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: 10683221
• 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
• 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/10683221
• 关键词: Acceleration; Address; Adherence; Adult; Animal Model; Animals; Anti-Retroviral Agents; Antibodies; Antigen-Presenting Cells; Binding; 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; Immunologic Deficiency Syndromes; 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; T cell response; T cell therapy; T-Lymphocyte; Technical Expertise; Technology; Testing; Translations; Vaccination; Vaccines; Viral; Viral Load result; Viral Physiology; Viral load measurement; Viremia; Virus; Virus Replication; Work; Xenograft Model; Xenograft procedure; anti-viral efficacy; antiretroviral therapy; arm; cost effectiveness; experience; experimental study; flexibility; gene product; graft versus host disease induction; 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 感染者或未感染者的免疫细胞 (PBMC)，不会诱发移植物抗宿主病 (GvHD)。使用成体细胞都避免了对胎儿组织的需要。在这个项目中，我们将测试HIV是否-。 特定的 T 细胞反应在该小鼠模型中自然出现，以及这些反应是否在抑制病毒方面发挥作用 然后我们将测试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 mRNA 疫苗技术，类似于针对 COVID-19 的技术。最后，我们将测试是否可以。 疫苗诱导的反应可以控制病毒复制，如果成功，这将产生一种新的小动物。 我们相信，我们可以使用 mRNA 平台快速测试和优化 HIV 疫苗接种策略。 这将有助于将最佳方法转化为临床试验。