Exploring the features of HIV exceptional elite controllers in humanized mice

探索人源化小鼠中艾滋病毒杰出精英控制者的特征

基本信息

批准号：
10326905
负责人：
Ramesh Akkina
金额：
$ 24.44万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-20 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10326905
关键词：
Animal Model Antibodies Area Autologous Biological Assay CD34 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Clinical Virology Colorado Complex Comprehension DNA Detection Disease remission Dose Enterochromaffin Cells Evaluation Exhibits Genetic Transcription Goals HIV HIV Infections HIV drug resistance Hematopoietic stem cells Human Immune Immune response Immunologics Immunology procedure In Vitro Individual Infection Inflammation Investigation Mediating Modeling Mus Peripheral Blood Mononuclear Cell Population Proviruses Recommendation Residual state Resistance Resources Role Site T cell response T-Lymphocyte Testing Time Umbilical Cord Blood Universities Viral Viral Physiology Viral reservoir Virus Virus Latency Withdrawal Work base cohort experience humanized mouse in vivo insight novel reconstitution superinfection viral detection virology

Animal Model Antibodies Area Autologous Biological Assay CD34 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Clinical Virology Colorado Complex Comprehension DNA Detection Disease remission Dose Enterochromaffin Cells Evaluation Exhibits Genetic Transcription Goals HIV HIV Infections HIV drug resistance Hematopoietic stem cells Human Immune Immune response Immunologics Immunology procedure In Vitro Individual Infection Inflammation Investigation Mediating Modeling Mus Peripheral Blood Mononuclear Cell Population Proviruses Recommendation Residual state Resistance Resources Role Site T cell response T-Lymphocyte Testing Time Umbilical Cord Blood Universities Viral Viral Physiology Viral reservoir Virus Virus Latency Withdrawal Work base cohort experience humanized mouse in vivo insight novel reconstitution superinfection viral detection virology

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项目摘要

Project Summary/Abstract: Newer insights into long-term natural control of HIV infection in the absence of ART will inform efforts to induce a functional cure or “remission.” Recent work has identified a subset of HIV elite controllers (EC) who are considered “exceptional” (EEC) with decades of virologic control without immunologic decline. Multiple mechanisms likely contribute to control in EECs, including a potent and sustained CD8+ T cell response. However, it is unclear whether EECs can maintain this status indefinitely, whether they have any ongoing viral activity and benefit from initiation of ART (or are harmed by withdrawal of ART), or whether they spontaneously cleared viral reservoirs. Whether such individuals may represent a true model of durable HIV control or, in some cases, a functional cure are important questions needing further investigation. Leveraging the largest elite controller cohort in the USA, the UCSF SCOPE cohort, our recent work focused on the question: is there a subset of ECs that might serve as a model for long-term ART-free HIV remission? Using the new intact proviral DNA assay (IPDA) to detect intact proviruses as well as sensitive antibody and T-cell immune-assays, we identified a small subset of 21 exceptional ECs with ultra-low reservoir size. Recent analyses using a combination of IPDA and FLIP-seq suggested that some ECs have ultralow levels of intact proviruses existing in a deeply latent state making their detection difficult. Therefore, novel virological assays to detect ultralow levels of latent HIV and immunological analyses to evaluate the role of CD8+ T cell control need to be employed to further our understanding of EECs. Towards this goal, we propose to employ our new ultrasensitive in vivo humanized mouse viral outgrowth assay (hmVOA) model for latent viral detection. This model also provides a unique in vivo setting to examine the role of immune control since CD4+ T cells from the EEC can be tested for viral outgrowth in the presence or absence of autologous CD8+ T cells believed to mediate control which is otherwise not possible to evaluate in a human setting. While full comprehension of EECs is a complex undertaking, here we propose to start with simpler initial goals to: 1. Determine whether intact HIV can be recovered (via viral outgrowth) from exceptional elite controllers not currently on ART and elite controllers on long-term ART using the humanized mouse viral outgrowth (hmVOA) assay 2. Ascertain if the predominant viral control in EEC is indeed mediated by CD8+ T cells and assess if this control can also provide resistance to a potential new HIV exposure (superinfection) in vivo. Results from here will help in furthering our understanding of the latent virus and the role of strong cell-mediated virus control in EECs.

项目摘要/摘要：在没有艺术的情况下，对艾滋病毒感染的长期自然控制的新见解将为诱导努力功能治愈或“缓解”。最近的工作已经确定了艾滋病毒精英控制者（EC）的子集被认为是“异常”（EEC），具有数十年的病毒控制，而没有免疫学下降。多种的机制可能有助于控制EEC，包括电位和持续的CD8+ T细胞反应。但是，目前尚不清楚EEC是否可以无限期地维持此状态，是否有任何持续的病毒启动艺术的活动和受益清除病毒储层。这些人是否可以代表耐用的艾滋病毒控制的真实模型，或者在某些人中案例，功能治愈是需要进一步研究的重要问题。利用最大的精英美国的控制器队列，UCSF范围同类，我们最近的工作着重于一个问题：是否有一个 EC的子集可能是长期无艺术艾滋病毒缓解模型的模型？使用新的完整前病毒 DNA分析（IPDA）检测完整的病毒以及敏感抗体和T细胞免疫测定，我们确定了21个具有超低储层尺寸的特殊EC的一小部分。使用组合的最新分析 IPDA和Flip-Seq的作品表明，某些EC具有深度存在的完整原理病毒水平潜在状态使其检测困难。因此，新的病毒学评估以检测潜在的超高水平需要聘请HIV和免疫学分析来评估CD8+ T细胞控制的作用以进一步对EEC的理解。为了实现这一目标，我们建议采用我们的新超敏化体内人性化的小鼠病毒产物生长测定（HMVOA）模型用于潜在病毒检测。该模型还提供了一个独特的体内设置检查免疫控制的作用，因为可以测试来自EEC的CD4+ T细胞的病毒生长在存在或不存在自体CD8+ T细胞的情况下，据信介导控制可以在人类环境中进行评估。虽然对EEC的充分理解是一项复杂的事业，但我们在这里提案以更简单的初始目标开始： 1。确定是否可以从非凡的精英控制器中回收（通过病毒出生）（通过病毒出生）目前使用人源化小鼠病毒生长（HMVOA）的艺术和精英控制器关于长期艺术测定 2。确定EEC中主要的病毒对照是否确实是由CD8+ T细胞介导的还可以在体内对潜在的新艾滋病毒暴露（超级感染）提供抗性。这里的结果将有助于进一步了解我们对潜在病毒的理解和强细胞介导的作用 EEC中的病毒控制。