HIV Reservoir Ecology of Viral Remission

病毒缓解的 HIV 储存生态学

基本信息

批准号：
10322982
负责人：
Jonathan Li
金额：
$ 86.67万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-07 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322982
关键词：
Aftercare Anti-Retroviral Agents Biological Assay Biological Markers Characteristics Chromatin Clinical Trials Complex DNA Disease remission Distal Ecology Environment Gene Silencing Genetic Transcription Genome Goals HIV Individual International Interruption Laboratories Lead Length Location Lymph Node Tissue Measures Modeling Molecular Peripheral Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Play Poly A Polyadenylation Proviruses RNA RNA Splicing Reporting Research Research Personnel Role T memory cell T-Lymphocyte Subsets Therapeutic Intervention Tissues Transcription Initiation Transcriptional Regulation Transposase Viral Viral reservoir Withholding Treatment antiretroviral therapy cohort design experience holistic approach insight integration site novel peripheral blood transcriptome sequencing transcriptomics viral rebound

项目摘要

PROJECT SUMMARY Among the top priorities of the HIV field is the search for therapeutic interventions that can lead to sustained antiretroviral therapy (ART)-free HIV remission. Although the majority of HIV-infected persons will experience rapid viral rebound after ART interruption, there are rare individuals, termed post-treatment controllers (PTCs), who demonstrate sustained virologic suppression for months or years after treatment cessation. These individuals are considered an ideal example of durable HIV control, with direct implications for HIV cure research. However, our understanding of the virologic determinants of HIV remission remains incomplete. This is in part due to the scarcity of PTCs identified through any one research center or clinical trial, and in part because of the limited scope of viral reservoir studies that have been performed to date. The main goal of this proposal is to perform an in-depth virologic analysis of PTCs and our overarching hypotheses are that HIV reservoir characteristics can provide mechanistic insights behind their ability to achieve HIV remission. Through an international effort, we have established the Control of HIV after Antiretroviral Medication Pause (CHAMP) study, the largest study of PTCs world-wide. Our initial studies of PTCs from the CHAMP cohort has already yielded intriguing findings, including the identification of the first HIV reservoir biomarker, total proviral genome numbers, that predicts which individuals will become PTCs after treatment interruption. While these results are promising, the HIV reservoir is far more complex than just the total number of proviral genomes in the peripheral blood mononuclear cells (PBMCs). The activity and impact of the HIV reservoir must take into account a constellation of factors in a conceptual framework that we call the “HIV reservoir ecology”. This paradigm incorporates the combined proviral, cellular and molecular circuits that contribute to HIV persistence, including: 1) diversity of proviral quasispecies; 2) distribution within cellular subsets and tissue compartments; 3) transcriptional regulation; and 4) the chromosomal environment of the HIV integration sites in the host genome. Using novel assays developed in the laboratories of the proposing investigators, we propose to take a holistic approach in characterizing the HIV reservoir ecology in both PTCs and non-controllers (NCs). The results of such studies will advance our understanding of the mechanisms of HIV control in PTCs, with implications for predicting post-treatment control and determining which of these circuits may be the best targets in the design of HIV remission strategies for all individuals living with HIV.

项目概要 HIV 领域的首要任务之一是寻找能够导致持续性治疗的治疗干预措施。尽管大多数艾滋病毒感染者都会经历无需抗逆转录病毒治疗（ART）的艾滋病毒缓解。 ART 中断后病毒快速反弹，有极少数个体，称为治疗后控制者（PTC），停止治疗后数月或数年表现出持续病毒学抑制的患者。个人被认为是持久艾滋病毒控制的理想范例，对艾滋病毒治愈具有直接影响然而，我们对艾滋病毒缓解的病毒学决定因素的理解仍然不完整。部分原因是通过任何一个研究中心或临床试验发现的 PTC 都很稀缺，部分原因是由于迄今为止已进行的病毒库研究的范围有限。建议对 PTC 进行深入的病毒学分析，我们的首要假设是 HIV 储存库特征可以提供其实现艾滋病毒缓解能力背后的机制见解。通过国际努力，我们建立了抗逆转录病毒药物暂停后艾滋病毒的控制 (CHAMP) 研究是全球最大的 PTC 研究，我们对 CHAMP 队列中的 PTC 进行了初步研究。已经取得了有趣的发现，包括第一个 HIV 储存生物标志物的鉴定，即总前病毒基因组编号，可预测治疗中断后哪些个体将成为 PTC。结果是有希望的，HIV病毒库远比仅存在于体内的原病毒基因组总数要复杂得多。必须考虑外周血单核细胞 (PBMC) 的活性和影响。在我们称之为“艾滋病毒储存生态学”的概念框架中考虑了一系列因素。范例结合了有助于艾滋病毒持续存在的前病毒、细胞和分子回路，包括：1）原病毒准种的多样性；2）细胞亚群和组织区室中的分布； 3）转录调控；4）宿主体内HIV整合位点的染色体环境我们建议使用提议研究人员的实验室开发的新检测方法进行基因组分析。描述 PTC 和非控制者 (NC) 中 HIV 储存生态学特征的整体方法。此类研究的结果将增进我们对 PTC 中 HIV 控制机制的理解，对预测治疗后控制和确定这些回路中哪一个可能是最好的影响为所有艾滋病毒感染者设计艾滋病毒缓解策略的目标。