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-摘要 尽管抗逆转录病毒疗法（ART）成功地改善了艾滋病毒感染者（PWH）的生活， 对于减少与艾滋病毒感染相关的耻辱感和长期并发症， 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 在其艾滋病毒专用微环境（HOME）的动态，以确定水库的脆弱性，可以有针对性。 病毒免疫学，药物和成像（VIDI）研究项目（RP）将专注于免疫，药理学， 宿主的表观遗传细胞环境和组织结构控制着HIV储存库的连续性 动力学仅VIDI RP的这种表征将为该领域增加相当多的新知识。在 HOME程序，这些检测结果将与HIV病毒库动态特征相结合进行表征 所有数据集将由维西RP进一步整合和分析。 对于实验规划，HIV库动态连续体被简化为以下库状态： ·在抗逆转录病毒治疗（ART）期间，当HIV从组织（再）激活时离开家（即，像包装其 袋和准备离开），并在ART中断期间引起反弹病毒血症。 ·当艾滋病毒（重新）在ART病毒血症期间通过克隆传播在组织中繁殖时， 在接受ART治疗的同时扩增HIV感染的细胞。（克隆扩增就像在家里增加家庭成员。） ·当艾滋病毒（无声地）在血液和组织库中持续存在时（开启和关闭ART），留在家中。 为了优化资源分配，我们开发了一种两步自适应学习方法。在映射期间 VIDIRP将检查细胞和可溶性炎症环境与ART水平之间的关系 对于每个储集器状态（即，离开，到来，停留）。国际中心联络点将协助整合和分析 识别具有预定义的储层状态和足够的细胞的“感兴趣的样品” 为深入调查创造条件。在确认阶段，VIDIRP将使用单细胞和成像 技术，以进一步表征与更深层次的储层动态相关的环境因素。 重要的是，我们的VIDI RP的可行性大大增强了从我们以前的P01获得的知识 （AI 131385）及其最后一次捐赠队列，该队列从接受捐赠的PWH收集生前和死后标本（n=5） 或在死亡前未停止ART（n=15）。HOME计划将允许这一群体继续下去， 扩大科学研究艾滋病毒在人体内的单基因组和单细胞水平的动力学。 总而言之，整个HOME计划将提供一个管理艾滋病毒的环境因素的深刻描述 储层动力学，直接响应理解HIV储层动力学RFA AI-21-013。 这一新知识将为艾滋病毒治疗策略提供信息，旨在逆转潜伏期（“休克和杀死”）或沉默 永久性深层水库（“封锁”），并提供新的见解，以减少当地艾滋病毒相关的 组织损伤，这与炎症相关的疾病有关。