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

参与者衍生的异种移植小鼠模型，用于研究 T 细胞介导的病毒控制和 mRNA 疫苗策略

• 批准号: 10483703
• 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: 2022
• 资助国家: 美国
• 起止时间: 2022-08-12 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483703
• 关键词: Address; Adherence; Adult; Animal Model; Animals; Anti-Retroviral Agents; Antibodies; Antigen-Presenting Cells; CD8-Positive T-Lymphocytes; COVID-19; Cells; Cellular Assay; Clinical Trials; Complex; Data; Development; Engraftment; Epidemic; Equipment; Evaluation; Fetal Tissues; Foundations; HIV; HIV Infections; Histocompatibility; Human; Immune; Immune system; Immunization; Immunotherapeutic agent; Individual; Infection; Knockout Mice; Macaca mulatta; Mediating; Messenger RNA; Methods; Modeling; Modernization; Modification; Mus; Mutation; Operative Surgical Procedures; Participant; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Plasma; Play; Preventive vaccine; Property; Publications; RNA vaccination; RNA vaccine; Reporting; Resource-limited setting; Robotics; Role; Smallpox; Study models; Suggestion; T cell response; T cell therapy; T-Lymphocyte; Technical Expertise; Technology; Testing; Translations; Vaccination; Vaccines; Viral; Viral Load result; Viral load measurement; Viremia; Virus; Virus Replication; Work; Xenograft Model; Xenograft procedure; anti-viral efficacy; arm; base; cost effectiveness; experience; experimental study; flexibility; gene product; graft vs host disease; humanized mouse; immunogenicity; improved; in vivo; lipid nanoparticle; memory CD4 T lymphocyte; mouse model; next generation; novel; pre-clinical; response; therapeutic development; therapeutic vaccine; tool; vaccination strategy; vaccine response; vaccine strategy

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.

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 来自HIV感染或未感染的成年人的免疫细胞（PBMC），没有诱导的移植物与宿主疾病 （GVHD）。成人细胞的使用都避免了对胎儿组织的需求。在这个项目中，我们将测试HIV-是否 在该鼠标模型中自然出现了特定的T细胞响应，并且这些反应是否在抑制病毒中起作用 复制。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 使用类似于与Covid-19的MRNA疫苗技术相似。最后，我们将测试是否 疫苗诱导的反应可以控制病毒复制。如果成功，这将导致一种新颖的小动物 我们可以使用mRNA平台快速测试和优化HIV疫苗接种策略的模型。我们相信 这将有助于将最佳方法转化为临床试验。