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：
10472752
负责人：
Ramesh Akkina
金额：
$ 19.34万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10472752
关键词：
Animal Model Antibodies Area Autologous Biological Assay CD34 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cells Clinical 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

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：在缺乏抗逆转录病毒治疗的情况下对艾滋病毒感染进行长期自然控制的新见解将为诱导努力提供信息功能性治愈或“缓解”。最近的工作已经确定了艾滋病毒精英控制者（EC）的一个子集，他们是被认为是“例外”（EEC），数十年的病毒学控制，没有免疫学下降。机制可能有助于控制 EEC，包括有效且持续的 CD8+ T 细胞反应。然而，目前尚不清楚 EEC 是否可以无限期地维持这种状态，以及它们是否有任何持续的病毒感染。开始 ART 的活动和益处（或因停止 ART 受到损害），或者是否自发地清除了病毒库，这些人是否可以代表持久艾滋病毒控制的真正模型，或者在某些情况下。病例中，功能性治疗是需要利用最大的精英进一步研究的重要问题。美国的控制者队列，UCSF SCOPE 队列，我们最近的工作重点是这个问题：是否存在一个 ECs 的子集可以作为长期无 ART 艾滋病毒缓解的模型吗？ DNA 测定 (IPDA) 用于检测完整的原病毒以及敏感的抗体和 T 细胞免疫测定，我们最近使用组合分析确定了 21 个特殊 EC 的一小部分，其储层尺寸超小。 IPDA 和 FLIP-seq 的研究表明，一些 EC 存在超低水平的完整原病毒，存在于深层潜伏状态使其检测变得困难，因此，需要采用新的病毒学检测方法来检测超低水平的潜伏状态。需要采用 HIV 和免疫学分析来评估 CD8+ T 细胞控制的作用，以进一步推进我们的研究。为了实现这一目标，我们建议采用我们新的超灵敏体内人源化。用于潜伏病毒检测的小鼠病毒生长测定（hmVOA）模型该模型还提供了独特的体内病毒检测。设置检查免疫控制的作用，因为可以测试来自 EEC 的 CD4+ T 细胞的病毒生长情况在存在或不存在自体 CD8+ T 细胞的情况下，据信可以介导控制，否则则不会虽然完全理解 EEC 是一项复杂的任务，但我们在这里进行评估。建议从更简单的初始目标开始： 1. 确定完整的艾滋病毒是否可以从特殊的精英控制者那里恢复（通过病毒生长）目前正在接受 ART 治疗，精英控制者则使用人源化小鼠病毒生长物 (hmVOA) 进行长期 ART 治疗化验 2. 确定 EEC 中的主要病毒控制是否确实由 CD8+ T 细胞介导，并评估这种控制是否有效还可以对体内潜在的新的 HIV 暴露（重复感染）提供抵抗力。这里的结果将有助于进一步了解潜伏病毒和强细胞介导的作用东部经济走廊中的病毒控制。