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

基本信息

批准号：
10242093
负责人：
R. Brad Jones
金额：
$ 21.19万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-19 至 2023-07-31
项目状态：
已结题

项目摘要

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.

项目概要/摘要尽管现代疗法极大地改善了艾滋病毒感染者的前景，但他们无法治愈感染，使这些人终生承受抗逆转录病毒（ARV）药物治疗的负担。对于任何特定的个人来说，维持终生坚持用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，尤其是那些生活在此外，消除艾滋病毒流行的努力也因缺乏有效性而受到影响。预防性或治疗性疫苗——生物医学工具，在消除其他疾病方面发挥了关键作用近年来，在利用抗体方面取得了重要进展。尽管免疫系统的 T 细胞仍然存在巨大的挑战，但免疫系统仍无法实现这些目标。专门识别和消除病毒感染细胞的系统，有望在为这些努力作出了贡献，但在发展方面却落后了，这在一定程度上可以归因于实质性的努力。目前可用的临床前动物模型对于 T 细胞反应研究的适用性存在局限性。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识别受病毒感染的细胞的方式与它们本来的方式不同目前的提案旨在建立在令人信服的初步结果的基础上，其中我们观察到，对人源化小鼠模型进行相对简单但功能强大的修改可以解决许多问题也就是说，我们提出了一种可以稳定雕刻的鼠标模型。使用来自 HIV 感染或未感染成人的免疫细胞，不会诱发移植物抗宿主病 (GvHD)。使用成体细胞既避免了对胎儿组织的需要，又允许进行抗病毒药物的体内测试由这些产生的免疫效应子的活性 - 例如包括 CD8+ T 细胞和自然杀伤细胞这些效应器可以以自体方式直接离体取出来进行研究。自然控制病毒的个体与自然控制病毒的个体之间的差异 ii) 体外采集的病毒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模型一样。我们提出了实验，我们期望该模型能够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储存库的疗法通过抗逆转录病毒疗法——达到治愈感染的目标。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Relationships between Neutralization, Binding, and ADCC of Broadly Neutralizing Antibodies against Reservoir HIV.

针对水库 HIV 的广泛中和抗体的中和、结合和 ADCC 之间的关系。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Ren, Yanqin;Korom, Maria;Ward, Adam R;Truong, Ronald;Chan, Dora;Huang, Szu;Kovacs, Colin M;Benko, Erika;Safrit, Jeffrey T;Lee, John;Garbán, Hermes;Lynch, Rebecca;Jones, R Brad
通讯作者：
Jones, R Brad

Roles of fragment crystallizable-mediated effector functions in broadly neutralizing antibody activity against HIV.

片段可结晶介导的效应器功能在广泛中和抗 HIV 抗体活性中的作用。