HIV Reservoir Ecology of Viral Remission

病毒缓解的 HIV 储存生态学

• 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
• 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

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.

项目总结 艾滋病毒领域的最优先事项之一是寻找能够导致持续 抗逆转录病毒疗法(ART)-艾滋病毒缓解。尽管大多数艾滋病毒感染者将经历 病毒在ART中断后迅速反弹，有罕见的个体，称为治疗后控制者(PTCs)， 在停止治疗后的几个月或几年内表现出持续的病毒学抑制。这些 个人被认为是艾滋病毒持久控制的理想范例，对艾滋病毒的治愈有直接影响 研究。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。这 部分原因是通过任何一个研究中心或临床试验确定的PTC的稀缺性，部分原因是 因为迄今已进行的病毒库研究的范围有限。这样做的主要目标是 建议对PTC进行深入的病毒学分析，我们的首要假设是HIV 储蓄者的特征可以提供他们实现艾滋病毒缓解能力背后的机械洞察力。 通过国际努力，我们在抗逆转录病毒药物暂停后建立了对艾滋病毒的控制 (CHAMP)研究，世界上最大的PTCS研究。我们对来自CHAMP队列的PTC的初步研究 已经产生了耐人寻味的发现，包括识别出第一个艾滋病毒储存生物标记物--总前病毒 基因组编号，这预测了哪些人在治疗中断后将成为PTC。而这些 结果是有希望的，艾滋病毒储存库远远比仅仅是前病毒基因组的总数复杂得多 外周血单个核细胞(PBMCs)。艾滋病毒宿主的活动和影响必须考虑到 在我们称之为“艾滋病毒宿主生态学”的概念框架中考虑一系列因素。这 范型结合了有助于艾滋病毒持续存在的前病毒、细胞和分子电路， 包括：1)前驱体准种的多样性；2)细胞亚群和组织室内的分布； 3)转录调控；4)宿主内HIV整合位点的染色体环境 基因组。使用在提出建议的研究人员的实验室中开发的新分析方法，我们建议采取 在PTC和非控制者(NCS)中描述HIV宿主生态的整体方法。这个 这些研究的结果将促进我们对PTC中艾滋病毒控制机制的理解， 对预测治疗后控制和确定这些电路中哪一个可能是最好的电路的影响 为所有艾滋病毒携带者设计艾滋病毒缓解战略的目标。