决了许多 迄今为止效用有限的关键问题。即，我们提出了一个可以稳定植入的鼠标模型 没有诱导的移植物与宿主疾病（GVHD）的HIV感染或未感染的成年人的免疫细胞。 成人细胞的使用都避免了胎儿组织的需求，并且可以进行抗病毒的体内测试 免疫作用的活性 - 包括CD8+ T细胞和天然杀伤细胞 - 由这些活动产生 人类捐助者，以一种自动的方式。这些效果也许可以：i）直接在体内进行 - 研究 控制病毒的个体自然与不属于的人之间的差异ii） 人类志愿者III）或体外增强的疫苗接种 - 基于模型的基于细胞治疗的方法也将进行。 我们提出的实验我们期望该模型的实用性既可以测试策略来控制病毒 复制，以及研究旨在减少或消除持续存在的病毒储层的疗法 通过ARV疗法 - 实现治愈感染的目标。