Project 002 - VIDI

项目 002 - VIDI

• 批准号: 10602744
• 负责人: Sara Gianella Weibel
• 金额: $ 67.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10602744
• 关键词: Antigens; Architecture; Area; Autopsy; Binding; Biological Assay; Blood; CCR6 gene; CD4 Positive T Lymphocytes; Cells; Cessation of life; Chromatin; Clonal Expansion; Data Analyses; Data Set; Detection; Effector Cell; Environment; Environmental Risk Factor; Epigenetic Process; Family; Fire - disasters; Genes; Genetic Transcription; Genome; Gifts; Goals; HIV; HIV Infections; Home; Human body; Image; Imaging technology; Immune; Immunology; Inflammation; Integration Host Factors; Interruption; Intrinsic factor; Investigation; Knowledge; Lymphoid Tissue; Maps; Microscopy; Mucous Membrane; Natural Killer Cells; Penetration; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Plasma; Population Dynamics; Population Process; Predisposition; Process; Provirus Integration; Proviruses; Research Project Grants; Resource Allocation; Running; Sampling; Science; Shock; Site; Source; Specimen; Surface; Techniques; Technology; Tissues; Viral; Viral Physiology; Viremia; Virus; adaptive learning; antiretroviral therapy; brain tract; cohort; comorbidity; end of life; high dimensionality; improved; in vivo; inflammatory milieu; innovation; insight; interest; pharmacologic; programmed cell death protein 1; programs; reproductive tract; single cell technology; social stigma; success; therapeutic target; viral rebound

PROJECT 2. Viral Immunology, Drugs, and Imaging (VIDI) Research Project - ABSTRACT Despite the success of antiretroviral therapy (ART) improving the lives of persons with HIV (PWH), curing HIV would be important to reduce stigma and long-term co-morbidities associated with HIV infection that occur even during ART. Developing a successful cure will need to better identify the viral and host factors that govern HIV dynamics in its HIV Obligate MicroEnvironment (HOME) to identify reservoir vulnerabilities that can be targeted. The Viral Immunology, Drugs, and Imaging (VIDI) Research Project (RP) will focus on immune, pharmacological, host epigenetic cellular environments, and tissue architecture that govern the continuum of HIV reservoir dynamics. This characterization by the VIDI RP alone will add considerable new knowledge to the field. In the HOME program, these assay results will be integrated with viral features of HIV reservoir dynamics characterized by VENI RP, and all datasets will be further integrated and analyzed by VICI RP. For experimental planning, the HIV reservoir dynamic continuum is simplified as the following reservoir states: · Leaves HOME when HIV (re)activates from tissues during antiretroviral therapy (ART) (i.e., like packing its bag and getting ready to leave) and causes rebound viremia during ART interruption. · Comes HOME when HIV (re)populates tissues during viremia off ART and through the spread of clonally expanded HIV-infected cells while on ART. (Clonal expansion is like adding family to the home.) · Stays HOME when HIV (silently) persists in blood and tissue reservoirs (on and off ART). To optimize allocated resources, we developed a two-step Adaptive Learning Approach. During the Mapping phase, the VIDI RP will examine how cellular and soluble inflammatory milieus and ART levels are associated with each reservoir state (i.e., leaving, coming, staying). The VICI RP will assist in the integration and analysis of these data to identify ‘samples-of-interest’ that have pre-defined reservoir states and sufficient cellular environment for deeper investigation. In the Confirmation phase, the VIDI RP will use single-cell and imaging technologies to further characterize environmental factors associated with reservoir dynamics at a deeper level. Importantly, the feasibility of our VIDI RP is greatly enhanced by the knowledge gained from our previous P01 (AI131385) and its Last Gift Cohort, which collects pre- and post- mortem specimens from PWH who did (n=5) or did not stop ART (n=15) before death. The HOME program will allow the continuation of this cohort while expanding the science to study HIV dynamics across the human body at the single-genome and single-cell level. In summary, the overall HOME program will provide a deep delineation of environmental factors governing HIV reservoir dynamics, which is directly responsive to the Understanding HIV Reservoir Dynamics RFA AI-21-013. This new knowledge will inform HIV cure strategies aiming at reversing latency (“Shock and Kill”) or at silencing permanently deep reservoirs (“Block and Lock”) and provide new insights in ways to reduce local HIV-associated tissue damage, which has been implicated in inflammation-related illnesses.

项目2.病毒免疫学、药物和成像(VIDI)研究项目 尽管抗逆转录病毒疗法(ART)取得了成功，但改善了艾滋病毒携带者的生活(PWH)，治愈了艾滋病毒 对于减少与艾滋病毒感染相关的耻辱和长期共病是很重要的 在艺术上。开发成功的治疗方法需要更好地识别控制艾滋病毒的病毒和宿主因素 艾滋病毒的动态使微环境(家庭)有义务确定可以作为目标的水库脆弱性。 病毒免疫学、药物和成像(VIDI)研究项目(RP)将重点放在免疫、药理学、 宿主表观遗传细胞环境和控制HIV储存库连续体的组织结构 动力学。仅VIDI RP的这一特征就将为该领域增加相当多的新知识。在 Home计划，这些检测结果将与HIV病毒储存库动力学特征相结合 所有数据集将由VIEI RP进行进一步的整合和分析。 为了进行实验规划，HIV储备库动态连续体被简化为以下储存库状态： ·在抗逆转录病毒治疗(ART)期间，当艾滋病毒(重新)从组织中激活时离开家(即，如包装其 袋子和准备离开)，并在艺术中断期间引起反弹病毒血症。 ·当艾滋病毒(重新)在ART病毒血症期间和通过克隆性传播传播组织时回家 在接受抗逆转录病毒治疗时扩大艾滋病毒感染细胞。(克隆扩张就像在家里增加了家庭。) ·当艾滋病毒(静默地)在血液和组织储存库中持续存在时，呆在家里(接受和不接受抗逆转录病毒治疗)。 为了优化分配的资源，我们开发了一种两步自适应学习方法。在映射过程中 阶段，VIDI RP将检查细胞和可溶性炎性环境与ART水平之间的关系 具有每种水库状态(即，离开、到来、停留)。VICI RP将协助整合和分析 以识别具有预定义的储集层状态和足够的蜂窝数据的“感兴趣样本” 为更深入的调查提供了环境。在确认阶段，VIDI RP将使用单细胞和成像 在更深层次上进一步描述与油藏动态相关的环境因素的技术。 重要的是，我们的VIDI RP的可行性大大增强了从我们之前的P01获得的知识 (AI131385)及其最后一份礼物队列，收集威尔斯亲王死前和死后的标本(n=5) 或临死前未停止ART(n=15)。家庭计划将允许继续这一队列，同时 扩展科学，在单基因组和单细胞水平上研究艾滋病毒在人体内的动态。 总而言之，整个家庭计划将深入描述控制艾滋病毒的环境因素 油藏动力学，这是对了解HIV油藏动力学的直接反应，RFA AI-21-013。 这一新知识将为旨在扭转潜伏期(“电击和杀死”)或沉默的艾滋病毒治疗策略提供信息 永久性深层水库(“阻塞和锁定”)，并为减少当地艾滋病毒感染提供新的见解 组织损伤，这与炎症相关的疾病有关。