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）取得了成功，改善了艾滋病毒感染者（PWH）的生活，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合并症非常重要，这些疾病甚至发生在 ART 期间。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 其 HIV 义务微环境 (HOME) 的动态变化可识别可针对的病毒库脆弱性。 病毒免疫学、药物和成像 (VIDI) 研究项目 (RP) 将重点关注免疫、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 的这种表征就将为该领域增添大量新知识。在 HOME 计划中，这些检测结果将与 HIV 病毒库动力学特征相结合 由 VENI RP 提供，所有数据集将由 VICI RP 进一步整合和分析。 对于实验规划，HIV 储存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 HIV 从组织中（重新）激活时离开家（即，将其打包） 包并准备离开）并在 ART 中断期间导致病毒血症反弹。 · 当 HIV 在 ART 后的病毒血症期间以及通过克隆性传播在组织中（重新）繁殖时，您就回家了 在 ART 期间扩增了 HIV 感染细胞。 （克隆扩张就像在家里增添家人一样。） · 当艾滋病毒（默默地）持续存在于血液和组织储存库中时（无论是否接受抗逆转录病毒治疗），请待在家里。 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。测绘期间 阶段，VIDI RP 将检查细胞和可溶性炎症环境与 ART 水平之间的关系 每个水库状态（即离开、到来、停留）。 VICI RP 将协助整合和分析 这些数据来识别具有预先定义的储存状态和足够的细胞的“感兴趣的样本” 进行更深入调查的环境。在确认阶段，VIDI RP 将使用单细胞和成像 进一步表征与更深层次的油藏动态相关的环境因素的技术。 重要的是，我们从之前的 P01 中获得的知识大大增强了我们 VIDI RP 的可行性 (AI131385) 及其最后的礼物队列，该队列从 PWH 中收集死前和死后样本 (n=5) 或在死亡前未停止 ART (n=15)。 HOME 计划将允许该队列继续进行，同时 扩大科学范围，在单基因组和单细胞水平上研究人体中的艾滋病毒动态。 总之，整个 HOME 计划将深入描述控制艾滋病毒的环境因素 储库动力学，直接响应理解 HIV 储库动力学 RFA AI-21-013。 这一新知识将为艾滋病治疗策略提供信息，旨在逆转潜伏期（“休克和杀戮”）或沉默 永久深水库（“封锁和锁定”），并为减少当地艾滋病毒相关的方法提供新见解 组织损伤，这与炎症相关疾病有关。