权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结/文摘: